![Multifaceted effects of neutrophils on hematopoiesis in the bone marrow. (A) Zebrafish neutrophils promote HSC emergence in the hemogenic endothelium by releasing the pro-inflammatory cytokine TNF-\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\:{\upalpha\:}$$\end{document}. (B) Neutrophils in the bone marrow of mice and humans regulates HSCs directly or indirectly through affecting niche cells, such as mesenchymal stem cells and endothelial cells. (Abbreviations can be found at the end of the text)](https://www.researchgate.net/publication/384667071/figure/fig1/AS:11431281282087350@1728179342346/Multifaceted-effects-of-neutrophils-on-hematopoiesis-in-the-bone-marrow-A-Zebrafish_Q320.jpg)
Access to this full-text is provided by Springer Nature.
Content available from Cellular and Molecular Life Sciences
This content is subject to copyright. Terms and conditions apply.
REVIEW
Cellular and Molecular Life Sciences (2024) 81:420
https://doi.org/10.1007/s00018-024-05445-3
BLC Bone Lining Cell
bmDCs Bone Marrow Resident DCs
CDK Cyclin-dependent kinases
CDPs Common DC Progenitors
CFU Colony Forming Unit
CG Cathepsin G
CHT Caudal Hematopoietic Tissue
c-Kit Stem Cell Factor Receptor
Chrna7 Cholinergicα7NicotinicReceptor
CMPs Common Myeloid Progenitors
CTLA-4 Cytotoxic T-Lymphocyte Antigen 4
CXCR3 C-X-C Chemokine Receptor 3
CXCR4 C-X-C Chemokine Receptor 4
CXCL12 C-X-C Motif Chemokine Ligand 12
Col2a1 Collagen Type II alpha 1
Col11a1 Collagen Type XI alpha 1
COX2 Cyclooxygenase 2
DARC(CD234) DuyAntigenReceptorforChemokines
DCs Dendritic Cells
Ebf1 Early B-cell factor 1
E2A(TCF3) Transcription Factor-3
ECs Endothelial Cells
ERK Extracellular Signal-Regulated Kinase
Abbreviations
ADP Adenosine Diphosphate
AMP Adenosine Monophosphate
angpt1 Angiopoietin 1
APCs Antigen Presenting Cells
APRIL A Proliferation-Inducing Ligand
ATP Adenosine Triphosphate
Yinghui Li
liyinghui@ihcams.ac.cn
Yingdai Gao
ydgao@ihcams.ac.cn
Hui Xu
xuhui@ihcams.ac.cn
1 State Key Laboratory of Experimental Hematology, Haihe
Laboratory of Cell Ecosystem, PUMC Department of Stem
Cell and Regenerative Medicine, CAMS Key Laboratory of
Gene Therapy for Blood Diseases, Institute of Hematology
andBloodDiseasesHospital,NationalClinicalResearch
Center for Blood Diseases, Chinese Academy of Medical
Sciences & Peking Union Medical College, Tianjin
300020, China
2 Tianjin Institutes of Health Science, Tianjin 301600, China
Abstract
Certain immune cells, including neutrophils, macrophages, dendritic cells, B cells, Breg cells, CD4+ T cells, CD8+ T
cells, and Treg cells, establish enduring residency within the bone marrow. Their distinctive interactions with hematopoi-
esis and the bone marrow microenvironment are becoming increasingly recognized alongside their multifaceted immune
functions.Thesecellsplayadualroleinshapinghematopoiesis.Theydirectlyinuencethequiescence,self-renewal,and
multi-lineagedierentiationofhematopoieticstemandprogenitorcellsthrougheitherdirectcell-to-cellinteractionsorthe
secretion of various factors known for their immunological functions. Additionally, they actively engage with the cellular
constituents of the bone marrow niche, particularly mesenchymal stem cells, endothelial cells, osteoblasts, and osteoclasts,
to promote their survival and contribute to tissue repair, thereby fostering a supportive environment for hematopoietic stem
and progenitor cells. Importantly, these bone marrow immune cells function synergistically, both locally and functionally,
rather than in isolation. In summary, immune cells residing in the bone marrow are pivotal components of a sophisticated
network of regulating hematopoiesis.
Keywords Normalhematopoiesis·Immunity ·Niche·Stemnessmaintenance·Mobilization·Graft-versus-hostdisease
Received: 29 November 2023 / Revised: 9 September 2024 / Accepted: 9 September 2024
© The Author(s) 2024
The role of immune cells settled in the bone marrow on adult
hematopoietic stem cells
HuiXu1,2· YinghuiLi1,2· YingdaiGao1,2
1 3
Cellular andMolecular Life Sciences
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
H. Xu et al.
MAKP Mitogen-Activated Protein Kinase
FACS Fluorescence Activated Cell Sorting
FGF1 Fibroblast Growth Factor 1
G-CSF Granulocyte Colony-Stimulating Factor
G-CSFR G-CSF Receptor
GMPs Granulocyte-Monocyte Progenitors
GVHD Graft-Versus-Host Disease
H2R Histamine Receptor 2
HSCs Hematopoietic Stem Cells
HSPCs Hematopoietic Stem And Progenitor
Cells
ICAM-1 Intercellular Cell Adhesion Molecule 1
IgG Immunoglobulin G
IGF-1 Insulin-like Growth Factor-1
IGFBP-3 Insulin-like Growth Factor Binding
Protein-3
IL-1β Interleukin-1β
IL-6 Interleukin 6
IL-7 Interleukin 7
IL-10 Interleukin 10
IL-12 Interleukin 12
IL-10R Interleukin-10 Receptor
ITP Idiopathic Thrombocytopenic Purpura
Kai1(CD82) Kangai1
LFA-1 Leukocyte Function-associated Antigen
1
LT-HSCs Long-Term Hematopoietic Stem Cells
mac Macrophage
MDPs Monocyte-Dendritic cell Progenitors
MHC-II Major Histocompatibility Complex II
MSCs Mesenchymal Stem Cells
moDCs Monocyte derived Dendritic Cells
Mks Megakaryocytes
NADPH NicotinamideAdenineDinucleotide
Phosphate
NE NeutrophilElastase
NF-κB NuclearFactorkappaB
Osteomac Osteal macrophage
Pax5 Paired box 5
PCR Polymerase Chain Reaction
PF4 Platelet Factor 4
PITPs Phosphatidylinositol Transfer Proteins
pre-cDCs pre-conventional Dendritic Cells
PSGL-1 P-Selectin Glycoprotein Ligand
PTEN PhosphataseandTensinHomolog
Ptdlns Phosphoinositides
PT Prolonged isolated Thrombocytopenia
PTH Parathyroid Hormone
pTreg peripherally Induced Regulatory T cells
ROS Reactive Oxygen Species
SAA Severe Aplastic Anemia
Saa3 Serum Amyloid A3
SCF Stem Cell Factor
S1P1R Sphingosine-1-Phosphate Receptor 1
STK11(LKB1) Serine-Threonine Kinase Liver Kinase
B1
STAT Signal Transducer and Activator of
Transcription
Th cells T helper cells
TNF-α TumorNecrosisFactoralpha
TNFR2 TumorNecrosisFactorReceptor2
TPO Thrombopoietin
TLRs Toll-like Receptors
tTreg cells Thymic Regulatory T cells
VCAM-1 Vascular Adhesion Molecule 1
VEGF-A Vascular Endothelial Growth Factor A
VLA-4 VeryLateAntigen4orα4β1
Introduction
Hematopoietic stem cells (HSCs) function as the founda-
tional cells generating all hematopoietic cell types and
orchestrating the renewal of the entire blood system. Beyond
intrinsic mechanisms, they are subject to modulation by
extrinsic factors. Predominately housed in the bone mar-
row postnatally, HSCs rely on a critical microenvironment,
often referred to as the niche, for regulation of key processes
suchasquiescence,self-renewal,anddierentiation[1, 2].
This niche, primarily constituted of non-hematopoietic
cells, dynamically responds to cues from neighboring cells,
growth factors, cytokines, and its own constituents, thereby
governingbothnormaland specialized hematopoiesis [3–
5].Nonetheless,thebonemarrowisnotsolelycomprisedof
non-hematopoietic elements; it also harbors hematopoietic
cells,notablyimmune cells.Thequestionarises: dothese
immune cells contribute to the regulation of hematopoietic
stem cells, and if so, by what mechanisms?
Graft-versus-host disease (GVHD), characterized by an
uncontrolled assault by donor-derived T cells on recipient
tissues, including donor hematopoietic stem and progeni-
tor cells (HSPCs) and the recipient’s bone marrow niche,
remains a challenge in hematopoietic stem cell transplanta-
tion[6]. Initially, extensive T-cell depletion coupled (TCD)
alongside high stem cell numbers appeared to eliminate
GVHD incidence in fully haplotype-mismatched trans-
plants yet resulted in graft failure [7, 8]. Partial T cell
deletion in the graft, however, circumvented graft failure,
relapse, and infection, while also reducing GVHD occur-
rence[9].Recentinquirieshavedelvedintotheinuenceof
retained T cells in partially TCD bone grafts or recipient T
cells in the bone marrow on HSPCs, indicating that immune
populations fostering hematopoietic transplantation dier
fromthoseprovokingGVHD[7]. Hematopoietic stem cell
1 3
420 Page 2 of 20
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
The role of immune cells settled in the bone marrow on adult hematopoietic stem cells
transplantation has emerged as a cornerstone treatment for
refractoryhematologicaldisorders[10]. Hence, elucidating
the role of bone marrow immune cells in HSPCs and hema-
topoiesisholdsparamountclinicalsignicance.
Immune cells, which are classic hematopoietic compo-
nents derived from HSPCs, predominantly mature in the
bone marrow, with the exception of T cells. Upon encoun-
tering diverse pathogens, some migrate to the periphery
to execute immunological roles, often in conjunction with
other physiological systems such as the nervous and endo-
crinesystems[11, 12] Post-immune response, a portion of
these cells reverts to and establishes residence within the
bone marrow for extended periods, thus designating the
bone marrow as both a primary hematopoietic locus and
a secondary lymphoid tissue. Recent investigations have
unveiled the capacity of bone marrow immune cells to mod-
ulate HSCs and their respective niches. Additionally, cer-
tain hematopoietic cells, including megakaryocytes, their
progenitor, their fragments platelet, and red cells, have been
foundedtohaveimmunologicalfunctions[13–15]. Amidst
signicant alterations in the hematopoietic system during
infectionorinammation,aconspicuousinterplaybetween
hematopoiesis and the immune system emerges. Here, we
aim to elucidate our comprehension of immune cells (such
as neutrophils, macrophages, dendritic cells, B cells, Breg
cells, T cells, and Treg cells) and hematopoietic cells pro-
cessing immunological functions (such as megakaryocytes),
which have contributed substantially to delineating the reg-
ulation of HSC fate and niche. Our objective is to furnish
insightful perspectives for forthcoming investigations, with
aprimaryemphasisontheeectsonnormaladulthemato-
poiesis,whilebrieyaddressingdevelopmentalandaber-
rant hematopoietic processes.
Neutrophils and their major role on HSCs
Neutrophils,themostabundantimmunecellsinperipheral
blood, freely circulate in the bloodstream, enabling rapid
responses to pathogens at the forefront of host defense
during early infection or tissue injury. Due to their short
lifespan, approximately 12.5 h in mice and 90 h in humans,
neutrophilsrequirecontinuousreplenishmentfromthebone
marrow[16]. Originating from HSCs, neutrophils undergo
dierentiation into multipotent progenitors (MPPs), com-
mon myeloid progenitors (CMPs), and granulocyte-
monocyteprogenitors(GMPs), sequentiallyleadingto the
formation of neutrophil precursors (preNeus), immature
neutrophils,and terminallymatureneutrophils[17]. These
constitute the three main neutrophil subpopulations in the
bonemarrowofbothmiceandhumans[17]. In the steady
state, the ratio of bone marrow neutrophils to blood neutro-
philsis10:1,andpreNeusand immature neutrophils are
absentintheblood[17, 18]. Aligned with their phenotypical
dierences(Table 1) [17], neutrophils are physiologically
retained in the bone marrow through the CXCR4/ CXCL12
(SDF-1)axisinbothmiceandhumans[17, 19, 20]. Con-
versely, their release into the circulation is propelled by
CXCR2 signaling [17, 21]. Under stress conditions, pre-
Neusexpandsignicantlyin thebonemarrowand spleen
to replenish neutrophil populations, while immature neu-
trophils are recruited to the blood and the spleen in mice,
wheretheymaturetomeetimmediatedemands[17]. How-
ever, it remains unclear whether the mechanism driving
migration from the bone marrow under stress mirrors that
of the steady state. Inhibition of CXCR4 or stimulation of
CXCR2 by G-CSF can mobilize neutrophils from the bone
marrowinbothmiceandhumans[20, 22].
During infection, neutrophils actively secrete interleu-
kin (IL)-1
β
[23],tumornecrosisfactoralpha(TNF-α)[24],
andvarious chemokinestoparticipateintheinammatory
response [25]. Even in the absence of infection, TNF-α
derivedfromembryoniczebrashneutrophilscanactivate
TNFreceptor2(TNFR2),whichsubsequentlytriggersthe
Notchandnuclearfactorkappa-B(NF-κB)pathway,regu-
lating the emergence of HSCs from hemogenic endothelium
[26] (Fig. 1A). The majority of neutrophils are stored pref-
erentially in the bone marrow, hinting at a potential func-
tional interplay [22]. In mice, bone marrow neutrophils
escalate the production of reactive oxygen species (ROS)
byphagocyticNADPHoxidaseinresponsetoacuteinam-
mation,aidingintheeliminationofinvadingpathogens[27,
28]. Concurrently, these ROS foster the proliferation and
dierentiationofHSCsandGMPsthroughthephosphatase
andtensinhomolog(PTEN)-Aktpathway,supportingemer-
gency hematopoiesis and granulopoiesis [27] (Fig. 1B).
Additionally, as part of the myeloid lineage, murine neutro-
phils may utilize the histamine/histamine receptor 2 (H2R)
axis to maintain bone marrow myeloid-biased HSCs and
progenitorsina quiescentstate,thuspreventing over-pro-
liferationinresponsetoacuteinammationorinjury[29].
Table 1 Phenotypicaldenitionofneutrophilsubsetsinthebonemar-
row and blood
Specie Subset Bone marrow Blood
Mouse preNeus Gr1+CD11b+CXCR4hickit+CXCR2−Gr1+
CD11
b+Ly
6G+C
XCR2+
Immature
neutrophils
Gr1+CD11b+CXCR4lockitloCXCR2−
Mature
neutrophils
Gr1+CD11b+CXCR4−ckit−Ly6G+
CXCR2+
Human preNeus CD15+CD66b+CD101−CD49d+
Immature
neutrophils
CD15+CD66b+CD101+CD16−CD10−
Mature
neutrophils
CD15+CD66b+CD101+CD16+CD10+
1 3
Page 3 of 20 420
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
H. Xu et al.
leadingtoasignicantlyreductionintheexpressionlevels
of key molecules for HSC retention, such as CXCL12, stem
cellfactor(SCF),andVCAM-1[32] (Fig. 1B).
Neutrophils exert not only direct eects on HSCs and
their progenitors but also indirectly impact HSCs by modu-
lating the bone niche where they reside. Myeloablation
induced by chemotherapy or radiotherapy prior to trans-
plantation disrupts the integrity of bone marrow vasculature
[33, 34], typically responsible for secreting angiocrine fac-
torssuchasCXCL12,SCF,andNotchligands,crucialfor
facilitating hematopoietic regeneration post-transplantation
NeutrophilsexertinuenceonHSCmigrationandresi-
dency in the bone marrow. Bone marrow neutrophil-derived
serine proteases, including neutrophil elastase (NE) and
cathepsin G (CG) engage in G-CSF-induced HSC mobiliza-
tioninmice[30, 31]. These proteases cleave vascular cell
adhesion molecule-1 (VCAM-1), hindering its binding to
its receptor, very late antigen-4 (VLA-4), crucial for HSC
retentioninthebonemarrow[30, 31] (Fig. 1B). Moreover,
G-CSF-induced HSC mobilization in mice correlates with
bone marrow neutrophil-mediated apoptosis of mesenchy-
mal stem cells and osteoblasts through ROS production,
Fig. 1 Multifacetedeectsofneutrophilsonhematopoiesisinthebone
marrow. (A) Zebrash neutrophils promote HSC emergence in the
hemogenicendotheliumbyreleasing the pro-inammatory cytokine
TNF-
α
. (B)Neutrophilsinthebonemarrowofmiceandhumansreg-
ulatesHSCsdirectlyorindirectlythroughaectingnichecells,suchas
mesenchymal stem cells and endothelial cells. (Abbreviations can be
found at the end of the text)
1 3
420 Page 4 of 20
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
The role of immune cells settled in the bone marrow on adult hematopoietic stem cells
ofthecellsandsubsequentreleaseof“eatme”signals[45].
ThisinteractionensuresthequalityofHSPCsand stimu-
lates their proliferation via the macrophage-derived Il1b-
inducedERK/MAKPpathway[45]. Following birth, in the
adult mouse bone marrow, macrophages are strategically
positioned in close proximity to HSC niches, including the
endothelial niche and the perivascular niche. In this capac-
ity, they serve as niche-supporting cells alongside endo-
thelial cells (ECs), mesenchymal stem cells (MSCs), and
osteoblasts within the bone marrow.
Bone marrow-resident macrophages, comprising only
0.4% of the total bone marrow cell population in mice,
demonstratesignicantdiversity[46, 47] (Fig. 2). Around
60–70% of F4/80+ bone marrow macrophages within arte-
riolarandendostealnichesexpressDARC (CD234) [48].
DARC stabilizes KAI1 (CD82), a molecule selectively
expressed on long-term hematopoietic stem cells (LT-
HSCs)[48]. The interaction between DARC and KAI1 acti-
vatestheTGF-β1/Smad3signalingpathway,resultinginthe
expression of cyclin-dependent kinase (CDK) inhibitors and
subsequentcell-cyclearrest[48]. This interaction ultimately
preserves the quiescent state of LT-HSCs, a phenomenon
relevant to human biology [48]. Additionally, a subset of
αSMA+ COX-2+ bone marrow macrophages in mice, over-
lapping with the DARC+ macrophages by approximately
10%,contributestomaintainingthequiescentstateofprim-
itive HSCs. These cells accomplish this by regulating the
production of PEG2, which limit the production of ROS in
HSCsthrough theinhibitionofthekinaseAkt[49]. Stress
can elevate the numbers of this subset in the bloodstream
[49].
Osteal macrophages, colloquially known as osteo-
macs, inhabit the endothelial niche in both murine (F4/80+
CD169+ VCAM1+) and human (CD15− CD163+ CD169+
VCAM1+) skeletal systems, exhibiting a dual function in
erythropoiesisandcellularclearanceinmurinemodels[50].
Furthermore, osteomacs are recognized as functional pre-
cursorstoosteoclasts[46], distinguished by their absence of
F4/80 expression, and are localized on bone surfaces within
trabecular and endosteal cortical regions. These osteoclasts
areaccountableforboneresorptionandremodeling[51]. A
central macrophage, positioned within erythroblastic islands
amidst numerous erythroid precursors in murine bone mar-
row,orchestrateserythroidproliferation,dierentiation,and
eventually enucleation, wherein integrins play a critical role
[52, 53].
Perivascular regions host approximately 80% of HSCs
[54], where they come into contact with microorganisms or
their byproducts from the bloodstream. Butyrate, a micro-
bial metabolite, plays a critical role in maintaining iron bal-
ance within the bone marrow by regulating the clearance of
aged red blood cells by bone marrow macrophages in mice
[35, 36]. Neutrophils are recruited to the injured sinusoi-
dal and arteriolar vessels within the murine bone marrow
through direct cell-to-cell interactions, contrary to the pre-
dominant role of CXCR4 and CXCR2 in steady-state neu-
trophiltracking.Subsequently, the recruited neutrophils
produce TNF-α, which fosters endothelial regeneration,
thereby facilitating the restoration of post-transplant HSPCs
[37] (Fig. 1B).Hence,TNF-αnotonlydirectly[38] inu-
ences HSPCs but also indirectly impacts hematopoiesis by
aiding in the repair of damaged bone marrow vessels. This
immediate repair of compromised vasculature by neutro-
phils corresponds with the observation that patient neutro-
phils are the primary innate cells involved in post-transplant
reconstruction within the initial week, while other innate or
adaptiveimmunecellsmayrequireweeksorevenyearsfor
completeregeneration[39]. Additionally, Pietras et al. have
illustrated that regenerating donor HSCs initially generate
myeloid-biased MPP 2/ MPP 3 to ensure a stable myeloid
output and lymphoid-biased MPP4 to reconstitute lymphoid
lineages[40]. Essentially, post-transplantation, donor HSCs
predominantly produce neutrophils, which serve dual roles
in infection control and the bone marrow vessel repair,
thereby providing HSCs with an intact vascular niche essen-
tial for long-term reconstitution of the entire blood system.
Macrophages and their major role on HSCs
Macrophages play a crucial role in innate immunity, serv-
ing distinct functions in maintaining tissue balance by clear-
ing cellular debris and providing frontline defense during
tissue surveillance [41, 42]. In mice, these cells display
signicantdiversityand aredistributedacrossvarious tis-
sues,eachexhibitinguniquemorphology,phenotypes,and
functions inuenced by tissue-specic factors. Notable
examplesincludeKupercellsintheliver,microgliainthe
brain,andosteoclastsinthebonemarrow[43]. Under nor-
mal conditions, most tissue-resident macrophages originate
during embryonic development and maintain their numbers
through limited proliferation. However, in response to stress
orchallenges,theirsurvivaldependsontheinuxofmono-
cytes originating from the bone marrow or extramedullary
sites like the spleen and lung [43]. Interestingly, macro-
phagesfromdierentsourcescancoexistwithinthesame
tissue, highlighting their remarkable versatility and adapt-
ability[42, 44].
In early development, experiments conducted in zebraf-
ish caudal hematopoietic tissue (CHT) and murine fetal liver
have demonstrated that resident macrophages engage with
newlygeneratedHSPCs[45]. These interactions involve the
recognition and binding of surface calreticulin on HSPCs
by macrophages, leading to partial or complete engulfment
1 3
Page 5 of 20 420
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
H. Xu et al.
reconstitution post-transplantation. This repair mechanism
involves the mechanosensitive Piezo1 channel and acti-
vatesthecalcineurin/NFAT/HIF-1αsignalingpathway[58].
Similarly, in individuals exposed to irradiation prior to
transplantation, central macrophages are depleted and then
regeneratedwithintherstmonthpost-transplantation,pro-
motingerythropoiesis[59].
Dendritic cells and their major role on HSCs
Beyond monocytes and macrophages, dendritic cells (DCs)
are essential components of the mononuclear phagocyte
system[60] and they primarily function as specialized anti-
gen-presenting cells (APCs) to maintain immune tolerance
toself-antigensorinitiateantigen-specicimmunity.Stud-
ies in mice have demonstrated that these cells originate from
a more committed common DC progenitor (CDP), which
dierentiatesfromtheprecursorsharedwithmonocytesand
macrophages known as monocyte-dendritic cell progenitors
(MDPs).Subsequently,theyundergodierentiationwithin
the bone marrow into pre-conventional DCs (pre-cDCs)
and pre-plasmacytoid DCs (pre-pDCs), ultimately generat-
ingthreemajorDCsubpopulationsintheperiphery:cDC1s,
cDC2s,andpDCs[61]. Under stress conditions, circulating
monocytes can be recruited to generate monocyte-derived
“inammatory” DCs (moDCs) [62]. Both immature and
mature DCs circulating in the blood of mice can be recruited
[55]. Iron levels are pivotal for HSC functions, impacting
theirself-renewalanddierentiationinsteady-statecondi-
tions, as well as their ability to repopulate during hemato-
poieticstress,suchasbonemarrowtransplantation[55, 56].
Moreover, a distinct subset of macrophages (characterized
as Gr-1− F4/80+ CD169+ in mice) located in the perivascu-
lar niche participates in granulocyte colony-stimulation fac-
tor (G-CSF)-induced HSC mobilization. Following G-CSF
treatment, these macrophages undergo depletion, leading to
reduced production of CXCL12, possibly by nestin+ MSCs.
This decrease in CXCL12 levels facilitates the mobilization
of HSCs towards the periphery through sinusoidal vessels
[47].Nevertheless,theprecisemechanismsbywhichmac-
rophages modulate nestin+ MSCs remain elusive.
Furthermore, macrophages play an active role in repair-
ing injured bone marrow vasculature. Pre-transplantation
radiotherapy or chemotherapy eliminates residual host
cellstocreatespace for transplantedcells[57]. However,
these treatments disrupt the bone marrow environment,
particularly aecting the sinusoidal vasculature [33, 34].
This vasculature is critical for hematopoietic reconstitution
post-transplantation, as around 80% of HSCs reside there to
completethehematopoieticprocess[54]. In response to this
disruption, bone marrow macrophages in mice, which are
less susceptible to irradiation compared to other monocytes,
increase the expression of vascular endothelial growth factor
A (VEGF-A). This upregulation aids in the repair of dam-
aged sinusoids, preparing for subsequent HSC-mediated
Fig. 2 Role of distinct macrophage subsets on hematopoiesis in the
bone marrow. Bone marrow macrophages are heterogeneous and are
involvedinregulatingseveralaspectsofhematopoiesis,includingqui-
escent maintenance, HSC mobilization, erythrocyte metabolism, bone
metabolism, iron homeostasis, and sinusoidal repair. (Abbreviations
can be found at the end of the text)
1 3
420 Page 6 of 20
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
The role of immune cells settled in the bone marrow on adult hematopoietic stem cells
vitro-producedbmDCsmayoeramorefavorableoption
for mitigating neutropenia following HSC transplantation.
B cells and their major role on HSCs
B cells, which initiate humoral immunity, not only serve
as APCs but also produce antibodies facilitating various
immune processes such as antibody-dependent cellular
cytotoxicity, complement-dependent cytotoxicity, or phago-
cytosis[71].Additionally,theysecretebothpro-inamma-
tory and anti-inammatory cytokines to regulate immune
responses[72]. The development of B cells is a tightly regu-
lated, beginning with progenitors in the fetal liver, progress-
ing to immature B cells in the bone marrow, and ultimately
resulting in the formation of mature B cells in the spleen
[73]. Key transcription factors including Ebf1, E2A (TCF3),
and Pax5 play crucial roles in guiding the transition from
progenitorstoB-lymphoidcells in thebonemarrow[74–
76].Recentstudieshavealsoconrmedthat newlygener-
ated immature B cells (IgM+ IgG−) in mouse bone marrow
can undergo maturation simultaneously in both the bone
marrowandspleen[77]. Approximately two-thirds of these
newly generated B cells migrate from the bone marrow to
the spleen for further maturation, while the remaining one-
third complete maturation within the bone marrow [78].
Newlymatured Bcellsinthebonemarrowmaypromptly
enter the peripheral circulation, whereas newly activated or
memory B cells from the periphery may access the bone
marrow. Thus, the bone marrow functions both as the pri-
mary lymphoid organ, generating and exporting B cells, and
as a secondary lymphoid tissue where B lineage cells are
harbored, facilitating allowing humoral immunity.
Within the bone marrow, mature B cells display dynamic
heterogeneity and are categorized into three primary types
[78]. The majority of these cells are newly generated B
cells, undergoing rapid renewal. They dierentiate from
precursor cells in the bone marrow, mature within its con-
nes,andthenentertheperipheralcirculationtoreplenish
the lymphatic pool. A small fraction of these cells has the
opportunity to dierentiate into long-lived recirculating
plasma cells, while the majority become short-lived circu-
lating plasma cells that typically perish within a few weeks
[79, 80]. Another subset of B cells in the bone marrow con-
sists of slowly renewed, long-lived cells recruited from the
periphery. These cells can freely recirculate between the
bone marrow and the blood, serving as replacement cells
fortheperipherallymphaticpool[81]. This subset includes
antigen-specicBmemorycellsthataccumulateinthebone
marrowovertime[82]. The third subset of B cells in the
bone marrow comprises recently activated B cells migrat-
ing from the spleen after secondary antigenic stimulation,
to the bone marrow through the VCAM-1/VLA4 axis, simi-
lar to the migration of HSPCs and T cells into the bone mar-
row[63].
Resident dendritic cells (bmDCs) within the murine bone
marrow, are notably sparse, constituting only 0.11-0.22% of
BMNCs[64]. The main constituents of endogenous bmDCs
are blood-borne DCs, which assemble into distinct peri-
vascular clusters surrounding specic blood vessels. This
spatialarrangementservesasauniquesitewherematureB
cellsandTcellsarelocalized[65]. Proximity often indicates
functional correlation. bmDCs have demonstrated a capac-
itytoecientlyactivateCD8+ central memory T (TCM) cells
within the bone marrow, thereby expediting the initiation of
there-immuneresponse[63]. Additionally, they contribute
to the maintenance of long-lived plasma cells secreting IgM
and provide survival signaling via macrophage migration
inhibitory factor (MIF) to mature recirculating B cells in the
bonemarrow[65].
Real-timequantitativePCRmonitoringhas shown that
ablating perivascular bmDCs in mice results in a notable
upsurge in CXCR2 expression, which in turn triggers vascu-
larpermeabilityandHSPCmobilization[66]. This indicates
the pivotal role of bmDCs in governing HSPC migration
fromthebonemarrowbyinuencingCXCR2expressionin
sinusoidalendothelialcells [66]. The distinct mechanisms
underlyingHSPCtrackingregulationbetween G-CSF,a
frequently utilized clinical mobilizing agent, and bmDCs
suggestthepotentialforsynergisticeectsinHSPCmobi-
lization[67, 68].
In vitro experiments have revealed that coculturing
CD34+ HSPCs with bmDCs or their supernatants not only
signicantlyboostscellnumbersbutalsoenhancesthefor-
mation of CFU-MK and CFU-GM with increasing concen-
trationsofbmDCs[69]. Moreover, transplantation of bone
marrow cells containing bmDCs into irradiated mice has
been demonstrated to facilitate the recovery of peripheral
leukocytes and platelets while prolonging the survival period
ofthemice[69]. Antibody neutralization experiments have
suggested that bmDCs support hematopoiesis, particularly
megakaryopoiesis in HSPCs, by secreting thrombopoietin
(TPO),IL-6,andIL-12[69].
Opportunisticfungalinfections frequentlyarisefollow-
ing HSC transplantation due to prolonged neutropenia.
Studies have demonstrated that zymosan (fungal antigens)-
stimulated bmDCs in mice stimulate the production of neu-
trophils from HSCs in a G-CSF-dependent manner without
inducingHSCexhaustion[64]. This underscores the poten-
tial of bmDCs to interpret and induce hematopoietic bias in
response to immune stimuli. Considering the inherent chal-
lenges associated with G-CSF administration, such as the
need for repeated injections and symptoms like bone pain,
nausea,headache,andfatigue[70], the administration of in
1 3
Page 7 of 20 420
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
H. Xu et al.
Long-lived plasma cells, identied as CD19−/B220−/
MCH IIlo CD138+ in mouse bone marrow, represent a sub-
stantial local source of IL-10 under steady-state conditions
[97, 98]. IL-10 assumes a pivotal role in regulating the
proliferationanddierentiationofmyeloidcells,DCs,and
macrophages within the bone marrow, operating in a non-
redundantcapacity[98, 99]. Myeloid-biased hematopoiesis
increasesinagedmiceandtheelderly[100], a phenomenon
attributed to the age-related accumulation of plasma cells in
the bone marrow. In aged mice, bone marrow plasma cells
exhibit heightened expression of pathogen sensors such as
Toll-like receptors (TLRs), thereby instigating the secretion
ofinammatorycytokinesandchemokines(e.g.,IL-1,IL-6,
TNF-α)bystromalnichecells[101]. These mediators then
bind to receptors on HSPCs, promoting myelopoiesis and
inhibiting lymphopoiesis as a defense mechanism against
pathogens[102–104].
IL-10-producing B cells, also termed regulatory B (Breg)
cells, reside within the bone marrow and demonstrate
immunosuppressiveattributes[105]. These Breg cells wield
pivotal roles in immune regulation across various clinical
scenarios, including autoimmune diseases [106], cancer
[107], acute myeloid leukemia [108], graft-versus-host
disease following hematopoietic stem cell transplantation
[109],andtissuedamage[110]. Diverging from the conven-
tionalindependentdierentiationpathwayobservedinreg-
ulatoryTcells,Bregcelldierentiationiscontingentupon
theimmuneenvironmentinwhichtheyoperate.Notably,
owcytometryanalyseshaverevealedthatundersteady-
state conditions, IL-10-producing cells constitute 0.1–0.2%
of bone marrow cells, with 65% arising from plasma cells
and 5% from B cells [98]. Consequently, Breg cells can
emergeatdierentstagesofBcellmaturation,encompass-
ing immature and mature B cell populations, accounting for
the variable immunophenotypes observed in both murine
andhumancontexts[111, 112].
Analysis of tissue-specic Breg cells via single-cell
sequencinginmiceunveiled that2.11%of Bcellswithin
the bone marrow exhibited characteristic gene proles
akin to Breg cells, a proportion notably lower than those
observed in peripheral blood (69.56%), spleen (13.54%),
liver(5.34%),andlymphnodes(3.57%)[113]. This dispar-
ity in distribution could undergo reversal in disease states
[114]. Predominantly, bone marrow Breg cells secrete either
IL-10, TGF-
β
, or both concurrently, rather than IL-35, to
exertimmunosuppressiveeectsacrossmurineandhuman
systems, while exhibiting heightened expression of genes
associated with the positive regulation of regulatory T
cells [113, 114]. With accumulating evidence implicating
both regulatory T cells and Breg cells in the bone marrow
immunosuppression during disease states [115, 116], it is
conceivable that Breg cells contribute to the maintenance of
with the potential to evolve into long-lived plasma cells
within the bone marrow. While the majority of circulating
plasmacells,dierentiatedfromnaïveormemoryBcellsin
secondary lymphoid organs such as the spleen and lymph
nodes,perishrapidlyafterinammation,aminority,likely
originating from germinal centers, can mature into long-
lived plasma cells within the bone marrow. These long-lived
plasma cells sustain elevated levels of immunoglobulin (Ig)
G secretion over an extended duration, even in the absence
of an infectious trigger [83]. Additionally, in mice, these
long-livedplasmacellsexhibitquiescenceinthebonemar-
row due to the downregulation of S1P1R and CXCR3, criti-
cal for their migration from blood towards the bone marrow
[84]. They demonstrate increased expression of CXCR4,
the receptor for CXCL12, pivotal for their retention within
thebonemarrow[85].
Two-dimensional confocal imaging in mice reveals that
plasma cells are dispersed throughout the bone marrow
parenchyma, often in close proximity to eosinophils and
stromalcells[86]. This spatial organization creates a dis-
tinct microenvironment that fosters the survival and longev-
ity of plasma cells through direct cellular interactions or the
secretion of soluble factors, such as CXCL12, APRIL, IL-6,
IL-5,andTNF-α[86, 87].Thedierentialutilizationofcel-
lular components between the HSC niche and the plasma
cell niche implies a nuanced connection between HSCs and
plasma cells. Indeed, a plethora of data exists to explore the
impact of B lineage cells on hematopoiesis.
Recent ndings emphasize the pivotal role of the ner-
vous system in modulating bone remodeling, metabolism,
hematopoiesis, and immunity [88–93]. Acetylcholine, a
neurotransmitter of the parasympathetic nervous system,
is predominantly synthesized in B220+ B cells and CD19+
IgM+ immature B cells within the bone marrow. This
neurotransmitter disrupts hematopoietic homeostasis by
enhancing HSPC retention in the bone marrow while dimin-
ishingHSPCproliferation.Itachievesthis by inuencing
the phenotypes of various stromal niche cells, leading to
altered expression of CXCL12, angpt1, Col2a1, Col11a1,
Saa3,andTNFinMSCsinbothmiceandhumans.These
eects are elicited when these cells detect acetylcholine
throughthecholinergicα7nicotinicreceptor(Chrna7)[94].
Actually, Chrna7 is widely expressed across all bone mar-
row cell types [95]. Knockout assays and morphological
analyses have demonstrated that Chrna7 primarily facili-
tates the maturation of myeloid and erythroid cells within
thebonemarrowunderphysiologicalconditions[95]. In the
contextofinammatorydiseases,thestimulationofChrna7
on bone marrow-derived macrophages/monocytes and neu-
trophilsusingagonist caneectivelyinhibitinammatory
responsesandthereleaseofinammatoryfactors[96].
1 3
420 Page 8 of 20
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
The role of immune cells settled in the bone marrow on adult hematopoietic stem cells
Under sterile conditions, activated/memory CD4+ T cells,
identiedbyCD44hi CD45RBlo CD62L− in mice, exhibit a
comparable proportion in the bone marrow to that observed
in the periphery (spleen and lymph nodes) [124]. These
cells, constantly stimulated by cognate antigens, actively
contributeto“normal hematopoiesis” inthebone marrow
throughthepromotionofIL-6andG-CSFproduction[125].
However, exposure to exogenous antigens triggers a higher
inuxofactivated/memoryCD4+ T cells, primarily stimu-
latedintheperiphery,intothebonemarrow.Consequently,
this migration leads to their accumulation in the bone mar-
row, constituting up to 44.4% of the total cell population (in
contrast to 10% observed in the bone marrow of germ-free
mice) [124]. Various conditional transgenic mouse mod-
els have illustrated the regulatory role of numerous cyto-
kines and chemokines, predominantly secreted by CD4+ T
helper(Th)cells,inhematopoiesisatdierentstages[126].
Merely analyzing the regulation of hematopoiesis within a
specicsubsetofThcellsbasedontheeectsofcytokines
orgrowth factorsisinadequate,astheproductionofthese
hematopoietins is not restricted to CD4+ T cells.
CD8+ T cells’ main impact on HSCs
In the bone marrow, CD4+ T cells to CD8+ T cells ratio is
approximately1:2,contrasting withtheratiosobserved in
peripherallymphnodes(2:1to3:1)andblood(2:1)[127].
Similar to CD4+ T cells, CD8+ T cells in the bone marrow
predominantly exhibit a memory phenotype, characterized
by high expression of mouse CD44hi or human CD45RAlo/−
markers, constituting nearly 60% of the total CD8+ T cell
populationinthe bonemarrow[128]. These cells demon-
strate prolonged persistence within the bone marrow and
exhibit a heightened responsiveness to antigens compared
totheircounterpartsin theperiphery[129]. This suggests
that the bone marrow functions as a secondary lymphoid
organ for both CD4+ and CD8+ T cells, particularly serving
as a favored homing site for memory cells. Intravital imag-
ing of the femur has revealed that CD8+ T cells localize
in proximity to perivascular stromal cells, which not only
express high level of CXCL12, a crucial factor for CD8+ T
cells homing to the bone marrow via the CXCL12-CXCR4
axis under homeostatic conditions but also secrete cytokines
such as IL-7 and IL-15 essential for their survival [120].
Nevertheless,thedirectimpactofCD8+ T cells in the bone
marrow on normal hematopoiesis, beyond their immune
defense functions, remains less explicitly elucidated. Con-
sequently,furtherinvestigationiswarrantedtounraveltheir
role in hematopoiesis based on indirect evidence.
A study in mice rstly discovered that during acute
viral infections, peripheral cytotoxic CD8+ T cells (CTL)
actively secrete the major cytokine IFN-γ. This cytokine
the bone marrow immune environment under physiological
conditions.Nonetheless,directevidencesubstantiatingthe
regulatory role of bone marrow Breg cells in physiological
hematopoiesis remains limited.
T cells and their major role on HSCs
T cells assume a crucial role in coordinating cellular immu-
nity against pathogens, allergens, and tumor cells that evade
innate immunity across the human lifespan, thereby uphold-
ing immune homeostasis within the body. Unlike other lym-
phocytes originating and maturing in the bone marrow, T
progenitor cells depart from this site to undergo maturation
anddierentiationinthethymus.Thesedevelopmentalpro-
cesses are facilitated by critical interactions between stromal
cells and thymocytes [117]. Upon maturation, T cells are
released into the periphery, where they encompass various
subpopulations, including the well-known CD4+ T cells,
CD8+ T cells, and Treg cells, further categorized based on
renedcriteria.Notably,evenwithinthesameT-cellsubset,
variationsexistin phenotypes,cytokinesecretionproles,
graft-versus-tumor activity, and graft-versus-host activity
inboththebonemarrowandtheblood[118]. Intriguingly,
asignicantproportion,approximately8-10.8%,ofmature
T cells in the periphery migrate back to the bone marrow,
assuming the role of sentinels in maintaining immune and
hematopoietic homeostasis [119]. Conditional knockout
experiments have demonstrated the dependence of both
CD4+ T cells and CD8+ T cells on the CXCL12-CXCR4
axis for homing to and migration through the bone marrow
underhomeostaticconditions[120].
CD4+ T cells’ main impact on HSCs
Transcriptome datasets unveil that HSPCs in both murine
and human bone marrow manifest elevated expression of
genes linked to major histocompatibility complex (MHC)-II
moleculesandantigenpresentationviaMHC-II[121, 122].
Despite not specializing in antigen presentation, HSPCs pos-
sessthecapacitytodirectlyactivatingnaïveCD4+ T cells
while presenting both endogenous and exogenous antigens
viaMHC-II[121].Thisactivationcontributestothedier-
entiation and exhaustion of recognized antigens by HSPCs,
driving naïve CD4+ T cells into an immunosuppressive
state, thereby preserving the bone marrow from excessive
immunereactions[121]. Upon activation, CD4+ T cells dif-
ferentiateintospeciceectorormemorycellsinresponse
to stimulatory signals, each expressing distinctive surface
markers,uniquecytokines,chemokines,andgrowthfactors.
The production and secretion of these molecules hinge on
distinct members of the signal transducer and activator of
transcription(STAT)proteinfamily[123].
1 3
Page 9 of 20 420
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
H. Xu et al.
Regulatory T cells and their major role on
HSCs
Upon reaching the CD3+ CD4+ signal-positive stage of
development, thymocytes undergo a two-step process. Ini-
tially,they acquire expressionofCD25(IL2Rα)and sub-
sequently Foxp3, ultimately mature into CD25+ Foxp3+
thymic Treg (tTreg) cells responsible for upholding sys-
temicimmunetolerance[138]. Another source of functional
Treg cells is in the periphery, known as peripherally induced
Treg cells (pTreg). These cells arise from mature peripheral
CD4+TcellsundertheinuenceofTGF-β,aregulatorof
CD25andFoxp3[139]. In essence, newly generated Treg
cells(identiedasCD45RA+ CCR7+ CD4+ CD25+ Foxp3+
in mice) can originate from either de novo development in
the thymus, though this process is impeded with age, or
peripheral self-proliferation originating from CD4+ T cells
[140].
Under normal physiological conditions, peripheral Treg
cells are recruited to and maintained within the bone mar-
row in both mice and humans through hCXCL12 (SDF-
1)-mediated CXCR4 signaling. Conversely, they can be
mobilized into the periphery by the action of G-CSF, which
downregulates the expression of CXCL12 by bone marrow
stromal cells [141]. Activated Treg cells exhibit elevated
levels of CXCR4. Both FACS and PCR assays consistently
indicate the propensity of Treg cells to inhabit in the bone
marrow in both mice and humans.
In both mice and humans, Treg cells make up approxi-
mately 30% of the total CD4+ T cell population in the bone
marrow, a notably higher proportion compared to other
lymphoid sites such as the thymus, peripheral blood, lymph
nodes, and spleen, where Treg cells constitute 6-10% of
total CD4+Tcells[141, 142]. This emphasizes their distinc-
tive association with the bone marrow (Fig. 3).
Invivoimaginginmicehasrevealedasignicantco-
localization of HSCs with Treg cells on the endosteal
surface of the skull and trabecular bone marrow, forming
theendogenousniche[143]. Within this niche, Treg cells
establish an immunosuppressive environment that shields
HSPCs from immune attacks, partly through the secretion
oftheanti-inammatoryfactorIL-10[143]. This immune-
privileged site also oers protection to allogeneic HSCs,
allowing them to evade immune responses and regenerate
the entire blood system. Additionally, murine bone marrow
Treg cells provide immune protection to perivascular cells,
the primary source of IL-7 production, crucial for the nor-
maldierentiationofHSCsintoBlineagecells.Depletion
of bone marrow Treg cells in mice leads to a reduction in
the proportion and number of B220+ B cells in the bone
marrow and hinders the reconstitution of B lineage cells, an
secretion subsequently stimulates bone marrow MSCs to
release IL-6. This signaling cascade then initiates urgent
myelopoiesis by MPPs and myeloid precursors, ensuring
sucient recruitment of myeloid cells, including mono-
cytesandneutrophils, tothesiteof infectionforeective
pathogenclearance[130]. The induction of hematopoiesis
by viral infection not only provides a valuable model for
understanding the interplay between adaptive and innate
immunitybutalsoillustratestheindirect,distantinuence
of CD8+ T cells on hematopoietic cells.
Secondly, valuable insights into normal hematopoiesis
can be gleaned from evidence concerning abnormal hema-
topoiesis. Investigations involving mice and humans focus-
ing on the pathogenesis of idiopathic thrombocytopenic
purpura (ITP) and prolonged isolated thrombocytopenia
(PT) have unveiled a notable increase in activated CD8+ T
cellswithinthebonemarrow ofaectedindividuals.This
specicpopulationofcellshasbeendemonstratedtohinder
apoptosis in megakaryocytes (Mks) by downregulating Fas
expression in Mks, thereby impairing platelet production
[131, 132]. However, the mechanism behind the recruit-
ment of CD8+ T cells to the bone marrow post-transplan-
tation remains unclear. A study conducted by Terauchi et
al. suggests that intermittent administration of Parathyroid
hormone (iPTH) leads to heightened Wnt10b production by
bone marrow CD8+ T cells. Consequently, this upregula-
tion activates canonical Wnt signaling in osteoblastic cells,
promoting osteoblast dierentiation, and increasing bone
density[133]. This discovery enables the exploration of the
link between inhibited osteogenesis, as observed in patients
with severe aplastic anemia (SAA) characterized by defects
in the reduced proliferation capacity but increased apoptosis
ofMSCs,andthediminishedexpressionofPTH-1RmRNA
and protein in CD8+Tcells[134, 135]. Abnormalities in the
immune system of SAA render PTH-1R insensitive to its
ligandPTH,consequentlydiminishingthesecretionofWnt
factors by CD8+ T cells. These factors play a pivotal role in
regulating MSC proliferation and directing their dieren-
tiation into osteoblasts rather than adipocytes, observed in
bothmice andhumans[135]. While adipocytes negatively
impact HSCs, osteoblasts constitute an essential element of
the bone niche responsible for maintaining normal hema-
topoiesis. This underscores the vital role of CD8+ T cells
in preserving bone homeostasis by modulating MSCs activ-
ity through PTH. Moreover, PTH expands HSPCs in mice
and enhances post-transplantation survival, a phenomenon
attributedtoOBs-dependent activationofNotchsignaling
[136]. A recent study has further unveiled the signicant
contribution of bone marrow T cells in expanding ST-HSCs
in vivo, with intermittent PTH potentially enhancing short-
termengraftment withoutaecting long-termrepopulation
inmice[137].
1 3
420 Page 10 of 20
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
The role of immune cells settled in the bone marrow on adult hematopoietic stem cells
multidimensional interactions with osteoblasts, osteoclasts,
and their progenitors. These interactions collectively con-
tribute to maintaining the structural integrity of the bone
niche. Additionally, depletion experiments have highlighted
the essential role of BM Treg-derived IL-10 in MSC homeo-
stasis, ensuring the production of factors necessary for stem
cellmaintenance[142]. Y. Lin et al. demonstrated that Rux-
olitinib protects MSCs in the bone marrow of acute GVHD
mouse models or patients, thereby enhancing hematopoi-
etic regeneration [149]. Furthermore, the serine-threonine
kinase liver kinase B1 (LKB1, or STK11), a recognized
tumor suppressor, stabilizes Foxp3 expression in Treg cells.
The absence of LKB1 in bone marrow Treg cells leads to the
depletion of the HSC pool and compromises the regenera-
tive capacity of HSPCs, highlighting the importance of Treg
cellsinthebonemarrowformaintainingHSCs[150, 151].
Treg cells also contribute to maintaining long-lived
plasma cells in the bone marrow, as these plasma cells
depend on support from Treg cells for survival, along-
side their association with eosinophils and stromal cells.
Roughly half of Treg cells and nearly all long-lived plasma
cells are situated alongside DCs within the HSC niche, with
theformertwocelltypescloselypositionedspatially[152].
Functionally, DCs within the HSC niche serve as potent
APCs, providing crucial co-stimulatory signals for plasma
cell survival and antibody production. Additionally, DCs
eectthatcanbereversedbytheadaptiveinfusionofTreg
cells[144].
Moreover, Treg cells perform multiple non-immuno-
logical functions related to HSPCs and bone stromal cells.
Within the endogenous niche of adult mice, there exists a
distinct subpopulation of Treg cells highly expressing the
HSC marker CD150, termed CD150hi Treg cells [145].
These CD150hi Treg cells continue to express cell-surface
ectoenzymes CD39 and CD73, which collectively generate
adenosine. This adenosine production aids in reducing ROS
inHSPCs,therebymaintainingHSCquiescenceandabun-
dance[145, 146]. Interestingly, conventional CD4+ T cells
(Tcons) in the bone marrow, also expressing high level of
CD150,CD39,andCD73(identiedasCD150hi CD39int/hi
CD73hi CD4+Tconsinmice),fulllasimilarfunction[146].
Treg cells in the bone marrow indirectly regulate hema-
topoiesisbyinuencing bonestromalcells. Inmice,bone
marrow Treg-derived cytotoxic T-lymphocyte antigen 4
(CTLA-4) targets CD80/CD86 on osteoclasts or their pre-
cursors, thus inhibiting osteoclast dierentiation [147].
Moreover, Treg cells directly impact osteoblasts and their
progenitor MSCs at various stages, thereby promoting bone
regeneration[148]. Considering the crucial roles of osteo-
blasts and osteoclasts in hematopoiesis, HSPC maintenance,
andmobilization[3, 4], it is evident that Treg cells in the
bonemarrowindirectlyaecthematopoiesisthroughtheir
Fig. 3 Eectsof Treg cellsonhematopoietic stemcells inthe bone
marrow. Bone marrow Treg cells provide a site of immunosuppression
forHSCsviaIL-10,maintainHSCsquiescencebyloweringROSlevel
viaadenosine,regulateB-lineagedierentiationbyprotectingperivas-
cular cells, and participate in bone metabolism. (Abbreviations can be
found at the end of the text)
1 3
Page 11 of 20 420
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
H. Xu et al.
responsible for Mk
α
-granulebiogenesis[165]. The mol-
ecules FGF1, IGF-1, and IGFBP-3 secreted by Mks have
been shown to promote the proliferation of HSCs [161,
162]. Besides secreting inammatory factors, cytokines,
and chemokines, Mks can regulate HSC fate by secret-
ing microparticles produced by membrane budding. In
humans, HSCs can uptake megakaryocytic microparticles
(MkMPs)andinitiatedierentiationintoMks[166].
These multifaceted roles of Mks, including platelet
production, immune regulation, and HSC support, have
intrigued researchers. We have questioned whether these
functions, particularly immune regulation and niche support,
are carried out by a single cell population or distinct sub-
populations.Recentadvancementsinsinglecellsequencing
andanalysistechniqueshaveunveiledtheheterogeneityof
Mks across various developmental stages and organisms. H.
Wang et al. (2021) demonstrated that human Mks comprise
six subpopulations with specialized functions, even during
early embryonic development in the yolk sac and fetal liver.
They are MK1 (glycolysis regulation), MK2 (cell cycle reg-
ulation), MK3 (platelet production), MK4 (niche support),
MK5 (immature Mks), and MK6 (immune regulation).
AlthoughMK4andMK6wereinitiallydenedasseparate
clusters, gene expression proling revealed that, besides
MK4, MK6 exhibited high expression of hematopoietic
support-related genes [167]. Trajectory analysis indicated
that MK6 shared a common developmental pathway with
MK4[167], suggesting that immune regulatory Mks (MK6)
possess the potential to support the HSC niche. Similar
observationsweremadeinmice[13, 168]. In a study by J.
Lietal.,Cluster4,identiedasimmuneMks,expressedthe
geneofIGF1,criticalforHSCproliferation[13, 162]. How-
ever, direct evidence linking immune Mks to the regulation
of HSCs or the HSC niche remains limited. Mk progeni-
tors in the human bone marrow, expressing MHC class II
and functioning as professional APCs, not only promote the
expansion of Th1 and Th17 cells, enhancing their response
to pathogens, but also potentially mobilize HSCs from the
bone marrow, initiating emergency myelopoiesis by pro-
ducing interferon-
α
inresponse tostimuli[14, 169, 170].
Mks, akin to their progenitors, may simultaneously mediate
immune regulation and hematopoiesis under stress, albeit
throughdierentmoleculesmechanisms.However,under
physiological conditions, distinct Mk subpopulations under-
takespecicfunctions.
Concluding remarks
Immune cells derived from HSCs have long been recog-
nized for their roles in immune recognition, regulation, and
defense. However, emerging evidence indicates that these
assist in maintaining Treg cell homeostasis, thereby regulat-
ing DC function, while Treg cells curb plasma cell activity
in the bone marrow through their high CTLA-4 expression
[152–154]. Therefore, Treg cells and DCs are two essential
cellular components of the plasma cell niche. As mentioned
earlier, both long-lived plasma cells and DCs in the bone
marrow play crucial regulatory roles in HSCs and hemato-
poiesis. However, it remains unclear whether and how these
three cell types within the plasma niche share common reg-
ulatoryeectsonHSCs.
In summary, this data indicates that BM Treg cells can
directly impact HSPCs, hematopoiesis, and HSC-mediated
reconstitution after transplantation. However, their main
modeofinuenceseemstobethroughregulatingbonestro-
mal cells, including perivascular cells, long-lived plasma
cells, DCs, osteoblasts, MSCs, and osteoclasts mentioned
previously, to reshape the niche homeostasis in favor of
hematopoiesis.
The role of megakaryocytes on HSCs
Megakaryocytes (Mks) are large (50 to100
µ
m in diam-
eter) and rare (0.05–0.1%) blood cells primarily found in
the bone marrow of adults. Their classic function involves
platelet production responsible for hemostasis [155]. In
both mouse and human bone marrow, they are guided by
CXCL12 to migrate into the vascular niche and achieve
transendothelial migration via the CXCL12/CXCR4 axis,
thereby promoting thrombogenesis at steady state or under
irradiation [156, 157]. Over the past decade, numerous
studies have highlighted their atypical immune functions
of Mks and their functional fragments, including pathogen
surveillance, antigen presentation, promotion of T-helper
cellexpansion,andantiviralfunction[14, 158, 159]. Con-
sequently,these Mks have gradually been recognized as
immuneMks.As terminallydierentiatedhematopoietic
cells derived from HSCs, Mks can, in turn, act as HSC
niche cells to regulate HSC functions. When regenerating
in the bone marrow of mice, Mks can express crucial extra-
cellular matrix components such as bronectin, type IV
collagen, and laminin, which are essential molecules for
HSCproliferationanddierentiation,thusrestoringniche
homeostasis[160]. In murine bone marrow, we detected
a random distribution of Mks, with approximately 20%
of HSCs directly connected to them. Even transplanted
HSCs showed a preference for being within two cells of
Mks[161, 162]. Under physiological conditions, Mks in
adult murine bone marrow secrete CXCL4 (PF4), TGF-
β
,andTPO tomaintainHSCquiescence [160, 163, 164].
Our team discovered that the release of TGF-
β
by Mks is
regulated via intracellular PITPs and the Ptdlns pathway,
1 3
420 Page 12 of 20
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
The role of immune cells settled in the bone marrow on adult hematopoietic stem cells
control and the proliferation of HSPCs in both zebrash
caudalhematopoietictissueandmurinefetalliver[45]. Fol-
lowing birth, the bone marrow becomes the principal site of
hematopoiesis, where immune cells residing in this environ-
mentexertdiverseinuencesonHSCs.
Firstly, these immune cells within the bone marrow play
directrolesinregulatingquiescence,self-renewal,andmulti-
lineagedierentiationofHSCs.DARCexpressedonbone
cells,as terminallydierentiatedprogenyofHSCs,canin
turn, act as HSC niche cells to modulate the functions of
the HSCs themselves. This reciprocal relationship is evident
across various developmental stages, beginning from early
embryonic development. For instance, neutrophils-derived
TNF-αinzebrashregulatestheemergenceofHSCsfrom
hemogenicendotheliumundersteady-stateconditions[26]
(Table 2).Inaddition,macrophagescontributetocellquality
Table 2 Eectsofbonemarrow-residentimmunecellsonHSCs
Cell types Residency in BM Functions on HSCs
Neutrophils Mice and humans; retained
in the bone marrow through
CXCR4/CXCL12axis[19,
20], and released into the
blood by CXCR2 signaling
[21].
1)Zebrash;regulateHSCemergencefromhemogenicendothelium[26];
2)Mice;promoteproliferationanddierentiationofHSCsandGMPsviaROS[27];
3)Mice;maintainHSCretentioninthebonemarrowviaNEandCG[31];
4)Miceandhumans;promoteendothelialregenerationpostmyeloablationviaTNF-
α
[37].
Macrophages Mice; located in close proxim-
itytoHSCniches[48, 49].
1)Zebrash;ensureHSCqualityandpromoteHSCproliferation[45];
2)Miceandhumans;maintainLT-HSCquiescenceviaDARCexpression[48];
3)Mice;maintainHSCquiescenceviaPEG2[49];
4)Mice;regulateerythropoiesisandcellclearance[50, 53];
5)Mice;regulateHSCfatedecisionviathebutyrate-ironaxis[55];
6)Mice;participateinG-CSF-inducedHSCmobilization[47];
7)Miceandhumans;repairdamagedsinusoidspostmyeloablationviaVEGF-A[58,
59].
Dendritic cells Mice; recruited to the bone
marrow via the VCAM-1/
VLA4axis[63].
1) Mice; maintain HSC retention in the bone marrow by suppressing CXCR2 expres-
sion[66];
2)Miceandhumans;promoteHSCproliferationanddierentiationinMks[69];
3)Mice;promoteneutrophilsproductionfromHSCsinresponsetofungalantigen[64].
B cells Mice; recruited to and retained
within the bone marrow
via CXCR4/CXCL12 axis,
CXCR3/CXCL9 or CXCL10
or CXCL11 axis, and S1P1/
S1P1Raxis[84, 85].
1) Mice and humans; indirectly disrupt hematopoietic homeostasis via acetylcholine
[94];
2) Mice and humans; regulate myeloid-biased hematopoiesis via IL-10, IL-1, IL-6, and
TNF-
α
[98, 100–103].
CD4+T cells Mice; recruited to and retained
within the bone marrow via
CXCR4/CXCL12 axis under
homeostaticconditions[120].
1)Miceandhumans;promotedierentiationandexhaustionofantigenrecognized
HSPCs[121];
2)Mice;promote“normalhematopoiesis”viaIL-6andG-CSF[125];
3)Mice;regulatehematopoiesisviavariouscytokinesandchemokines[126].
CD8+ T cells Mice; recruited to and retained
within the bone marrow via
CXCR4/CXCL12 axis under
homeostaticconditions[120].
1)Mice;indirectlypromotemyeloidhematopoiesisviaIFN-γ[130];
2) Mice and humans; inhibit Mk apoptosis and impair platelet production in patients
viaITPandPT[131, 132];
3)Mice;promoteosteoblastdierentiationviaWnt10b[133];
4)Miceandhumans;regulateMSCproliferationanddierentiationviathePTH-1/
PTH-1Raxis[135].
CD4+Treg cells Mice and humans; recruited to
and retained within the bone
marrow via CXCR4/CXCL12
axis[141].
1)Mice;createimmune-protectionforHSPCsandperivascularcellviaIL-10[143,
144];
2)Mice;maintainHSCquiescenceandabundancebyexpressingcell-surfaceectoen-
zymesCD39andCD70[145, 46];
3)Mice;maintainbonegenerationofosteoclastsandMSCsviaCTLA-4[147, 148];
4)Mice;maintainMSChomeostasisviaIL-10[142];
5)Mice;regulateHSCquiescenceandhomeostasisviaLKB1,thestabilizerofFoxp3
[150, 151];
6)Mice;maintainplasmanichewithDCs[152–154].
Megakaryocytes Mice and humans; directed to
the vascular niche and achieve
transendothelial migration
by CXCL12/CXCR4 axis for
thrombopoiesis at steady state
orunderirradiation[156, 157].
1)Mice;maintainnichehomeostasisviabronectin,typeIVcollagenandlaminin
[160];
2)Mice;maintainHSCquiescenceviaCXCL4,TGF-
β
,andTPO[163, 163];
3)Mice;promoteHSCproliferationviaFGF1,IGF-1,andIGFBP-3[161, 162];
4)Human;promoteHSCdierentiationintoMksviaMkMPs[166].
1 3
Page 13 of 20 420
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
H. Xu et al.
chemotherapypriortotransplantation [33, 34] and subse-
quently promote endothelial regeneration through TNF-
α
[37]. The integrated microvasculature of the bone is essential
for long-term hematopoiesis and HSC-mediated reconstitu-
tion following transplantation. Additionally, bone marrow
macrophage-derived VEGF-A facilitates the repair of dam-
agedsinusoids[58]. Moreover, Treg cells from mouse bone
marrow support the generation of osteoblasts in the bone
[148], which is crucial for maintaining the structural integ-
rity of the bone niche.
Subsequently, these immune cells interact with niche-
supporting cells to facilitate the retention and mobilization
of HSCs. Under physiological conditions, murine bmDCs
reducetheexpressionofCXCR2byinuencingsinusoidal
endothelial cells, thereby promoting HSC retention within
thebonemarrow[66]. Additionally, B cells modulate the
expression of critical factors for HSC retention, such as
CXCL12,angpt1,TNF,byaectingvarious stromal cells
[94]. Some of these immune cells are involved in G-CSF-
induced HSC mobilization, which is commonly utilized
in clinical settings. Following G-CSF treatment, neutro-
phils induce the downregulation of VCAM-1 and CXCL12
expression on MSCs, thereby disrupting the VCAM-1/
VLA-4andCXCL12/CXCR4axes,respectively[32]. Mac-
rophages exhibit a similar function [47] (Table 2). These
axes are crucial for the retention of HSCs and neutrophils
within the bone marrow. However, the mechanisms under-
lyingG-CSF-inducedtrackingdierbetween HSCsand
neutrophils [176]. Neutrophil mobilization induced by
G-CSF relies on the CXCR2 pathway [18, 20]. Interest-
ingly, these two processes are interconnected; following
G-CSF administration, the increase in bone marrow neutro-
phil leads to the production of serine proteases that cleave
VCAM-1, thereby interfering with VCAM-1/VLA-4 bind-
ingandfacilitatingHSCegressfromthebonemarrow[31].
The CXCL12/CXCR4 pathway is essential for both
the homing and retention of cells within the bone mar-
row. CXCL12 is primarily expressed in osteoblasts, bone
marrow stromal cells, as well as endothelial and perivas-
cular cells, while its receptor, CXCR4, is widely expressed
acrossvariouscelltypes[177]. As a potent chemoattractant,
CXCL12 promotes the homing of HSCs and immune cells
to the bone marrow under normal physiological conditions
by binding to its receptor (Table 2). However, there is cur-
rently limited discussion regarding the distinct regulatory
mechanisms of mobilization via the CXCL12/CXCR4 axis
between these two cell types. The homing process to the
bone marrow encompasses multiple steps, including rolling,
arrest,rmadhesion,spreading,andextravasation,which
requirevariousselectins,chemokines,adhesionmolecules
and their respective ligands [178]. Alongside CXCL12
and CXCR4, key molecules involved in homing include
marrow macrophages induces cell-cycle arrest by activat-
ingtheTGF-β1/Smad3signalingpathwayuponinteraction
with CD82 on HSCs, which contributes to the mainte-
nanceofHSCquiescence[48]. Reactive stress can induce
theproliferation,dierentiation,andmaturation of HSCs.
Consequently,thenicherequiresahypoxicenvironmentto
sustainthequiescentstateofHSCs,therebyavoidingstem
cell exhaustion and preserving their long-term regenerative
capacity[171–173].PEG2 derived fromαSMA+ COX-2+
bone marrow macrophages in mice, located near the arte-
rial and endosteal niches, limits the generation of ROS in
HSCs and the expression of CXCL12, further contributing
tothepreservationofHSC quiescence[48, 49]. Addition-
ally, CD150hi bone marrow Treg cells, situated adjacent to
HSCs, protect HSCs from oxidative stress by producing
adenosine. Transfer of these Treg cells have been shown to
improve the engraftment outcomes of allogeneic HSC trans-
plantationinmice[145, 146].
Various strategies for expanding HSPCs ex vivo have
been tested in laboratory settings to address the issue of
insucient HSPC doses [174]. However, the compro-
misedstemnessofculturedHSPCsandsubsequentlineage
recovery failures in HSC-based therapies, particularly Mk
lineage,posesignicantchallengesforresearchers[175].
Antigen-activated bmDCs have been shown to enhance
both the expansion of functional CD34+ HSPCs and mega-
karyopoiesis, when cocultured with HSPCs or exposed to
theirsupernatantsinvitro.Thiseectismediatedby the
secretionofthrombopoietin(TPO),IL-6,andIL-12[69].
Central macrophage-derived integrins in murine bone
marrow facilitate erythroid proliferation, dierentiation,
andultimatelyenucleation[52, 53]. CD4+ Th cells sup-
port normal hematopoiesis through the secretion of vari-
ouscytokinesandchemokines[126]. External stimuli can
induce specic dierentiation within hematopoiesis. For
instance, long-lived plasma cells respond to the increas-
ing demand for myelopoiesis during aging by producing
IL-10 [98–100]. CTLs produce IFN-γ to initiate urgent
myelopoiesis during viral infections [130]. Additionally,
immune Mks, a non-conventional type of immune cell, can
inuencemultipleaspectsofHSCfunctions,includingthe
maintenanceofquiescence[160, 163, 164], promotion of
proliferation [161, 162], and initiation of dierentiation
towardsMks[166] through secretion of various signaling
molecules.
Secondly, certain immune cells within the bone marrow
indirectlyregulateHSCfunctionsand migration by inu-
encing the primary niche-supporting cells, such as endo-
thelial cells, stromal cells, and osteoblasts, thereby creating
a favorable environment for HSC maintenance [5]. Bone
marrow neutrophils are recruited to injured sinusoids and
arteriolar vessels, which are damaged by radiotherapy or
1 3
420 Page 14 of 20
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
The role of immune cells settled in the bone marrow on adult hematopoietic stem cells
Open Access This article is licensed under a Creative Commons
Attribution-NonCommercial-NoDerivatives4.0InternationalLicense,
which permits any non-commercial use, sharing, distribution and
reproduction in any medium or format, as long as you give appropri-
ate credit to the original author(s) and the source, provide a link to the
CreativeCommonslicence,andindicateifyoumodiedthelicensed
material. You do not have permission under this licence to share
adapted material derived from this article or parts of it. The images or
other third party material in this article are included in the article’s Cre-
ative Commons licence, unless indicated otherwise in a credit line to
the material. If material is not included in the article’s Creative Com-
mons licence and your intended use is not permitted by statutory regu-
lation or exceeds the permitted use, you will need to obtain permission
directly from the copyright holder. To view a copy of this licence, visit
http://creativecommons.org/licenses/by-nc-nd/4.0/.
References
1. Schoeld R (1978) The relationship between the spleen col-
ony-forming cell and the haemopoietic stem cell. Blood Cells
4(1–2):7–25
2. ZhangJ,NiuC,YeL,HuangH,HeX,TongWG,RossJ,Haug
J, Johnson T, Feng JQ, Harris S, Wiedemann LM, Mishina Y, Li
L(2003).Identicationofthehaematopoieticstemcellnicheand
controlofthenichesize.Nature.425(6960):832-6
3. Calvi LM et al (2003) Osteoblastic cells regulate the haematopoi-
eticstemcellniche.Nature425(6960):841–846
4. Miyamoto K et al (2011) Osteoclasts are dispensable for hema-
topoietic stem cell maintenance and mobilization. J Exp Med
208(11):2175–2181
5. Ding L et al (2012) Endothelial and perivascular cells maintain
haematopoieticstemcells.Nature481(7382):457–462
6. Billingham RE (1959) Reactions of grafts against their hosts. Sci-
ence130(3381):947–953
7. SykesM,SheardM,SachsDH(1988)EectsofTcelldepletion
in radiation bone marrow chimeras. I. evidence for a donor cell
population which increases allogeneic chimerism but which lacks
thepotentialtoproduceGVHD.JImmunol141(7):2282–2288
8. Franco Aversa Md, Antonio Tabilio Md, Andrea Velardi Md, Isa-
bel Cunningham Md, Adelmo Terenzi Md, Franca Falzetti Md,
Loredana Ruggeri Md, Giuliana Barbabietola Md, Cynthia Aris-
tei Md, Paolo Latini Md, Yair Reisner Phd, And, Martelli Massi-
mof (1998) M.D., Treatment Of High-Risk Acute Leukemia With
T-Cell–Depleted Stem Cells From Related Donors With One
FullyMismatchedHlaHaplotype.TheNewEnglandJournalOf
Medicine,339:Pp.1186–1193
9. Chalandon Y et al (2006) Can only partial T-cell depletion of
the graft before hematopoietic stem cell transplantation mitigate
graft-versus-host disease while preserving a graft-versus-leuke-
mia reaction? A prospective phase II study. Biol Blood Marrow
Transpl12(1):102–110
10. Chivu-Economescu M, Rubach M (2017) Hematopoietic stem
cellstherapies.CurrStemCellResTher12(2):124–133
11. Schluter J et al (2020) The gut microbiota is associated with
immunecelldynamicsinhumans.Nature588(7837):303–307
12. Mayo L et al (2014) B4GALT6 regulates astrocyte activation dur-
ingCNSinammation.NatMed20(10):1147–1156
13. LiJJetal(2024)Dierentiationroutedeterminesthefunctional
outputsofadultmegakaryopoiesis.Immunity57(3):478–494e6
14. Finkielsztein A et al (2015) Human megakaryocyte progenitors
derived from hematopoietic stem cells of normal individuals are
MHC class II-expressing professional APC that enhance Th17
andTh1/Th17responses.ImmunolLett163(1):84–95
P-selectin/PSGL-1,E-selectin/CD44[179], ICAM-1/LFA-1
[180],andVCAM-1/VLA-4 [31].Consequently,thecyto-
kine environment within the bone marrow plays a pivotal
role.Environmentalcuesnotonlyinuencetheexpression
ofhoming-relatedmoleculesacrossdierentcelltypesbut
also impact the survival capabilities of these cells. Ulti-
mately, ensuring the maintenance of survival is a crucial
consideration upon homing to the bone marrow.
In summary, traditional immune cells and Mks with
immunological functions in the bone marrow actively par-
ticipate in molecular pathways that regulate HSPCs and
hematopoiesis. These pathways involve processes such as
maintaining quiescence, preserving stemness, modulating
dierentiation,andfacilitatingthemobilizationofHSPCs.
Additionally, they inuence niche cellular components,
including perivascular stromal cells, endothelial cells,
osteoblasts, and osteoclasts, collectively shaping a support-
ive bone marrow environment that enhances the mainte-
nanceofHSPCsandhematopoiesis.Thisarticlespecically
delves into the role of bone marrow immune cells in regulat-
ing HSC functions under normal physiological conditions.
However, there is limited exploration of whether these regu-
latory mechanisms are altered under stressful conditions or
in disease states. Furthermore, the fate decisions of HSCs
areoftenregulatedbymultipleimmunecells,raisingques-
tions about the synergistic or compensatory nature of their
eectsandtheconditionsunderwhichthesedynamicsman-
ifest. These considerations are critical and warrant further
investigation.
Author contributions Conceptualization and design: YG, YL, and
HX.Writingofthe rstdraft: HX.Figures:HX.Revision:YG,YL,
andHX.Finaleditingoftext:YG,YL,andHX.
Funding This review was supported by grands from Haihe Labora-
tory of Cell Ecosystem Innovation Fund (HH22KYZX0002, and HH-
22KYZX0040), the National Natural Science Foundation of China
(92068204, 81870083, 81970105, 82370120, and 82200126), CAMS
Innovation Fund for Medical Science (2021-I2M-1-019), a SKLEH-
Pilot Research Grant, and the Special Research Fund for Central Uni-
versities, Peking Union Medical College Fundamental Research Funds
for the Central Universities (3332023168).
Data availability Notapplicable.
Declarations
Ethical approval Notapplicable.
Content to participate Notapplicable.
Content to publish Notapplicable.
Conict of interest Theauthorsdeclaretheyhavenonancialornon-
nancialintereststodisclose.
1 3
Page 15 of 20 420
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
H. Xu et al.
36. Greenbaum A et al (2013) CXCL12 in early mesenchymal pro-
genitors is required for haematopoietic stem-cell maintenance.
Nature495(7440):227–230
37. BowersEetal(2018)Granulocyte-derivedTNFalphapromotes
vascularandhematopoieticregenerationinthebonemarrow.Nat
Med24(1):95–102
38. RezzougFetal(2008)TNF-alphaiscriticaltofacilitatehemopoi-
eticstemcellengraftmentandfunction.JImmunol180(1):49–57
39. Ma DD, Varga DE, Biggs JC (1987) Haemopoietic reconstitution
afterallogeneicbonemarrowtransplantationinman:recoveryof
haemopoietic progenitors (CFU-Mix, BFU-E and CFU-GM). Br
JHaematol65(1):5–10
40. Pietras EM et al (2015) Functionally distinct subsets of lineage-
biased multipotent progenitors Control Blood production in nor-
malandregenerativeconditions.CellStemCell17(1):35–46
41. Dueld JS et al (2005) Selective depletion of macrophages
reveals distinct, opposing roles during liver injury and repair. J
ClinInvest115(1):56–65
42. Lavine KJ et al (2014) Distinct macrophage lineages con-
tribute to disparate patterns of cardiac recovery and remodel-
inginthe neonatal andadultheart.Proc NatlAcadSci USA
111(45):16029–16034
43. Schulz C (2012) 2* Elisa Gomez Perdiguero,1,2* Laurent
Chorro,1,2 Heather Szabo-Rogers,3 Nicolas Cagnard,4 Katrin
Kierdorf,5 Marco Prinz,5 Bishan Wu,6 Sten Eirik W. Jacobsen,6
Jerey W. Pollard,7 Jon Frampton,8 Karen J. Liu,3 Frederic
Geissmann1,2†, a lineage of myeloid cells Independent of Myb
andhematopoieticstemcells.Science336:86–90
44. Epelman S et al (2014) Embryonic and adult-derived resident car-
diac macrophages are maintained through distinct mechanisms at
steadystateandduringinammation.Immunity40(1):91–104
45. Samuel J, Wattrus1 ML (2022) Smith1,2, Cecilia Pessoa
Rodrigues1,2, Elliott J. Hagedorn1,2†, Ji Wook Kim1,2, Bogdan
Budnik3, Leonard I. Zon1,2*, Quality assurance of hematopoietic
stem cells by macrophages determines stem cell clonality. Sci-
ence,377:pp.1413–1419
46. Winkler IG et al (2010) Bone marrow macrophages maintain
hematopoietic stem cell (HSC) niches and their depletion mobi-
lizesHSCs.Blood116(23):4815–4828
47. Chow A et al (2011) Bone marrow CD169 + macrophages pro-
mote the retention of hematopoietic stem and progenitor cells in
themesenchymalstemcellniche.JExpMed208(2):261–271
48. Hur J et al (2016) CD82/KAI1 maintains the Dormancy of Long-
Term hematopoietic stem cells through Interaction with DARC-
Expressingmacrophages.CellStemCell18(4):508–521
49. Ludin A et al (2012) Monocytes-macrophages that express alpha-
smooth muscle actin preserve primitive hematopoietic cells in the
bonemarrow.NatImmunol13(11):1072–1082
50. Chow A et al (2013) CD169(+) macrophages provide a niche
promotingerythropoiesisunderhomeostasisandstress.NatMed
19(4):429–436
51. Dodds RA et al (1995) Human osteoclasts, not osteoblasts, deposit
osteopontinontoresorptionsurfaces:aninvitroandexvivostudy
ofremodelingbone.JBoneMinRes10(11):1666–1680
52. Bessis M (1958) Erythroblastic island, functional unity of bone
marrow.RevHematol13(1):8–11
53. Soni S et al (2006) Absence of erythroblast macrophage protein
(emp) leads to failure of erythroblast nuclear extrusion. J Biol
Chem281(29):20181–20189
54. CraneGM,JeeryE,MorrisonSJ(2017)Adult haematopoietic
stemcellniches.NatRevImmunol17(9):573–590
55. Zhang D et al (2022) The microbiota regulates hematopoietic
stem cell fate decisions by controlling iron availability in bone
marrow.CellStemCell29(2):232–247e7
15. XuCetal(2022)Single-celltranscriptomicanalysisidentiesan
immune-prone population in erythroid precursors during human
ontogenesis.NatImmunol23(7):1109–1120
16. Pillay J et al (2010) In vivo labeling with 2H2O reveals a human
neutrophillifespanof5.4days.Blood116(4):625–627
17. Evrard M et al (2018) Developmental Analysis of Bone Marrow
neutrophils reveals populations Specialized in expansion, traf-
cking,andEectorfunctions.Immunity48(2):364–379e8
18. Craig L, Semerad FL, Alyssa D, Gregory KS, Daniel C (2002)
Link1,G-CSFisanessentialRegulatorofNeutrophiltracking
fromthebonemarrowtotheblood.Immunity17:413–423
19. Suratt BT et al (2004) Role of the CXCR4/SDF-1 chemokine axis
incirculatingneutrophilhomeostasis.Blood104(2):565–571
20. Martin C et al (2003) Chemokines acting via CXCR2 and CXCR4
control the release of neutrophils from the bone marrow and their
returnfollowingsenescence.Immunity19(4):583–593
21. Devi S et al (2013) Neutrophil mobilization via plerixafor-
mediated CXCR4 inhibition arises from lung demargination and
blockade of neutrophil homing to the bone marrow. J Exp Med
210(11):2321–2336
22. Eash KJ et al (2010) CXCR2 and CXCR4 antagonistically reg-
ulate neutrophil tracking from murine bone marrow. J Clin
Invest120(7):2423–2431
23. Karmakar M et al (2020) N-GSDMD tracking to neutrophil
organellesfacilitatesIL-1βreleaseindependentlyofplasmamem-
braneporesandpyroptosis.NatCommun11(1):2212.https://doi.
org/10.1038/s41467-020-16043-9
24. Hatanaka E et al (2004) Serum amyloid A-induced mRNA
expression and release of tumor necrosis factor-alpha (TNF-
alpha)inhumanneutrophils.ImmunolLett91(1):33–37.https://
doi.org/10.1016/j.imlet.2003.09.011
25. TecchioC,CassatellaMA(2016)Neutrophil-derivedchemokines
ontheroadtoimmunity.SemImmunol28(2):119–128.https://
doi.org/10.1016/j.smim.2016.04.003
26. Espin-PalazonRetal(2014)Proinammatorysignalingregulates
hematopoieticstemcellemergence.Cell159(5):1070–1085
27. Kwak HJ et al (2015) Myeloid cell-derived reactive oxygen spe-
cies externally regulate the proliferation of myeloid progenitors
inemergencygranulopoiesis.Immunity42(1):159–171
28. NathanC,DingA(2010)SnapShot:reactiveoxygenintermedi-
ates(ROI).Cell140(6):951–951e2
29. Chen X et al (2017) Bone marrow myeloid cells regulate myeloid-
biased hematopoietic stem cells via a histamine-dependent Feed-
backLoop.CellStemCell21(6):747–760e7
30. PelusLMetal(2004)Neutrophil-derivedMMP-9mediatessyn-
ergistic mobilization of hematopoietic stem and progenitor cells
by the combination of G-CSF and the chemokines GRObeta/
CXCL2andGRObetaT/CXCL2delta4.Blood103(1):110–119
31. vesqueJ-PL,SusanYT,NilssonK,HaylockDN,SimmonsPJ
(2001) Vascular cell adhesion molecule-1 (CD106) is cleaved by
neutrophil proteases in the bone marrow following hematopoietic
progenitor cell mobilization by granulocyte colony-stimulating
factor. Blood, 98
32. Singh P et al (2012) Expansion of bone marrow neutrophils fol-
lowing G-CSF administration in mice results in osteolineage cell
apoptosis and mobilization of hematopoietic stem and progenitor
cells.Leukemia26(11):2375–2383
33. RussellNSetal(2009)Novelinsightsintopathologicalchanges
in muscular arteries of radiotherapy patients. Radiother Oncol
92(3):477–483
34. Shirota T, Tavassoli M (1991) Cyclophosphamide-induced altera-
tions of bone marrow endothelium: implications in homing of
marrowcellsaftertransplantation.ExpHematol19(5):369–373
35. Butler JM et al (2010) Endothelial cells are essential for the self-
renewal and repopulation of notch-dependent hematopoietic stem
cells.CellStemCell6(3):251–264
1 3
420 Page 16 of 20
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
The role of immune cells settled in the bone marrow on adult hematopoietic stem cells
helix-loop-helix genes, E2A, E2-2, and HEB. Mol Cell Biol
16(6):2898–2905
76. GyöryIetal(2012)TranscriptionfactorEbf1regulatesdieren-
tiationstage-specicsignaling,proliferation, and survival ofB
cells.GenesDev26(7):668–682
77. CariappaAetal(2007)NaiverecirculatingBcellsmaturesimulta-
neouslyinthespleenandbonemarrow.Blood109(6):2339–2345
78. OSMONDDG (1986)PopulationdynamicsofBoneMarrowB
lymphocytes. Immunologicat Rev, 93
79. Yoshida Y, Osmond DG (1978) Homing of bone marrow lym-
phoid cells. Localization and fate of newly formed cells in lym-
phocyte-rich marrow fractions injected into lethally X-irradiated
recipients.Transplantation25(5):246–251
80. Osmond DG (1980) The contribution of bone marrow to the
economyofthelymphoidsystem.MonogrAllergy16:157–172
81. Röpke C, Everett NB (1974) Migration of small lymphocytes
in adult mice demonstrated by parabiosis. Cell Tissue Kinet
7(2):137–150
82. Koch G et al (1981) The mechanism of thymus-dependent anti-
bodyformationinbonemarrow.JImmunol126(4):1447–1451
83. Slifka Markk, Ahmed* Mmandra (1995) Bone marrow is a
major site of long-term antibody production after Acute viral
infection.JVirol69:1895–1902
84. Kabashima K et al (2006) Plasma cell S1P1 expression deter-
mines secondary lymphoid organ retention versus bone marrow
tropism.JExpMed203(12):2683–2690
85. Anja E, Hauser GFD, † Sergio Arce,* Giuliana Cassese,* Alf
Hamann,† Andreas Radbruch,* and, Rudolf A (2002) Manz2*,
Chemotactic Responsiveness Toward Ligands for CXCR3 and
CXCR4 Is Regulated on Plasma Blasts During the Time Course
ofaMemoryImmuneResponse.JournalofImmunolgy,169:pp.
1277–1282
86. Zehentmeier S et al (2014) Static and dynamic components syner-
gize to form a stable survival niche for bone marrow plasma cells.
EurJImmunol44(8):2306–2317
87. SlamanigSA,NolteMA(2021)ThebonemarrowasSanctuary
forplasmacellsandmemoryT-Cells:implications foradaptive
immunity and vaccinology. Cells, 10(6)
88. Baldock PA et al (2002) Hypothalamic Y2 receptors regulate
boneformation.JClinInvest109(7):915–921
89. Elefteriou F et al (2005) Leptin regulation of bone resorp-
tion by the sympathetic nervous system and CART. Nature
434(7032):514–520
90. Katayama Y et al (2006) Signals from the sympathetic nervous
system regulate hematopoietic stem cell egress from bone mar-
row.Cell124(2):407–421
91. Schäfers M et al (2003) Tumor necrosis factor-alpha induces
mechanical allodynia after spinal nerve ligation by activa-
tion of p38 MAPK in primary sensory neurons. J Neurosci
23(7):2517–2521
92. McAlpine CS et al (2019) Sleep modulates haematopoiesis and
protectsagainstatherosclerosis.Nature566(7744):383–387
93. Vogrig A et al (2024) Central nervous system immune-related dis-
ordersafterSARS-CoV-2vaccination:amulticenterstudy.Front
Immunol15:1344184
94. Schloss MJ et al (2022) B lymphocyte-derived acetylcholine
limitssteady-stateand emergencyhematopoiesis. NatImmunol
23(4):605–618
95. KovalLMetal(2008)Nicotinicacetylcholine receptorsalpha-
4beta2 and alpha7 regulate myelo- and erythropoiesis within the
bonemarrow.IntJBiochemCellBiol40(5):980–990
96. Kiguchi N et al (2012) Activation of nicotinic acetylcholine
receptors on bone marrow-derived cells relieves neuropathic pain
accompanied by peripheral neuroinammation. Neurochem Int
61(7):1212–1219
56. Meyer SC et al (2013) Prognostic impact of posttransplantation
iron overload after allogeneic stem cell transplantation. Biol
BloodMarrowTranspl19(3):440–444
57. Mortimer M, Bortin MMMH, Robert Peter Gale MD, PhD;
MD, John Barrett A, MD;, Richard MKAD, Champlin E, Eliane
MDPD, Gluckman MD, Kolb PDH-J, MD;, and, Alberto MMM,
Marmont M, Kathleen MD, Sobocinski A, Roy MS, Weiner S,
Alfred MD (1992) A. Rimm, PhD, Changing Trends in Alloge-
neic Bone Marrow Transplantation for Leukemia in the 1980s.
JAMA:607–612
58. Zhang X et al (2022) Piezo1-mediated mechanosensation in bone
marrow macrophages promotes vascular niche regeneration after
irradiationinjury.Theranostics12(4):1621–1638
59. Thiele 1 J, Beelen Hmkdw, Pilgram B, Rose A, Leder LD, Schae-
fer UW (2000) Erythropoietic reconstitution, macrophages and
reticulinbrosisinbonemarrowspecimensofCMLpatientsfol-
lowingallogeneictransplantation.Leukemia14:1378–1385
60. vanFurth Ret al(1972)Themononuclearphagocytesystem:a
newclassicationofmacrophages,monocytes,andtheirprecur-
sorcells.BullWorldHealthOrgan46(6):845–852
61. NaikSHetal(2007)Developmentofplasmacytoidandconven-
tional dendritic cell subtypes from single precursor cells derived
invitroandinvivo.NatImmunol8(11):1217–1226
62. Naik SH et al (2006) Intrasplenic steady-state dendritic cell
precursors that are distinct from monocytes. Nat Immunol
7(6):663–671
63. Cavanagh LL et al (2005) Activation of bone marrow-resident
memory T cells by circulating, antigen-bearing dendritic cells.
NatImmunol6(10):1029–1037
64. GoedhartMetal(2021)BoneMarrowharborsaUniquePopula-
tion of dendritic cells with the potential to boost neutrophil for-
mation upon exposure to Fungal Antigen. Cells, 11(1)
65. Sapoznikov A et al (2008) Perivascular clusters of dendritic cells
provide critical survival signals to B cells in bone marrow niches.
NatImmunol9(4):388–395
66. Zhang J et al (2019) Bone marrow dendritic cells regulate
hematopoietic stem/progenitor cell tracking. J Clin Invest
129(7):2920–2931
67. NakamuraYetal(2004)Solublec-kitreceptormobilizeshema-
topoietic stem cells to peripheral blood in mice. Exp Hematol
32(4):390–396
68. Ulyanova T et al (2005) VCAM-1 expression in adult hema-
topoietic and nonhematopoietic cells is controlled by tissue-
inductivesignalsandreectstheirdevelopmentalorigin.Blood
106(1):86–94
69. Quanxing Wang Wz, Guoshan Ding, Lifei Sun, Guoyou Chen,
And Xuetao Cao, Dendritic Cells Support Hematopoiesis Of
BoneMarrowCells,Transplantation(2001)72:Pp.891–899
70. Pulsipher MA et al (2013) Acute toxicities of unrelated bone mar-
rowversusperipheralbloodstemcelldonation:resultsofapro-
spectivetrial fromtheNationalMarrowDonorProgram.Blood
121(1):197–206
71. RonY,SprentJ(1987)Tcellpriminginvivo:amajorroleforB
cells in presenting antigen to T cells in lymph nodes. J Immunol
138(9):2848–2856
72. YanabaKetal(2008)Aregulatory Bcell subsetwithaunique
CD1dhiCD5 +phenotype controls T cell-dependent inamma-
toryresponses.Immunity28(5):639–650
73. Pieper K, Grimbacher B, Eibel H (2013) B-cell biology and
development.JAllergyClinImmunol131(4):959–971
74. BarberisAetal(1990)AnovelB-celllineage-specictranscrip-
tionfactor presentat earlybut notlatestagesofdierentiation.
GenesDev4(5):849–859
75. Zhuang Y, Cheng P, Weintraub H (1996) B-lymphocyte devel-
opment is regulated by the combined dosage of three basic
1 3
Page 17 of 20 420
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
H. Xu et al.
117.GrahamAnderson EJJ, NelC,Moore, OwenJJT(1993) MHC
class II-positive epithelium and mesenchyme cells are both
requiredforT-celldevelopmentinthethymus.Nature362:70–73
118.DefuZengPH,LanF,HuieP,HigginsJ,StroberS(2002)Unique
patterns of surface receptors, cytokine secretion, and immune
functions distinguish T cells in the bone marrow from those in
theperiphery:impactonallogeneicbonemarrowtransplantation.
Blood99:1449–1457
119.TrepelF(1974)Numberanddistributionoflymphocytesinman.
Acriticalanalysis.KlinWochenschr52(11):511–515
120. Goedhart M et al (2019) CXCR4, but not CXCR3, drives CD8(+)
T-cell entry into and migration through the murine bone marrow.
EurJImmunol49(4):576–589
121. Hernandez-Malmierca P et al (2022) Antigen presentation safe-
guards the integrity of the hematopoietic stem cell pool. Cell
StemCell29(5):760–775e10
122. Russell JL, van den Engh G (1979) The expression of histocom-
patibility-2 antigens on hemopoietic stem cells. Tissue Antigens
13(1):45–22
123. Guo L et al (2009) IL-1 family members and STAT activators
induce cytokine production by Th2, Th17, and Th1 cells. Proc
NatlAcadSciUSA106(32):13463–13468
124. Cerny PWPaJ (1999) Characterization of CD4 + T cells in mouse
bone marrow. I. increased activated/memory phenotype and
alteredTCRVirepertoire.EurJImmunol29:1051–1056
125.MonteiroJPetal(2005)Normalhematopoiesisismaintainedby
activated bone marrow CD4 +Tcells.Blood105(4):1484–1491
126.JahandidehBetal(2020)Thepro-inammatorycytokineseects
onmobilization,self-renewaland dierentiation ofhematopoi-
eticstemcells.HumImmunol81(5):206–217
127. Pabst JWaR (1992) Distribution of lymphocyte subsets and natu-
ralkillercellsinthehumanbody.ClinInvestig70:539–544
128. Mazo IB et al (2005) Bone marrow is a major reservoir and site
of recruitment for central memory CD8 + T cells. Immunity
22(2):259–270
129. Di Francesca (2002) Rosa1, 3 and Angela Santoni1,2, bone mar-
rowCD8 Tcellsareinadierentactivationstatethanthosein
lymphoidperiphery.EurJImmunol32:1873–1880
130. Schurch CM, Riether C, Ochsenbein AF (2014) Cytotoxic
CD8 + T cells stimulate hematopoietic progenitors by promoting
cytokine release from bone marrow mesenchymal stromal cells.
CellStemCell14(4):460–472
131. Li S et al (2007) CD8 + T cells suppress autologous megakaryo-
cyte apoptosis in idiopathic thrombocytopenic purpura. Br J Hae-
matol139(4):605–611
132. Zhang XH et al (2015) Recruitment of CD8(+) T cells into bone
marrow might explain the suppression of megakaryocyte apopto-
sis through high expression of CX3CR1(+) in prolonged isolated
thrombocytopenia after allogeneic hematopoietic stem cell trans-
plantation.AnnHematol94(10):1689–1698
133. Terauchi M et al (2009) T lymphocytes amplify the anabolic
activity of parathyroid hormone through Wnt10b signaling. Cell
Metab10(3):229–240
134. Hamzic E et al (2015) Characterization of bone marrow mes-
enchymal stromal cells in aplastic anaemia. Br J Haematol
169(6):804–813
135. Li S et al (2020) Insensitive to PTH of CD8(+) T cells regu-
late bone marrow mesenchymal stromal cell in aplastic anemia
patients.IntJMedSci17(12):1665–1672
136.ZhangJetal(2003)Identicationofthehaematopoieticstemcell
nicheandcontrolofthenichesize.Nature425(6960):836–841
137. Li JY et al (2012) PTH expands short-term murine hemopoietic
stemcellsthroughTcells.Blood120(22):4352–4362
138. Chan-Wang J (2008) Lio1 and chyi-song Hsieh1, a two-step
process for thymic regulatory T cell development. Immunity
28:100–111
97. Suzuki-Yamazaki N et al (2017) IL-10 production in murine
IgM(+) CD138(hi) cells is driven by Blimp-1 and downregulated
inclass-switchedcells.EurJImmunol47(3):493–503
98. Meng L et al (2019) Bone marrow plasma cells modulate local
myeloid-lineage dierentiation via IL-10. Front Immunol
10:1183
99. HaaijmanJJ,H.R.E.S.W.H.M.I.f.EG,RijswijkTN(1977)Immu-
noglobulin-containingcellsin dierent lymphoidorgansof the
CBAmouseduringitslife-span.Immunology32:427–434
100. Pang WW et al (2011) Human bone marrow hematopoietic stem
cells are increased in frequency and myeloid-biased with age.
ProcNatlAcadSciUSA108(50):20012–20017
101.Pioli PD et al (2019) Plasma cells are obligate eectors of
enhanced myelopoiesis in aging bone marrow. Immunity
51(2):351–366e6
102.DorshkindK(1988)IL-1 inhibits b celldierentiationinlong
termbonemarrowcultures.JImmunol141(2):531–538
103. Maeda K et al (2005) IL-6 blocks a discrete early step in lympho-
poiesis.Blood106(3):879–885
104. Burberry A et al (2014) Infection mobilizes hematopoietic stem
cellsthroughcooperativeNOD-likereceptorandtoll-likerecep-
torsignaling.CellHostMicrobe15(6):779–791
105. Fillatreau S et al (2002) B cells regulate autoimmunity by provi-
sionofIL-10.NatImmunol3(10):944–950
106. Matsushita T et al (2008) Regulatory B cells inhibit EAE initia-
tion in mice while other B cells promote disease progression. J
ClinInvest118(10):3420–3430
107. Van de Willem A Straumann3, Terufumi Kubo4, 1 1 1, 5 1
Daniëlle Verschoor, Oliver, Wirz F, Rückert FC-GGTB (2020),
and M.H. Urs Ochsner1, 7, Barbara Stanić1, Marloes van
Splunter1, Daan Huntjens1, Alexandra Wallimann1,6, Rodney
J. Fonseca Guevara1, Hergen Spits8,9, Desislava Ignatova10,
Yun-Tsan Chang10, Christina Fassnacht10, Emmanuella Gue-
nova10,11, Lukas Flatz12,13,14, Cezmi A. Akdis1,2, Mübeccel
Akdis1*, A novel proangiogenic B cell subset is increased in can-
cerandchronicinammation.SciAdv:1–11
108. Lv Y, Wang H, Liu Z (2019) The role of Regulatory B cells
in patients with Acute myeloid leukemia. Med Sci Monit
25:3026–3031
109. de Masson A et al (2015) CD24(hi)CD27(+) and plasmablast-like
regulatory B cells in human chronic graft-versus-host disease.
Blood125(11):1830–1839
110. Sirbulescu RF et al (2021) B cells support the repair of injured
tissues by adopting MyD88-dependent regulatory functions and
phenotype.FASEBJ35(12):e22019
111. Blair PA et al (2010) CD19(+)CD24(hi)CD38(hi) B cells exhibit
regulatory capacity in healthy individuals but are functionally
impaired in systemic Lupus Erythematosus patients. Immunity
32(1):129–140
112.NevesPet al(2010)Signaling viatheMyD88 adaptor protein
in B cells suppresses protective immunity during Salmonella
typhimuriuminfection.Immunity33(5):777–790
113.YangSYetal(2021)CharacterizationofOrgan-SpecicRegula-
toryBcells usingsingle-cellRNAsequencing.Front Immunol
12:711980
114. Yu TS et al (2021) Abnormalities of bone marrow B cells and
plasma cells in primary immune thrombocytopenia. Blood Adv
5(20):4087–4101
115. Zhang L et al (2017) Regulatory B cell-myeloma cell interaction
confers immunosuppression and promotes their survival in the
bonemarrowmilieu.BloodCancerJ7(3):e547
116. Boulassel MR et al (2018) Levels of regulatory T cells and invari-
ant natural killer cells and their associations with regulatory B
cells in patients with non-hodgkin lymphoma. Mol Clin Oncol
9(6):677–682
1 3
420 Page 18 of 20
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
The role of immune cells settled in the bone marrow on adult hematopoietic stem cells
160. Malara A et al (2014) Megakaryocytes contribute to the bone
marrow-matrixenvironmentbyexpressing bronectin, typeIV
collagen,andlaminin.StemCells32(4):926–937
161.ZhaoMetal(2014)Megakaryocytesmaintainhomeostaticqui-
escence and promote post-injury regeneration of hematopoietic
stemcells.NatMed20(11):1321–1326
162. Heazlewood SY et al (2013) Megakaryocytes co-localise with
hemopoietic stem cells and release cytokines that up-regulate
stemcellproliferation.StemCellRes11(2):782–792
163. Bruns I et al (2014) Megakaryocytes regulate hematopoi-
etic stem cell quiescence through CXCL4 secretion. Nat Med
20(11):1315–1320
164.Nakamura-IshizuAetal(2014)Megakaryocytesareessentialfor
HSCquiescencethroughtheproductionofthrombopoietin.Bio-
chemBiophysResCommun454(2):353–357
165. Capitano M (2018) * Liang Zhao,2,* Scott Cooper,1 Chelsea
Thorsheim,2 Aae Suzuki,2 Xinxin Huang,1 Alexander L. Dent,1
Michael S. Marks,3,4 and a.H.E.B. Charles S. Abrams, Phos-
phatidylinositol transfer proteins regulate megakaryocyte TGF-
b1 secretion and hematopoiesis in mice. Blood, 132(10): pp.
1027–1038
166. Jiang J, Kao CY, Papoutsakis ET (2017) How do megakaryocytic
microparticles target and deliver cargo to alter the fate of hemato-
poieticstemcells?JControlRelease247:1–18
167. Wang H et al (2021) Decoding Human Megakaryocyte Develop-
ment.CellStemCell28(3):535–549e8
168. Shu Sun - (2021) * Chen Jin,1–3,* Jia Si,1–3 Ying Lei,1–3 Kuny-
ing Chen,1–3 Yueli Cui,4–6 Zhenbo Liu,1,2 Jiang Liu,1–3 Meng
Zhao,7 Xiaohui Zhang,8–11 and -.M.T.R. Fuchou Tang, 12,13
Yueying Li,1–3* and Qian-fei Wang1-3*, Single-cell analysis of
ploidy and the transcriptome reveals functional and spatial diver-
gencyinmurinemegakaryopoiesis.Blood,138:pp.1211–1224
169.BuechlerMBetal(2013)Cuttingedge:typeIIFNdrivesemer-
gency myelopoiesis and peripheral myeloid expansion during
chronicTLR7signaling.JImmunol190(3):886–891
170.EssersMAetal(2009)IFNalphaactivatesdormanthaematopoi-
eticstemcellsinvivo.Nature458(7240):904–908
171. Keisuke Ito1, Atsushi Hirao1*, Arai F 1, Matsuoka S 1 (2004)
Keiyo Takubo1, Kana Nomiyama1, Kentaro Hosokawa1,
KazuhiroSakurada3,NaomiNakagata4, YasuoIkeda2,TakW.
Mak5, and T. Suda1, regulation of oxidative stress by ATM is
required for self-renewal of haematopoietic stem cells. Nature
431:997–1002
172. Ito K et al (2006) Reactive oxygen species act through p38
MAPKtolimitthelifespanofhematopoieticstemcells.NatMed
12(4):446–451
173. Juntilla MM et al (2010) AKT1 and AKT2 maintain hematopoi-
etic stem cell function by regulating reactive oxygen species.
Blood115(20):4030–4038
174.ZimranE,PapaL,HomanR(2021)Exvivoexpansionofhema-
topoieticstemcells:nallytransitioningfromthelabtotheclinic.
BloodRev50:100853
175. Shi MM et al (2016) Atorvastatin enhances endothelial
cell function in posttransplant poor graft function. Blood
128(25):2988–2999
176. Greenbaum AM, Link DC (2011) Mechanisms of G-CSF-medi-
ated hematopoietic stem and progenitor mobilization. Leukemia
25(2):211–217
177.IsraelF,CharoMD,Ph.D.,and,RansohoRM(2006)M.D.,The
ManyRolesofChemokinesandChemokineReceptorsinInam-
mation.theNEWENGLANDJOURNALOFMEDICINE,354:
pp. 610 – 21
178.PerlinJR, SporrijA,Zon LI(2017) Bloodonthetracks:hema-
topoietic stem cell-endothelial cell interactions in homing and
engraftment.JMolMed(Berl)95(8):809–819
139. Chen W et al (2003) Conversion of peripheral CD4 + CD25- naive
T cells to CD4 + CD25 + regulatory T cells by TGF-beta induc-
tionoftranscriptionfactorFoxp3.JExpMed198(12):1875–1886
140.ThiaultNetal(2015)PeripheralregulatoryTlymphocytesrecir-
culating to the thymus suppress the development of their precur-
sors.NatImmunol16(6):628–634
141. Linhua Zou BB, Safah H, LaRussa VF, Evdemon-Hogan M,
Mottram P, Wei S, David O (2004) Curiel, and Weiping Zou,
Bone Marrow is a Reservoir for CD4 + CD25 + Regulatory T
Cellsthattrac throughCXCL12/CXCR4 signals.CancerRes
64:8451–8455
142. Camacho V et al (2020) Bone marrow tregs mediate stromal cell
function and support hematopoiesis via IL-10. JCI Insight, 5(22)
143. Fujisaki J et al (2011) In vivo imaging of Treg cells providing
immuneprivilege tothehaematopoieticstem-cellniche.Nature
474(7350):216–219
144. Pierini A et al (2017) Foxp3(+) regulatory T cells maintain the
bone marrow microenvironment for B cell lymphopoiesis. Nat
Commun8:15068
145. Hirata Y et al (2018) CD150(high) bone marrow Tregs maintain
hematopoietic stem cell quiescence and Immune Privilege via
Adenosine.CellStemCell22(3):445–453e5
146. Hirata Y et al (2019) CD150(high) CD4 T cells and CD150(high)
regulatoryTcellsregulatehematopoieticstemcellquiescencevia
CD73.Haematologica104(6):1136–1142
147. Aline Bozec MMZ (2014) 1,2* Rosebeth Kagwiria,1 Reinhard
Voll,3 Manfred Rauh,4 ZhuChen,1 SandraMueller-Schmucker,1
RichardA.Kroczek,5 LucieHeinzerling,6 MurielMoser,7 Andrew
L. Mellor,8 Jean-Pierre David,9 Georg Schett1†, T cell Costimu-
lation Molecules CD80/86 inhibit Osteoclast dierentiation by
inducingtheIDO/TryptophanPathway.SciTranslMed6:235
148.LeiHetal(2015)RegulatoryTcell-mediatedanti-inammatory
eectspromotesuccessfultissuerepairinbothindirectanddirect
manners.FrontPharmacol6:184
149. Lin Y et al (2023) Ruxolitinib improves hematopoietic regen-
eration by restoring mesenchymal stromal cell function in acute
graft-versus-host disease. J Clin Invest, 133(15)
150. Chen J, Liu J, Huang H (2023) Lkb1 loss in regulatory T cells
leads to dysregulation of hematopoietic stem cell expansion and
dierentiationinbonemarrow.FEBSOpenBio13(2):270–278
151.Gan B et al (2010) Lkb1 regulates quiescence and meta-
bolic homeostasis of haematopoietic stem cells. Nature
468(7324):701–704
152. Glatman Zaretsky A et al (2017) Regulatory cells support plasma
cellpopulationsinthebonemarrow.CellRep18(8):1906–1916
153. Darrasse-Jèze G et al (2009) Feedback control of regula-
tory T cell homeostasis by dendritic cells in vivo. J Exp Med
206(9):1853–1862
154. Veldhoen M et al (2006) Modulation of dendritic cell func-
tion by naive and regulatory CD4 + T cells. J Immunol
176(10):6202–6210
155. Ebaugh FG Jr., Bird RM (1951) The normal megakaryocyte con-
centrationinaspiratedhumanbonemarrow.Blood6(1):75–80
156. By T, Hamada RM, Hesselgesser iJ (1998) Transendothe-
lial Migration of Megakaryocytes in response to stromal cell-
derived factor 1 (SDF-1) enhances platelet formation. J Exp Med
188:539–548
157.NiswanderLMetal(2014)SDF-1dynamicallymediatesmega-
karyocyte niche occupancy and thrombopoiesis at steady state
andfollowingradiationinjury.Blood124(2):277–286
158. Robert A, Campbell et al (2019) Human megakaryocytes pos-
sess intrinsic antiviral immunity through regulated induction of
IFITM3.Blood133(19):2013–2026
159.Koupenova M, Livada AC, Morrell CN (2022) Platelet and
megakaryocyte roles in Innate and adaptive immunity. Circ Res
130(2):288–308
1 3
Page 19 of 20 420
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
H. Xu et al.
role in transendothelial/stromal migration and engraftment of
NOD/SCIDmice.Blood95(11):3289–3296
Publisher’s note SpringerNatureremainsneutralwithregardtojuris-
dictionalclaimsinpublishedmapsandinstitutionalaliations.
179. By Irina B, Mazo J-CG-R, i Paul S, Frenette RO (1999) Hynes,
and a.U.H.v.A. Denisa D. Wagner, hematopoietic Progenitor Cell
Rolling in Bone Marrow microvessels: parallel contributions
by endothelial selectins and vascular cell adhesion molecule 1.
188:465–474
180. Peled A et al (2000) The chemokine SDF-1 activates the integrins
LFA-1, VLA-4, and VLA-5 on immature human CD34 +cells:
1 3
420 Page 20 of 20
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
1.
2.
3.
4.
5.
6.
Terms and Conditions
Springer Nature journal content, brought to you courtesy of Springer Nature Customer Service Center GmbH (“Springer Nature”).
Springer Nature supports a reasonable amount of sharing of research papers by authors, subscribers and authorised users (“Users”), for small-
scale personal, non-commercial use provided that all copyright, trade and service marks and other proprietary notices are maintained. By
accessing, sharing, receiving or otherwise using the Springer Nature journal content you agree to these terms of use (“Terms”). For these
purposes, Springer Nature considers academic use (by researchers and students) to be non-commercial.
These Terms are supplementary and will apply in addition to any applicable website terms and conditions, a relevant site licence or a personal
subscription. These Terms will prevail over any conflict or ambiguity with regards to the relevant terms, a site licence or a personal subscription
(to the extent of the conflict or ambiguity only). For Creative Commons-licensed articles, the terms of the Creative Commons license used will
apply.
We collect and use personal data to provide access to the Springer Nature journal content. We may also use these personal data internally within
ResearchGate and Springer Nature and as agreed share it, in an anonymised way, for purposes of tracking, analysis and reporting. We will not
otherwise disclose your personal data outside the ResearchGate or the Springer Nature group of companies unless we have your permission as
detailed in the Privacy Policy.
While Users may use the Springer Nature journal content for small scale, personal non-commercial use, it is important to note that Users may
not:
use such content for the purpose of providing other users with access on a regular or large scale basis or as a means to circumvent access
control;
use such content where to do so would be considered a criminal or statutory offence in any jurisdiction, or gives rise to civil liability, or is
otherwise unlawful;
falsely or misleadingly imply or suggest endorsement, approval , sponsorship, or association unless explicitly agreed to by Springer Nature in
writing;
use bots or other automated methods to access the content or redirect messages
override any security feature or exclusionary protocol; or
share the content in order to create substitute for Springer Nature products or services or a systematic database of Springer Nature journal
content.
In line with the restriction against commercial use, Springer Nature does not permit the creation of a product or service that creates revenue,
royalties, rent or income from our content or its inclusion as part of a paid for service or for other commercial gain. Springer Nature journal
content cannot be used for inter-library loans and librarians may not upload Springer Nature journal content on a large scale into their, or any
other, institutional repository.
These terms of use are reviewed regularly and may be amended at any time. Springer Nature is not obligated to publish any information or
content on this website and may remove it or features or functionality at our sole discretion, at any time with or without notice. Springer Nature
may revoke this licence to you at any time and remove access to any copies of the Springer Nature journal content which have been saved.
To the fullest extent permitted by law, Springer Nature makes no warranties, representations or guarantees to Users, either express or implied
with respect to the Springer nature journal content and all parties disclaim and waive any implied warranties or warranties imposed by law,
including merchantability or fitness for any particular purpose.
Please note that these rights do not automatically extend to content, data or other material published by Springer Nature that may be licensed
from third parties.
If you would like to use or distribute our Springer Nature journal content to a wider audience or on a regular basis or in any other manner not
expressly permitted by these Terms, please contact Springer Nature at
onlineservice@springernature.com
Available via license: CC BY-NC-ND 4.0
Content may be subject to copyright.
