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Mesenchymal Stem Cells in Clinical Trials for Immune Disorders

Global Medical Genetics

June 2024
11(03):196-199

DOI:10.1055/s-0044-1788044

License
CC BY 4.0

Authors:

Zongjin Li

Nankai University

Zhong Chao Han

Platelet counts over time in all patients. Platelet counts of all enrolled patients from baseline to 24 weeks after the completion of UC-MSC administration. Reproduced with permission from Chen et al 2024. 6 UC-MSC, umbilical cord-derived mesenchymal stem cell.

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MSCs act as immunomodulators, influencing the behavior of other immune cells to create a more balanced immune response. This property makes them a potential treatment for a wide range of diseases characterized by an imbalanced immune response, such as autoimmune disorders, graft-versus-host disease, and inflammatory conditions. Reproduced with permission from Huang et al 2022. 12 MSC, mesenchymal stem cell.

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Interactions of MSCs with tissue microenvironments after intravenous administration. Reproduced with permission from Leibacher and Henschler 2016. 16 MSC, mesenchymal stem cell.

…

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Editorial

Mesenchymal Stem Cells in Clinical Trials for Immune Disorders

Zongjin Li1Zhibo Han2,3 Zhong-Chao Han3

1Department of Pathophysiology, Nankai University School of

Medicine, Tianjin, China

2Academy of Medical Engineering and Translational Medicine, Tianjin

University, Tianjin, China

3Beijing Engineering Laboratory of Perinatal Stem Cells, Beijing Institute of

Health and Stem Cells, Health & Biotech Co., Beijing, China

Glob Med Genet 2024;11:196–199.

Mesenchymal stem cells (MSCs) are a population of adult

stem cells found in various tissues, including bone marrow,

adipose tissue, and perinatal-related tissues.1MSCs have

emerged as a promising therapeutic approach due to their

unique properties, including regeneration and immunomo-

dulation. The therapeutic mechanism of MSCs is complex

and not fully understood, but they are believed to involve

several different processes. One important mechanism is the

paracrine secretion of growth factors, cytokines, and other

signaling molecules.2,3 These molecules can help to promote

tissue repair, reduce inﬂammation, and modulate the im-

mune system by interacting with various components of

tissue microenvironments and modulating immune

responses.4The immunomodulatory effects of MSCs are

one of their most intriguing and therapeutically valuable

properties.5

A recent prospective, single-arm, phase I trial described

the efﬁcacy and safety of human umbilical cord-derived

MSCs (UC-MSCs) in the treatment of refractory immune

thrombocytopenia (ITP), highlighting the effectiveness and

good tolerance of UC-MSCs in treating refractory ITP.6These

ﬁndings offer insights that may advance our understanding

of the clinical application of MSCs in immune diseases. This

trial revealed that the overall response rate was 44.4% (8/18)

among all enrolled patients with mild adverse events. All

patients in the 2.0 10

cells/kg group achieved a platelet

count of approximately 50 10

/L for up to 28 weeks

(►Fig. 1), which revealed a dose-dependent trend of platelet

count. Most importantly, bleeding symptoms can be

completely relieved in 60.0 to 75.0% of patients after treat-

ment, and no serious treatment-related emergent adverse

events occur.

ITP is an acquired autoimmune hemorrhagic disease

resulting from an i mbalance of immune tolerance. Refractor y

ITP refers to patients who have failed multiple therapies, and

current guidelines have limited effectiveness in alleviating

bleeding symptoms.6In this clinical trial, off-the-shelf GMP

(Good Manufacturing Practice)-grade UC-MSCs from Tianjin

Amcellgene Co., Ltd., were used.7,8 MSCs are also k nown to be

heterogeneous populations with variable functions. Many

studies have comparatively analyzed the differential proper-

ties and biological functions of MSCs derived from perinatal

and adult tissues, including their molecular proﬁles, differ-

entiation potentials, proliferation/clonogenic formation ca-

pacities, immunomodulatory functions, and hematopoietic

support abilit ies. MSCs derived from perinatal tissues such as

the umbilical cord and placenta have attracted attention

because of their noninvasive isolation methods and minimal

ethical issues. Moreover, compared with ad ult tissue-derived

MSCs, perinatal tissue-derived MSCs are young cells without

increased possibilities of mutation.1,5 The banking of UC-

MSCs represents a noninvasive, simple, and safe means for

Address for correspondence

Zongjin Li, MD, PhD, Nankai

University School of Medicine,

Tianjin, China

(e-mail: zongjinli@nankai.edu.cn).

Zhibo Han, MD, Academy of Medical

Engineering and Translational

Medicine, Tianjin University,

Tianjin, China (e-mail: hanzhibo@

health-biotech.com).

Zhong-Chao Han, MD, PhD, Beijing

Engineering Laboratory of Perinatal

Stem Cells,Beijing Instituteof Health

and StemCells, Health & BiotechCo.,

Beijing, China

(e-mail: hanzhongchao@

health-biotech.com).

DOI https://doi.org/

10.1055/s-0044-1788044.

ISSN 2699-9404.

This is an open access article published by Thieme under the terms of the

Creative Commons Attribution License, permitting unrestricted use,

distribution, and reproduction so long as the original work is properly cited.

(https://creativecommons.org/licenses/by/4.0/).

Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart,

Germany

Editorial

THIEME

196

Article published online: 2024-06-27

harvesting MSCs.9In this phase I trial, systemic infusion

of UC-MSCs was applied, and the circulation dynamics of

UC-MSCs were detected by the SRY gene in peripheral blood.

However, UC-MSCs were not detectable in the blood 8 hours

after injection. The therapeutic mechanisms of UC-MSCs

were investigated, and the data revealed a temporary de-

crease in T-cell percentages during the infusion of UC-MSCs,

followed by a gradual increase in the proportion of CD8 þ

CD28suppressive T-cell subsets.

MSCs interact with various components of the immune

system and modulate immune responses in several ways.

First, MSCs can directly interact with T cells through cell

surface molecules such as PD-L1, which binds to the PD-1

receptor on T cells, leading to reduced T-cell proliferation and

activation.10 Secondly, MSCs secrete various soluble factors,

such as prostaglandin E2 (PGE2), indoleamine 2,3-dioxyge-

nase (IDO), transforming growth factor-beta (TGF-β), and

hepatocyte growth factor, all of which contribute to the

suppression of T-cell proliferation and activity.11 In addition,

MSCs inhibit B-cell maturation through the release of soluble

factors such as PGE2 and by producing IDO, decreasing the

differentiation of B cells into plasma cells and reducing

antibody production.12 However, opposite results were ob-

served in which MSCs promoted the proliferation and differ-

entiation of B cells.2Furthermore, MSCs reduce the cytotoxic

activity of natural k iller (NK) cells and their ability to produce

proinﬂammatory cytokines. MSCs inﬂuence macrophages to

adopt an anti-inﬂammatory M2 phenotype rather than a

proinﬂammatory M1 phenotype mediated by MSC-derived

IL-10, TGF-β, and PGE2.13 The immunomodulatory capacity

of MSCs is a critical aspect of their therapeutic potential,

enabling them to create a more favorable environment for

tissue repair and regeneration by modulating immune

responses in a controlled manner (►Fig. 2). The immuno-

modulatory properties of MSCs have signiﬁcant implications

for treating various inﬂammatory and autoimmune condi-

tions, such as graft-versus-host disease, rheumatoid arthri-

tis, multiple sclerosis, systemic lupus erythematosus,

Crohn’s disease, and ulcerative colitis.12

For MSC therapy, intravenous infusions of MSCs are a

prominent priority for repeated injection, noninvasive pro-

cedures, and easy operation. The intravenously trans-

planted MSCs disappeared in a short time, and an

increase in the number of MSCs might not prolong cell

retention. MSCs might interact within the blood circulation

after intravenous administration to function in immuno-

modulation (►Fig. 3). MSCs can modulate the immune

response by interacting with adaptive immune cells and

NK cells and exerting paracrine effects. However, most

MSCs return to and reach the lung after intravenous ad-

ministration.14 Therefore, how intravenously infused MSCs

bridge the spatial gap between the lung and other organs to

achieve immunomodulatory effects remains a challenge.

Recently, the process by which exogenous cells in an organ

affect distant recipient cells in another organ has been recog-

nized as transorgan communication.15 A recent study demon-

strated that intravenous infusion of MSCs could secrete

extracellular vesicles (EVs) and contribute to the therapeutic

effects of MSCs.14 This study revealed that intravenously

transplanted MSCs could serve as an endocrine reservoir to

secrete EVs into the blood continuously and gradually to

promote transorgan communication.

In summary, this phase I trial showed that UC-MSCs can

increase platelet counts and improve bleeding symptoms in

Fig. 1 Platelet counts over time in all patients. Platelet counts of all enrolled patients from baselin eto 24 weeks after the completion of UC-MSC

administration. Reproduced with permission from Chen et al 2024.6UC-MSC, umbilical cord-derived mesenchymal stem cell.

Editorial 197

Fig. 3 Interactions of MSCs with tissue microenvironments after intravenous administration. Reproduced with permission from Leibacher and

Henschler 2016.16 MSC, mesenchymal stem cell.

Fig. 2 MSCs act as immunomodulators, inﬂuencing the behavior of other immunecells to create a more balancedimmune response. This proper ty makes

them a potentialtreatment for a wide range ofdiseases characterizedby an imbalanced immune response, such as autoimmune disorders, graft-versus-host

disease, and inﬂammatory conditions. Reproduced with permission from Huang et al 2022.12 MSC, mesenchymal stem cell.

Editorial198

refractory ITP patients. MSCs have immense potential for

treating various diseases because of their immunomodulatory

properties. Research to address the distribution and metabo-

lism of MSCs in organ tissues is vital to translate thispotential

into effective and widely available clinical applications. As

our understanding of MSCs and their interactions with the

immune system deepens, we can look forward to a future

where MSC therapy becomes a mainstay in treating a broad

spectrum of immune-related conditions, including refrac-

tory ITP.

Authors’Contributions

Z.L. wrote the paper, and Z.H. and Z.C.H. revised and

approved the ﬁnal manuscript.

Funding

This work was supported by grants from the Tianjin Natural

Science Foundation (21JCZDJC00070, 22JCZXJC00170) and

the Nankai University Eye Institute (NKYKD202203).

Conﬂict of Interest

None declared.

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2Ji YR, Yang ZX, Han Z-B, et al. Mesenchymal stem cells support

proliferation and terminal differentiation of B cells. Cell Physiol

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3Zhao Q, Han Z, Wang J, Han Z. Development and investigational

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Editorial 199

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