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The Differentiation and Regeneration Potential of ABCB5 Mesenchymal Stem Cells: A Review and Clinical Perspectives

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Mesenchymal stem cells (MSCs) are a family of multipotent stem cells that show self-renewal under proliferation, multilineage differentiation, immunomodulation, and trophic function. Thus, these cells, such as adipose tissue-derived mesenchymal stem cells (ADSCs), bone marrow-derived MSCs (BM-MSCs), and umbilical cord-derived mesenchymal stem cells (UC-MSCs), carry great promise for novel clinical treatment options. However, the challenges associated with the isolation of MSCs and the instability of their in vitro expansion remain significant barriers to their clinical application. The plasma membrane-spanning P-glycoprotein ATP-binding cassette subfamily B member 5 positive MSCs (ABCB5⁺ MSCs) derived from human skin specimens offer a distinctive advantage over other MSCs. They can be easily extracted from the dermis and expanded. In culture, ABCB5⁺ MSCs demonstrate robust innate homeostasis and a classic trilineage differentiation. Additionally, their ability to modulate the recipients’ immune system highlights their potential for allogeneic applications in regenerative medicine. In this review, we primarily discuss the differentiation potential of ABCB5⁺ MSCs and their perspectives in regenerative medicine.
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Academic Editor: Carlo Finelli
Received: 2 December 2024
Revised: 15 January 2025
Accepted: 19 January 2025
Published: 21 January 2025
Citation: He, Z.; Starkuviene, V.;
Keese, M. The Differentiation and
Regeneration Potential of ABCB5+
Mesenchymal Stem Cells: A Review
and Clinical Perspectives. J. Clin. Med.
2025,14, 660. https://doi.org/
10.3390/jcm14030660
Copyright: © 2025 by the authors.
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Review
The Differentiation and Regeneration Potential of ABCB5+
Mesenchymal Stem Cells: A Review and Clinical Perspectives
Zheng He 1,2, Vytaute Starkuviene 1, 3, *,† and Michael Keese 4 ,*,
1BioQuant, Heidelberg University, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany;
zheng.he@bioquant.uni-heidelberg.de
2European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University,
Ludolf-Krehl-Straße 13-17, 68167 Mannheim, Germany
3Institute of Biosciences, Vilnius University Life Sciences Center, 10257 Vilnius, Lithuania
4Department of Vascular Surgery, Theresienkrankenhaus, Bassermannstraße 1, 68165 Mannheim, Germany
*Correspondence: vytaute.starkuviene@bioquant.uni-heidelberg.de (V.S.);
m.keese@theresienkrankenhaus.de (M.K.); Tel.: +49-6221-5451-259 (V.S.); +49-0621-424-4303 (M.K.)
These authors contributed equally to this work.
Abstract: Mesenchymal stem cells (MSCs) are a family of multipotent stem cells that
show self-renewal under proliferation, multilineage differentiation, immunomodulation,
and trophic function. Thus, these cells, such as adipose tissue-derived mesenchymal
stem cells (ADSCs), bone marrow-derived MSCs (BM-MSCs), and umbilical cord-derived
mesenchymal stem cells (UC-MSCs), carry great promise for novel clinical treatment
options. However, the challenges associated with the isolation of MSCs and the instability
of their
in vitro
expansion remain significant barriers to their clinical application. The
plasma membrane-spanning P-glycoprotein ATP-binding cassette subfamily B member
5 positive MSCs (ABCB5
+
MSCs) derived from human skin specimens offer a distinctive
advantage over other MSCs. They can be easily extracted from the dermis and expanded.
In culture, ABCB5
+
MSCs demonstrate robust innate homeostasis and a classic trilineage
differentiation. Additionally, their ability to modulate the recipients’ immune system
highlights their potential for allogeneic applications in regenerative medicine. In this
review, we primarily discuss the differentiation potential of ABCB5
+
MSCs and their
perspectives in regenerative medicine.
Keywords: ABCB5; mesenchymal stem cells; cell therapy; regeneration
1. Introduction
Mesenchymal stem cells, as non-hematopoietic multipotent stem cells, are capable of
differentiating into mesenchymal tissue lineages, such as adipocytes, osteocytes, chondro-
cytes, and endothelial cells [
1
,
2
]. These cells also regulate immune homeostasis by direct or
indirect influence on immune cells [
3
]. Furthermore, MSCs exhibit an exocrine function, se-
creting growth factors, chemokines, interleukins, and extracellular matrix (ECM) molecules
that are essential for the normal function of tissues and organs [
4
6
]. Initially identified
in bone marrow [
7
], human MSCs have been derived from adipose tissue [
8
,
9
], skeletal
muscle [
10
], placenta [
11
], umbilical cord blood [
12
], and nearly all other adult connective
tissues. To date, MSCs have been shown to play vital roles in regeneration, metabolic
homeostasis, immunomodulation, and trophic functions across various tissues [13].
While recent improvements in people’s quality of life has led to progress in medical
technologies, the epidemiological burden of both chronic local and chronic systemic dis-
eases has simultaneously increased rapidly. For many patients, there remains an unmet
J. Clin. Med. 2025,14, 660 https://doi.org/10.3390/jcm14030660
J. Clin. Med. 2025,14, 660 2 of 19
need for satisfactory treatment options. Since the first clinical therapeutic use of ex vivo-
expanded MSCs for hematologic malignancies in 1995 [
14
], the potential of MSCs has been
explored for a wide array of multiple clinical fields, such as in tissue and organ regeneration,
immune modulation, cardiovascular disorders, and in cancer therapy (Table 1).
Table 1. Potential clinical therapeutic application of human mesenchymal stem cells.
MSC Type Resource Investigated as Potential Therapeutic
Targets Citation
ADSCs Adipose tissue
chronic ischemic cardiomyopathy,
Sjogren’s syndrome, chronic kidney
disease, ovarian cancer,
knee osteoarthritis
[1520]
BM-MSCs Bone marrow
GvHD, aplastic anemia, Parkinson’s
Disease, pulmonary fibrosis, Chronic
Patellar Tendinopathy
[2125]
UC-MSCs Umbilical cord
Psoriasis, peripheral arterial disease,
liver cirrhosis, skin scars,
knee osteoarthritis
[2630]
Placenta-derived MSCs Placenta Perianal fistulae, knee osteoarthritis [27,31]
DPSCs Dental pulp Dental pulp regeneration, intrabony
defects, acute ischemic stroke [3234]
ADSCs: adipose tissue-derived mesenchymal stem cells; GvHD: graft-versus-host disease; UC-MSCs: umbilical
cord-derived mesenchymal stem cells; DPSCs: dental pulp stem cells.
MSCs possess several characteristics that allow them to be employed in therapy, such
as easy isolation,
in vitro
expansion, self-renewal ability, the potential for multilineage
differentiation, trophic functions, and immunomodulatory effects [
35
]. However,
in vitro
morphological abnormalities -and the degeneration or disappearance of specific surface
markers have been observed in bone marrow MSCs [
36
]. Similarly, genomic instability has
been reported in UC-MSCs [
37
]. Consequently, MSCs may exhibit reduced proliferation
and impaired differentiation, which can be attributed to factors such as the donor’s age,
prolonged culture duration, suboptimal media supplements, or culture conditions [
38
].
Moreover, when only a small number of autologous MSCs can be obtained, the process
of
in vitro
expansion can be time-consuming, potentially attenuating the treatment effect.
While induced pluripotent stem cell (iPSC) technology offers a method to generate autolo-
gous MSCs in large quantities, it is limited by low reprogramming efficiency, tumorigenesis
risks, high production costs, and regulatory challenges [
39
]. In contrast, ABCB5
+
MSCs can
be easily isolated from discarded skin tissue and expanded efficiently
in vitro
, offering a
practical and scalable alternative for regenerative therapies.
2. Characteristics of ABCB5+MSCs as a Novel Mesenchymal Stem Cell
ABCB5+MSCs are a distinct subpopulation of dermal MSCs that express the specific
surface marker ABCB5.
In vivo
, these cells are either confined to the peri-vascular endoge-
nous niche, closely associated with CD31
+
endothelial cells, or they can be found dispersed
within the interfollicular dermis independent of hair follicles [
40
]. ABCB5
+
MSCs can be
isolated from enzymatically digested skin tissue by ABCB5 magnetic bead sorting.
These cells are plastic-adherent and exhibit a fibroblastoid, spindle-shape morphology
similar to classic mesenchymal stem cells (Figure 1). When analyzed or sorted by flow
cytometry, ABCB5
+
MSCs express the core mesenchymal lineage markers CD90, CD105,
and CD73 while lacking hematopoietic and lineage-specific markers CD34, CD14, CD20 and
CD45 [
40
,
41
]. Thus, these cells meet the criteria for classification as a distinct mesenchymal
stem population [42].
J. Clin. Med. 2025,14, 660 3 of 19
J. Clin. Med. 2025, 14, x FOR PEER REVIEW 3 of 20
These cells are plastic-adherent and exhibit a broblastoid, spindle-shape
morphology similar to classic mesenchymal stem cells (Figure 1). When analyzed or
sorted by ow cytometry, ABCB5
+
MSCs express the core mesenchymal lineage markers
CD90, CD105, and CD73 while lacking hematopoietic and lineage-specic markers CD34,
CD14, CD20 and CD45 [40,41]. Thus, these cells meet the criteria for classication as a
distinct mesenchymal stem population [42].
Figure 1. ABCB5
+
MSCs. Cultured ABCB5
+
MSCs are shown at passage 5, grown in Hams F10
Medium supplemented with 10% (v/v) FBS, 1% (v/v) penicillin/streptomycin (P/S), and 1% (v/v) L-
glutamine (Scale bar: 100 µm).
ABCB5 is a transmembrane P-glycoprotein that regulates the eux of some
substances, including chemotherapeutic drugs, and is therefore recognized as a multidrug
resistance (MDR) transporter protein [43]. Additionally, ABCB5 is considered a cancer cell
marker, mediating chemoresistance through drug transport [44]. This p-glycoprotein
exhibits a selective tissue expression paern across human physiological tissues and
cancers and can also specically identify a subpopulation of skin progenitor cells [41,45].
Skin-derived ABCB5
+
MSCs can be easily and reliably isolated using a specic
antibody directed against an extracellular-loop sequence of the ABCB5 molecule [45]. In
vitro, cells can be expanded even on a large scale. Therefore, these cells can be
manufactured as a homogeneous, o-the-shelf product for clinical use [46]. They can be
administered topically, intramuscularly, or by intravenous administration as an
advanced-therapy medicinal product (ATMP) [47]. An additional advantage of ABCB5
+
MSCs over classic MSCs, such as ADSCs and BM-MSCs is that ABCB5
+
MSCs can be easily
obtained from discarded skin tissues donated primarily by individuals undergoing plastic
surgery, without the need for ad hoc invasive procedures [46].
Importantly, dermal ABCB5
+
MSCs possess the ability to modulate immune function
by interacting with immune cells including T-cells, neutrophils, and macrophages (Figure
2). ABCB5
+
MSCs can evade immune rejection, home to the recipient immune tissues, and
suppress alloantigen-dependent T-cell proliferation by interacting with programmed cell
Figure 1. ABCB5
+
MSCs. Cultured ABCB5
+
MSCs are shown at passage 5, grown in Ham’s F10
Medium supplemented with 10% (v/v) FBS, 1% (v/v) penicillin/streptomycin (P/S), and 1% (v/v)
L-glutamine (Scale bar: 100 µm).
ABCB5 is a transmembrane P-glycoprotein that regulates the efflux of some substances,
including chemotherapeutic drugs, and is therefore recognized as a multidrug resistance
(MDR) transporter protein [
43
]. Additionally, ABCB5 is considered a cancer cell marker,
mediating chemoresistance through drug transport [
44
]. This p-glycoprotein exhibits a
selective tissue expression pattern across human physiological tissues and cancers and can
also specifically identify a subpopulation of skin progenitor cells [41,45].
Skin-derived ABCB5
+
MSCs can be easily and reliably isolated using a specific anti-
body directed against an extracellular-loop sequence of the ABCB5 molecule [
45
].
In vitro
,
cells can be expanded even on a large scale. Therefore, these cells can be manufactured as a
homogeneous, off-the-shelf product for clinical use [
46
]. They can be administered topi-
cally, intramuscularly, or by intravenous administration as an advanced-therapy medicinal
product (ATMP) [47]. An additional advantage of ABCB5+MSCs over classic MSCs, such
as ADSCs and BM-MSCs is that ABCB5
+
MSCs can be easily obtained from discarded skin
tissues donated primarily by individuals undergoing plastic surgery, without the need for
ad hoc invasive procedures [46].
Importantly, dermal ABCB5
+
MSCs possess the ability to modulate immune function
by interacting with immune cells including T-cells, neutrophils, and macrophages (Figure 2).
ABCB5
+
MSCs can evade immune rejection, home to the recipient immune tissues, and
suppress alloantigen-dependent T-cell proliferation by interacting with programmed cell
death 1 (PD-1) expressed on the ABCB5
+
MSCs and PD-L1 expressed on the host cells. They
also induce splenic CD4
+
CD25
+
Foxp
3+
regulatory T-cells (Tregs)
in vivo
[
41
]. Additionally,
ABCB5
+
MSCs suppress the tissue damage caused by overactivated neutrophils through
the adaptive release of superoxide dismutase 3 (SOD3), which reduces reactive oxygen
species (ROS) levels in the microenvironment. This suppression prevents the formation
of neutrophil extracellular traps (NETs), neutrophil death, and the excessive spillage of
J. Clin. Med. 2025,14, 660 4 of 19
proteases [
48
]. Furthermore, ABCB5
+
MSCs stimulate a phenotypic shift in macrophages
from tumor necrosis factor-alpha (TNF-
α
)- and interleukin-1
β
(IL-1
β
)-secreting M1 pro-
inflammatory macrophages to IL-10-secreting M2 pro-regenerative macrophages, mediated
by the interleukin-1 receptor antagonist (IL-1RA) released from the stimulated ABCB5
+
MSCs [40].
J. Clin. Med. 2025, 14, x FOR PEER REVIEW 4 of 20
death 1 (PD-1) expressed on the ABCB5
+
MSCs and PD-L1 expressed on the host cells.
They also induce splenic CD4
+
CD25
+
Foxp
3+
regulatory T-cells (Tregs) in vivo [41].
Additionally, ABCB5
+
MSCs suppress the tissue damage caused by overactivated
neutrophils through the adaptive release of superoxide dismutase 3 (SOD3), which
reduces reactive oxygen species (ROS) levels in the microenvironment. This suppression
prevents the formation of neutrophil extracellular traps (NETs), neutrophil death, and the
excessive spillage of proteases [48]. Furthermore, ABCB5
+
MSCs stimulate a phenotypic
shift in macrophages from tumor necrosis factor-alpha (TNF-α)- and interleukin-1β (IL-
1β)-secreting M1 pro-inammatory macrophages to IL-10-secreting M2 pro-regenerative
macrophages, mediated by the interleukin-1 receptor antagonist (IL-1RA) released from
the stimulated ABCB5
+
MSCs [40].
Figure 2. Immunomodulatory mechanisms of ABCB5
+
MSCs.
The trophic and exocrine functions of ABCB5
+
MSCs are hallmark features of these
cells. In response to inammatory signals, ABCB5
+
MSCs secrete IL-1RA and produce
angiogenic growth factors such as the vascular endothelial growth factor (VEGF) and
angiogenin (ANG), as well as basement membrane proteins including collagen type VII
and laminin-322 [49–51]. Furthermore, upon short-term interaction with M1
macrophages, ABCB5
+
MSCs upregulate the immune cell recruitment molecules,
including chemokine (C-X-C motif) ligand (CXCL) family members CXCL2 and CXCL10,
and interleukins including IL-1β and IL-6. This suggests that during the early stages of
inammation when macrophages are critical for countering pathogen invasion and
clearing debris from injured sites, ABCB5
+
MSCs may play a role in stimulating
macrophage recruitment.
The angiogenic functions of ABCB5
+
MSCs are largely mediated by VEGF secretion
in response to hypoxic culture conditions through the activation of the hypoxia-inducible
transcription factor 1α (HIF-1α) pathway [49,52]. In db/db mice models, the injection of
ABCB5
+
MSCs has been shown to promote wound healing by enhancing angiogenin
release, which phosphorylates the downstream eector c-Src at Tyr416 position and pS6
ribosomal protein, thereby stimulating VEGFR2 signaling and enhancing growth
Figure 2. Immunomodulatory mechanisms of ABCB5+MSCs.
The trophic and exocrine functions of ABCB5
+
MSCs are hallmark features of these
cells. In response to inflammatory signals, ABCB5
+
MSCs secrete IL-1RA and produce
angiogenic growth factors such as the vascular endothelial growth factor (VEGF) and
angiogenin (ANG), as well as basement membrane proteins including collagen type VII
and laminin-322 [
49
51
]. Furthermore, upon short-term interaction with M1 macrophages,
ABCB5
+
MSCs upregulate the immune cell recruitment molecules, including chemokine
(C-X-C motif) ligand (CXCL) family members CXCL2 and CXCL10, and interleukins
including IL-1
β
and IL-6. This suggests that during the early stages of inflammation when
macrophages are critical for countering pathogen invasion and clearing debris from injured
sites, ABCB5+MSCs may play a role in stimulating macrophage recruitment.
The angiogenic functions of ABCB5
+
MSCs are largely mediated by VEGF secretion
in response to hypoxic culture conditions through the activation of the hypoxia-inducible
transcription factor 1
α
(HIF-1
α
) pathway [
49
,
52
]. In db/db mice models, the injection
of ABCB5
+
MSCs has been shown to promote wound healing by enhancing angiogenin
release, which phosphorylates the downstream effector c-Src at Tyr416 position and pS6
ribosomal protein, thereby stimulating VEGFR2 signaling and enhancing growth signaling.
Simultaneously, collagen deposition and Alpha-Smooth Muscle Actin (
α
-SMA) expression
are induced, facilitating cellular matrix interaction and improving tissue repair and wound
contraction, even in atrophic diabetic dermis [50].
3. Differentiation Potential of ABCB5+MSCs
The classic trilineage differentiation potential of MSCs includes adipocyte, chondro-
cyte, and osteocyte differentiation [
40
]. In addition to that, ABCB5
+
MSCs demonstrate a
myogenic differentiation potential [
53
]. Furthermore, ABCB5
+
MSCs can acquire the phe-
J. Clin. Med. 2025,14, 660 5 of 19
notypic and functional characteristics of endothelial cells [
49
]. However, multiple attempts
to induce hepatocytic lineage differentiation have been unsuccessful (Figure 3).
J. Clin. Med. 2025, 14, x FOR PEER REVIEW 5 of 20
signaling. Simultaneously, collagen deposition and Alpha-Smooth Muscle Actin (α-SMA)
expression are induced, facilitating cellular matrix interaction and improving tissue repair
and wound contraction, even in atrophic diabetic dermis [50].
3. Dierentiation Potential of ABCB5
+
MSCs
The classic trilineage dierentiation potential of MSCs includes adipocyte,
chondrocyte, and osteocyte dierentiation [40]. In addition to that, ABCB5
+
MSCs
demonstrate a myogenic dierentiation potential [53]. Furthermore, ABCB5
+
MSCs can
acquire the phenotypic and functional characteristics of endothelial cells [49]. However,
multiple aempts to induce hepatocytic lineage dierentiation have been unsuccessful
(Figure 3).
Figure 3. Dierentiation potential of ABCB5
+
MSCs.
3.1. Classic Trilineage Dierentiation
The trilineage dierentiation ability, which includes adipogenic, osteogenic, and
chondrogenic dierentiation under specic dierentiation conditions (Table 2), is one of
the hallmark features of MSCs [42] and has also been demonstrated for ABCB5
+
MSCs
[40].
Table 2. Classic trilineage dierentiation conditions of MSCs.
Differentiation
Type Conditions Citation
Adipogenic
differentiation
High glucose DMEM, 10% FBS, 1 µm dexamethasone, 200
µm indomethacin, 10 µg/mL insulin, 0.5 mm
methylisobutyxanthine
[54]
Osteogenic
differentiation
High glucose DMEM, 10% FBS, 50 µM ascorbic acid-2-
phosphate, 10 mm βglycerophosphate and 100 nm
dexamethasone
[54]
Figure 3. Differentiation potential of ABCB5+MSCs.
3.1. Classic Trilineage Differentiation
The trilineage differentiation ability, which includes adipogenic, osteogenic, and
chondrogenic differentiation under specific differentiation conditions (Table 2), is one of
the hallmark features of MSCs [
42
] and has also been demonstrated for ABCB5
+
MSCs [
40
].
Table 2. Classic trilineage differentiation conditions of MSCs.
Differentiation Type Conditions Citation
Adipogenic differentiation
High glucose DMEM, 10% FBS, 1 µm
dexamethasone, 200 µm indomethacin,
10 µg/mL insulin, 0.5 mm
methylisobutyxanthine
[54]
Osteogenic differentiation
High glucose DMEM, 10% FBS, 50 µM
ascorbic acid-2-phosphate, 10 mm
β–glycerophosphate and 100 nm
dexamethasone
[54]
Chondrogenic
differentiation
High Glucose DMEM, 10% FBS, 107M
dexamethasone, 1 µM
ascorbate-2-phosphate, 1% sodium
pyruvate, and 10 ng/mL transforming
growth factor-beta 1 (TGF-β1).
[55]
To further characterize the self-renewal capacity and differentiation potential of
ABCB5
+
MSCs, single cell-derived colony growth was assessed. The results showed
that 75.61% of these colonies exhibited clonogenic growth. Of these, 62.40% retained their
potential to differentiate into trilineage cells. Among those differentiable clones, 29.84%
J. Clin. Med. 2025,14, 660 6 of 19
were bipotent, 7.77% were unipotent for osteogenic differentiation, and none were negative
for all three lineages [
40
]. Interestingly, as donor age increased, ABCB5
+
cells demonstrated
an increased adipogenic differentiation capacity, which was accompanied by a reduced
ability for chondrogenic and osteogenic differentiation [56].
3.2. Endothelial-like Cell Differentiation
The ability of MSCs to differentiate into endothelial cells holds significant promise
for cardiovascular regeneration and angiogenesis [
57
,
58
]. ABCB5
+
MSCs can differentiate
into functional endothelial-like cells under special conditions. During an angiogenic
trans-differentiation assay, induced with a basic dose of recombinant human (rh) VEGF,
rhFGF-2, and rhPDGF-BB for 96 h, ABCB5
+
MSCs exhibited the increasing expression of
CD31 and Ki67, adopting the characteristics of proliferating endothelial cells. In contrast,
undifferentiated ABCB5+MSCs do not express CD31 [41,49].
Further evidence of endothelial differentiation was observed after the topical appli-
cation with low, mid, and high doses of human-derived ABCB5
+
MSCs to punch biopsy
wounds in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice, which have severe immun-
odeficiency. A dose-dependent increase in CD31 expression was detected, accompanied
by a decrease in wound size, providing additional support for the endothelial differen-
tiation capacity of ABCB5
+
MSCs [
59
]. Additionally, endothelial-differentiated ABCB5
+
MSCs formed capillary-like structures similar to those generated by human umbilical vein
endothelial cells (HUVECs) when cultured on a Geltrex™ gel matrix [49].
Animal experiments have further corroborated these findings. In a hind limb ischemia
model, the intramuscular injection of ABCB5
+
MSCs into Oncins France 1 (OF1) mice (a
strain characterized by rapid growth) resulted in increased perfusion recovery, enhanced
capillary proliferation, and vascularization [
49
]. Under physiological conditions, human
ABCB5
+
MSCs are primarily located in a peri-vascular endogenous niche, where they are
closely associated with CD31+endothelial cells [40].
3.3. Myogenic Differentiation Potential
Adult stem cells and muscle satellite cells play a pivotal role in muscle regenera-
tion
[60,61].
When the natural regeneration capacity of skeletal muscle tissue is insufficient,
it can lead to volumetric muscle loss (VML), which may result in chronic functional im-
pairment and even functional disability. Therefore, the regeneration of myogenic tissue
has become a focus of therapeutic interest. To date, MSCs derived from various tissues
including adipose tissue, bone marrow, skeletal muscle, umbilical cord tissue, and urine
have been differentiated into smooth muscle cells and skeletal muscle cells
in vitro
[
62
64
].
ABCB5
+
MSCs have also been shown to form human spectrin- and
δ
-sarcogly-
expressing skeletal myofibers, accelerating skeletal muscle regeneration in a mouse skeletal
muscle injury model. This finding highlights their myogenic differentiation potential
in vivo
[
53
]. As ABCB5
+
MSCs can be more easily derived from human tissues than other
MSCs [
51
], studies are currently optimizing their ability to fully differentiate into myogenic
tissues in vitro and in vivo.
3.4. Hepatocytic Differentiation Potential
In the search for liver replacement therapies, previous studies have explored whether
MSCs can differentiate into cells of the hepatocytic lineage. An established single-step
protocol [
65
], which has recently been used in other MSCs, was tested on ABCB5
+
MSCs.
While these cells failed to acquire the typical characteristics of hepatocytes after 14 days
of incubation in the differentiation medium [
66
], the cells expressed thrombospondin 1,
HGF, and monocyte chemoattractant protein 1 (MCP-1), all of which are involved in tissue
J. Clin. Med. 2025,14, 660 7 of 19
remodeling and morphogenesis in the liver [
66
,
67
]. It remains to be seen if further cell
culture protocols can induce clear hepatocytic differentiation.
4. The Therapeutic Potential of MSCs
The sources of MSCs-based therapy can be categorized into the following two types:
(1) autologous, where cells are derived from patients themselves, defined as self-to-self
therapy, and (2) allogeneic, where cells are isolated and expanded from healthy donors for
the treatment. In general, MSCs exhibit low immunogenicity, allowing their application
without the need for any immunosuppressive treatment in clinical settings [
13
,
68
]. This is
particularly significant given the limited availability of resources. Autologous applications
are often more time-consuming and costly for patients. In addition, both the limited
quantity and poor quality of the MSCs obtained from older patients or those with systemic
diseases, such as diabetes, significantly reduce the effectiveness of autogenous MSCs-
based treatments.
In contrast, allogenic ABCB5
+
MSCs, derived from rigorously selected donors and
expanded to a ready-to-use scale with proven purity, potency, safety, and tolerability, hold
the most promise for clinical applications.
5. Potential Clinical Applications of ABCB5+MSCs
After more than 20 years of development, MSCs-based therapy has expanded into a
wide range of clinical applications. As of 10 March 2024, over 1450 clinical trials involving
MSCs have been registered in the public clinical trial database, http://clinicaltrials.gov.
These trials address a variety of diseases affecting multiple systems and multiple organs.
ADSCs, in particular, have been clinically applied in fields such as orthopedics, cardiology,
and nephrology [
17
,
20
,
69
], and they also hold potential for angiogenesis [
70
]. Additionally,
the clinical applications of ABCB5
+
MSCs have been evaluated in several studies (Table 3).
Table 3. Summary of literature on the (potential) clinical applications of ABCB5+MSCs.
Clinical Application Study Type Reference
Chronic venous ulcer Clinical (Human) [59,71]
Diabetic foot ulcer Preclinical and Clinical [49,50]
Recessive dystrophic
epidermolysis bullosa Preclinical and Clinical [7275]
Chronic liver disease Preclinical (Animal) [66,67]
Graft-versus-Host Disease Preclinical (Animal) [41]
5.1. Chronic Skin Wounds
Wound healing is influenced by multiple factors, including depth, location, patients’
ages, and comorbidities. Chronic wounds fail to progress through the normal, orderly
sequence of repair required to restore normal tissue anatomy and function. These wounds
are typically characterized by elevated levels of cytokines and proteases, which degrade
essential ECM components, growth factors, and growth factor receptors [76].
MSCs have been shown to accelerate wound closure by reducing inflammation, en-
hancing angiogenesis, promoting re-epithelialization, and improving granulation [
77
,
78
].
Human skin-derived ABCB5
+
MSCs exhibit skin-homing and engraftment properties [
51
].
These cells facilitate the transition of an M1 pro-inflammation macrophage to an M2 pro-
regeneration macrophage, suppress ROS level and NET formation, and exert trophic effects
involved in angiogenesis and ECM remodeling [
40
,
48
,
49
,
51
]. These findings highlight the
potential therapeutic benefits of ABCB5+MSCs in the treatment of chronic wounds.
J. Clin. Med. 2025,14, 660 8 of 19
5.1.1. Chronic Venous Ulcers
Chronic venous ulcers (CVUs) account for approximately 75% of all leg wounds and
typically develop in the medial lower leg. These ulcers are primarily caused by chronic ve-
nous insufficiency, which results from conditions such as varicose veins or post-thrombotic
syndrome and leads to chronic venous hypertension in the affected tissue. Consequentially,
hemosiderin, derived from extravasated erythrocytes, induces macrophages to shift into
an iron-overloaded M1 pro-inflammatory state. These macrophages overexpress inflam-
matory mediators, including TNF-
α
and IL-1
β
, which exacerbate inflammation. Excessive
oxidative stress, caused by increased levels of ROS, promotes cell senescence and apoptosis,
contributing to tissue destruction and dermal disintegration. Furthermore, immune cells
secrete matrix metalloproteinases (MMP), such as MMP-2 and MMP-9, which degrade
the ECM and inhibit the progression to the proliferative stage of healing. Bacterial super-
infection of the wound may further perpetuate the inflammatory phase [
79
,
80
]. ABCB5
+
MSCs abrogate the M1 pro-inflammation state of macrophages and shift them into an M2
pro-regeneration state by secreting IL-1RA [
40
]. These cells are an option for the treatment
of therapy-resistant chronic venous ulcers.
Most clinical modalities for treating venous ulcers target venous hypertension. How-
ever, there is a certain percentage of patients who fail to respond to standard treatment. In
a first-in-human phase 1/2a clinical trial (NCT02742844), published in 2021 [
59
], investi-
gated autologous ABCB5
+
MSCs in 9 patients with 12 standard-treatment refractory CVUs
(9 target and 3 non-target wounds). Wounds were debrided under local anesthesia, and
a suspension of ABCB5
+
MSCs containing 1
×
10
7
cells/mL was applied to the wound
surface at a concentration of 5
×
10
5
cells/cm
2
wound area. The wounds were immediately
covered with Tegaderm film dressing, which was replaced by foam dressings after 1–3 days
and maintained until week 12, along with the standard compression dressings. Of the nine
target ulcers, six were eligible to determine treatment efficacy. By week 6, a median wound
size reduction of 59% (range, 29–84%) was observed, increasing to 63% (range, 32–100%) by
week 12. Patients reported improved wound quality and early pain relief, with no adverse
events related to cell treatment during a 12-month safety follow-up. Furthermore, this
trial first evaluated the efficacy and safety of autologous ABCB5
+
MSCs. For this, the cells
were expanded ex vivo following a strict standard, allowing them to generate a highly
functional homogeneous cell population manufactured as an ATMP. The producer ensured
the identity, vitality, viability, and potency of these cells as well as the purity and stability
of manufactured pharmaceutical products at the same time [59].
Based on this clinical trial using autologous ABCB5
+
MSCs, an interventional, mul-
ticenter, single-arm trial with allogeneic ABCB5
+
MSCs was conducted (NCT03257098).
The treatment involved the topical application of ABCB5
+
MSCs at a dose of 1
×
10
6
cells/cm
2
, followed by film dressing replacement with foam dressing after 1–3 days, along-
side standard compression dressings. A total of 31 patients with therapy-refractory ulcers
(wounds without decrease or increase above 25% after standard care) received treatment,
with 22 patients undergoing two administrations 6 weeks apart and 9 patients receiving
a single treatment. By week 12, 21 patients responded, achieving a median wound size
reduction of 87%, with 29% (6 of 21) of wounds showing complete wound closure. Up to
3 treatment-emergent adverse events (TEAEs) related to the cell product were reported,
including increased wound exudation, erythema, and venous ulcer pain, all of which were
mild or moderate and recovered without sequelae [
71
]. A subsequent larger, random-
ized, placebo-controlled, double-blind phase 2b clinical trial with a dose-ranging design is
ongoing (NCT04971161).
J. Clin. Med. 2025,14, 660 9 of 19
5.1.2. Diabetic Foot Ulcer
Diabetic foot syndrome (DFS) is one detrimental complication of diabetics, resulting
from poor glycemic control, peripheral vascular diseases, neuropathy, trauma, and im-
paired resistance to infection [
81
,
82
]. It often leads to recurrent infections, hospitalizations,
gangrene, and, in severe cases, amputation thus imposing a significant financial burden
on the health system. The potential capacity of MSCs in improving diabetic foot ulcer
healing has gained considerable attention. Up to now, both bone marrow-derived MSCs
and adipose-derived MSCs have been used as novel treatment options in diabetic foot
ulcers in both preclinical and clinical trials [83].
In vitro
, the peripheral vascular ischemia associated with diabetic patients can be
simulated by hypoxia in cell culture chambers. Under hypoxia, ABCB5
+
MSCs have
been shown to secrete VEGF through the HIF-1
α
pathway, increasing the expression of
endothelial-lineage marker CD31 and facilitating the formation of capillary-like structures
on a gel matrix [
49
,
52
]. Furthermore, the injection of ABCB5
+
MSCs at the edge of the
non-healing wounds in the diabetic db/db mice enhanced angiogenesis and accelerated
wound closure. These effects were significantly reduced when angiogenin was silenced in
ABCB5
+
MSCs before injection, indicating that ABCB5
+
MSCs may play a critical role in
the regenerative therapy of diabetic foot ulcers [50].
In a clinical trial (NCT03267784), one or two topical applications of ABCB5
+
MSCs at a
dose of 2
×
10
6
cells/cm
2
to therapy-refractory diabetic foot ulcers lead to a median wound
surface area reduction of 59% (full analysis set, n = 23), 64% (per-protocol set,
n = 20
)
and 67% (subgroup of responders, n = 17) by week 12. Complete wound closure was
achieved in six patients (26%, 30%, and 35% of patients in the full analysis set, per-protocol
set, and a subgroup of responders, respectively). No treatment-related adverse events were
observed [49].
5.1.3. Recessive Dystrophic Epidermolysis Bullosa
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, inherited, life-threatening
skin disease characterized by recurring, chronic non-healing wounds accompanied by pain
and itching. The condition is caused by mutations in the Col7a1 gene, leading to a defi-
ciency in functional collagen VII (C7). C7 promotes keratinocyte re-epithelization through
interaction with laminin-332 in hemidesmosomes, supports fibroblast migration, and regu-
lates cytokine production [
84
,
85
]. Systemic immunological defects in RDEB contribute to
an intrinsic pro-inflammatory state with high levels of cytokines, such as IL-1
β
, IL-2, and
IL-6. Extensive neutrophil infiltration and activation of CD38
+
inflammatory macrophages
further exacerbate tissue damage and chronic inflammation [
86
88
]. Although no curative
therapy exists for RDEB, stem cell-based therapies may lead to wound regeneration thus
alleviating symptoms [89].
Given their immunomodulatory properties and strong skin-homing ability, ABCB5
+
MSCs are promising candidates for RDEB therapy [
51
]. To verify this
in vivo
, the influence
of ABCB5
+
MSCs on RDEB was evaluated in an immunodeficient Col7a1
/
mouse
model of RDEB with blistered wounds. In this mouse strain, the clustered regularly
interspaced short palindromic repeats and associated nuclease (CRISPR/Cas9) system were
combined with microinjection into NOD/SCID IL2r
γ
cnull (NSG) embryos to knock out the
Col7a1
/
gene. These mice develop spontaneous blisters and wounds characteristic of
skin fragility seen in RDEB [
72
]. Treatment with 5
×
10
5
ABCB5
+
MSCs in 10
µ
L volume
via facial vein injection significantly improved general health status and survival compared
to non-transplanted controls.
Webber and colleagues suggested that the therapeutic effect and enhanced survival
could be attributed primarily to the immunomodulatory function of ABCB5
+
MSC, which
J. Clin. Med. 2025,14, 660 10 of 19
was supported by a significant reduction of skin infiltration with macrophages observed in
the ABCB5
+
MSC-treated Col7a1-knockout mice [
72
]. Another group compared ABCB5
+
MSCs to BM-MSCs. After intravenous injection into NOD-scid IL2r
γ
null (NSG) mice with
full-thickness dorsal skin wounds, ABCB5
+
MSCs showed a better skin engraftment poten-
tial than BM-MSCs, which the authors attributed to an increased expression of HOXA3.
ABCB5
+
MSCs furthermore showed an expression of C7 while bone marrow-derived MSCs
did not, even though they secrete the immunosuppressive IL-1RA [51].
In a phase 1/2a clinical trial (NCT03529877), 14 patients with RDEB received three
intravenous infusions of 2
×
10
6
ABCB5
+
MSCs/kg body weight on days 0, 17, and 35.
The treatment led to significant reductions in disease activity, itch, and pain scores [
73
].
A post-hoc analysis of 168 evaluable wounds that were present at baseline [
74
] showed
that the therapy facilitated wound closure compared to historical placebo data. Approxi-
mately 75% of closed wounds remained permanently closed for at least 7 to 9.5 weeks, a
period significantly longer than the typical recurrence interval of RDEB wounds, which
averages around 3 weeks [
75
]. Similar outcomes were observed in a post-hoc analysis
of 174 evaluable wounds that were newly developed over time [
90
]. Nearly half (44%)
of these wounds occurred by day 17, while only 28% developed by day 35, and another
28% emerged over a longer 7-week period, indicating that ABCB5
+
MSCs may delay the
occurrence of new wounds. Moreover, the wounds that developed by day 17 exhibited
a higher proportion of rapid healing (56% within 18 days) compared to baseline wounds
(27% within 17 days). Of these early healing wounds, 88% remained stably closed for at
least 7 weeks. These findings collectively support the application of ABCB5
+
MSCs as
a therapeutic option for symptomatic RDEB patients. A subsequent larger, randomized,
placebo-controlled, double-blind phase 3 clinical trial is ongoing (NCT05464381).
5.2. Chronic Liver Disease
Chronic liver disease (CLD) can lead to fibrosis and cirrhosis, conditions characterized
by ongoing inflammation, destruction, and regeneration of liver parenchyma, accompanied
by a progressive deterioration of liver function. This decline impairs the liver’s ability to
synthesize proteins (e.g., clotting factors), detoxify harmful substances, and excrete bile.
The etiology of CLD is diverse and includes alcoholic liver disease, non-alcoholic fatty
liver disease (NAFLD), liver toxins, autoimmune hepatitis, chronic viral hepatitis, and
genetic disorders such as alpha-1 antitrypsin deficiency, hereditary hemochromatosis, and
Wilson’s disease [
91
]. From a pathophysiological perspective, the inflammatory response
in CLD triggers the activation of hepatic stellate cells (HSCs), which, in turn, leads to
chemokine-mediated infiltration of immune cells, including macrophages, neutrophils,
monocytes, natural killer (NK) cells, and natural killer T (NKT) cells. These immune cells
collectively contribute to the progression of liver fibrosis [92,93].
When cultured in a hepatocytic differentiation medium, ABCB5
+
cells secrete a variety
of cytokines, chemokines, and growth factors, including vascular cell adhesion molecule
1 (VCAM-1), HGF, and MCP-1. These factors play key roles in tissue remodeling, mor-
phogenesis, inflammation, and immune regulation in liver repair. These
in vitro
findings
suggest that ABCB5
+
MSCs may contribute to or even prompt hepatic morphogenesis
during tissue remodeling after liver injury [
66
]. While BM-MSCs have been shown to
differentiate into fibrogenic myofibroblasts and potentially exacerbate fibrosis [
94
], ABCB5
+
MSCs demonstrated no such effects in the Mdr2KO mice, a model of induced liver fibrosis
and partial liver resection. Injection of ABCB5
+
MSCs into these mice did not result in liver
damage, inflammation, or fibrosis. Moreover, there was no increase in pro-inflammatory
cytokine expression, including IL1B and IL6, while tissue inhibitors of metalloproteinases
1 (TIMP1) showed a decreasing trend. Post-transplantation, there was no indication of
J. Clin. Med. 2025,14, 660 11 of 19
toxicity, and the key health indicators such as body weight, liver-to-body weight ratio, and
liver function parameters remained within the normal ranges, demonstrating a favorable
safety profile. Additionally, ABCB5
+
MSC treatment reduced collagen deposition and
decreased the number of activated HSCs, further supporting its anti-fibrotic potential [
67
].
Taken together, these findings suggest that ABCB5
+
MSCs may carry therapeutic
potential for chronic liver diseases by attenuating fibrosis and promoting functional recov-
ery through their immunomodulatory and trophic effects. However, further
in vivo
and
in vitro studies are required to confirm and expand upon these findings.
5.3. Graft-Versus-Host Disease
GvHD is a serious complication of allogeneic hematopoietic stem cell transplantation
(HSCT), characterized by a wide range of symptoms, including skin rash, gastrointestinal
dysfunction, and cholestatic liver disease. GvHD arises from a systemic cytotoxic attack
by alloantigen-specific donor T cells delivered with the graft [
95
97
]. The progression of
GvHD typically occurs in three distinct steps. First, tissue damage caused by pre-transplant
conditioning regimens and/or concurrent inflammatory processes triggers the secretion
of pro-inflammatory cytokines, such as TNF-
α
and IL-1, which activate the host antigen-
presenting cells (APCs). Second, following HSCT, these activated APCs cross-present host
antigens to donor T cells, leading to their allo-activation and proliferation. Finally, cytotoxic
donor T lymphocytes (CTLs) directly damage tissues through the induction of apoptosis
and necrosis [98].
ABCB5
+
MSCs have demonstrated the ability to suppress T-cell proliferation, evade
immune rejection, home to the recipient immune tissues, and induce Tregs
in vivo
through
interactions between PD-1 expressed on ABCB5
+
MSCs and PD-L1 expressed on the
host cells. These properties suggest that ABCB5
+
MSCs may hold significant potential
in treating GvHD [
41
]. Additionally, ABCB5
+
MSCs have been shown to modulate the
immune response by reducing the secretion of TNF-
α
and IL-2, two cytokines critical in
the development of GvHD, while concurrently increasing IL-10, a cytokine essential for
limiting GvHD progression [
40
,
99
101
]. However, further evidence is needed to confirm
the safety and efficacy of ABCB5+MSCs in potential clinical applications.
6. Discussion and Clinical Perspectives
The differentiation ability of ABCB5
+
MSCs has been demonstrated across multiple
experimental settings, highlighting their potential in tissue regeneration. Research into
their ability to differentiate into endothelial and myogenic cells, alongside optimizing
differentiation protocols, could uncover critical underlying mechanisms and broaden
clinical applications in regenerative medicine. Recently, the following two distinct types of
ABCB5
+
stem cells have been identified: human skin-derived ABCB5
+
MSCs and ABCB5
+
limbal stem cells [
102
,
103
]. The differentiation potential of these two cell types remains
an area of great interest and warrants further investigation. In particular, the potential
application of ABCB5
+
stem cells in ophthalmology is especially promising. For instance,
investigating whether and how ABCB5
+
MSCs can differentiate into corneal cells could
pave the way for innovative treatments for ocular diseases.
Traditionally, cell experiments have relied on 2D culture models, which fail to cap-
ture the complexity of human physiology. The emergence of 3D culture models provides
a more accurate representation of physiological and pathological conditions, providing
valuable insights into the immunomodulatory and regenerative properties of MSCs. Ap-
plying these advanced models may further characterize the unique properties of ABCB5
+
MSCs [104,105].
J. Clin. Med. 2025,14, 660 12 of 19
Although ABCB5 has been extensively studied in cancer biology, emerging evidence
suggests that it is also expressed by normal cells [
106
]. The prospect of MSCs-based thera-
pies in cancer is another fascinating facet of cutting-edge research. As a transmembrane
P-glycoprotein regulating the efflux of substances as an MDR transporter, ABCB5 regulates
the efflux of various substances, potentially enabling skin-derived ABCB5
+
MSCs to in-
terfere with drug resistance in cancers such as melanoma, thereby enhancing the efficacy
of chemotherapy.
Since MSCs are extensively studied and applied in clinical treatment, like regenerative
medicine, it is crucial to ensure their long-term safety, therapeutic efficacy, and close moni-
toring for any toxicities. Reports on traditional MSCs, including ADSCs and BM-MSCs,
have shown promising results across various conditions, demonstrating the safety, effec-
tiveness, and tolerability of MSC-based therapies. Similarly, clinical data on ABCB5
+
MSCs
have also confirmed their efficacy, stability, and safety. Nonetheless, extended long-term
studies are necessary to further validate these findings and ensure consistent outcomes.
To summarize, ABCB5
+
MSCs represent a novel and promising lineage of stem cells
that can currently be produced through rigorous manufacturing processes that ensure
homogeneity, potency, and safety. While ongoing research continues to validate their
efficacy and expand their clinical applicability, their unique properties and demonstrated
therapeutic potential already make them valuable tools in regenerative medicine and
clinical treatments.
Building on this foundation, ABCB5
+
MSCs hold great promise for broader clinical
applications in the future. Future research could investigate their roles in cardiovascular
regeneration, hepatic remodeling, autoimmune and non-autoimmune diseases, cancer
therapy and, as mentioned, ocular diseases. Emerging technologies, such as genetic engi-
neering, may unlock new possibilities for optimizing their differentiation, expansion, and
therapeutic efficacy. For example, their skin-homing ability, unique immunomodulatory
properties, and multilineage differentiation capabilities make them ideal candidates for
integration with gene therapy. By utilizing tools like CRISPR/Cas9, ABCB5
+
MSCs can
serve as carriers for therapeutic genes, addressing genetic disorders, such as hereditary skin
diseases and cancers. Additionally, their potential to enhance the engraftment and long-
term survival of gene-edited cells could significantly improve the stability and effectiveness
of gene therapies.
In postoperative recovery, ABCB5
+
MSCs may accelerate tissue regeneration and
minimize inflammation by secreting angiogenic factors like VEGF and promoting the
phenotypic shift of macrophages from the pro-inflammatory state to the pro-regenerative
state. These properties provide them with an essential role in complex surgical procedures,
such as vascular reconstructive surgeries and organ transplants, where improved healing
and reduced immune rejection are crucial. With continued advancements in research and
clinical applications, ABCB5
+
MSCs hold the potential to address unmet clinical needs
across diverse fields of medicine.
Author Contributions: Conceptualization, V.S. and M.K.; Writing—Original Draft Preparation, Z.H.;
Writing—Review and Editing, V.S. and M.K.; Supervision, V.S. and M.K. All authors have read and
agreed to the published version of the manuscript.
Funding: This work was supported by the program of China Scholarships Council (No. 202208500035)
awarded to He.
Conflicts of Interest: The authors declare no conflicts of interest.
J. Clin. Med. 2025,14, 660 13 of 19
Abbreviations
MSCs Mesenchymal stem cells
ADSCs Adipose tissue-derived mesenchymal stem cells
BM-MSCs Bone marrow-derived MSCs
UC-MSCs Umbilical cord-derived mesenchymal stem cells
ABCB5+MSCs ATP-binding cassette subfamily B member 5 positive MSCs
ECM Extracellular Matrix
GvHD Graft-versus-host disease
DPSCs Dental pulp stem cells
iPSC Induced pluripotent stem cell
MDR Multidrug resistance
ATMP Advanced-therapy medicinal product
PD -1 Programmed cell death 1
Tregs Regulatory T-cells
SOD3 Superoxide dismutase 3
ROS Reactive oxygen species
NET Neutrophil extracellular traps
TNF-αTumor necrosis factor-alpha
IL-1βInterleukin-1β
IL-1RA Interleukin-1 receptor antagonist
VEGF Vascular endothelial growth factor
PDGF Platelet-derived growth factor
ANG Angiogenin
HGF Hepatocyte growth factor
FGF Fibroblast growth factor
CXCL Chemokine (C-X-C motif) ligand
HIF-1αHypoxia-inducible transcription factor 1α
α-SMA Alpha-Smooth Muscle Actin
TGF-β1 Transforming growth factor-beta 1
HUVECs Human umbilical vein endothelial cells
OF1 Oncins France 1
VML Volumetric Muscle Loss
MCP-1 Monocyte chemoattractant protein 1
CVU Chronic venous ulcers
MMP Matrix metalloproteinases
TEAEs Treatment-emergent adverse events
DFS Diabetic foot syndrome
SPs Stromal precursors
RDEB Recessive dystrophic epidermolysis bullosa
CRISPR/Cas9 Clustered regularly interspaced short palindromic repeats
C7 Collagen VII
CLD Chronic liver disease
NAFLD Non-alcoholic fatty liver disease
HSCs Hepatic stellate cells
NK Natural killer
NKT Natural killer T
VCAM-1 Vascular cell adhesion molecule 1
TIMP1 Tissue inhibitors of metalloproteinases 1
HSCT Hematopoietic stem cell transplantation
APCs Antigen-presenting cells
CTLs Cytotoxic T lymphocytes
J. Clin. Med. 2025,14, 660 14 of 19
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