Int. J. Med. Sci. 2023, Vol.

20 1492

Ivyspring
International Publisher International Journal of Medical Sciences
2023; 20(11): 1492-1507. doi: 10.7150/ijms.87472
Review

Human umbilical cord mesenchymal stem cells in

diabetes mellitus and its complications: applications and
research advances
Luyao Li1, Jicui Li2, Haifei Guan1, Hisashi Oishi3, Satoru Takahashi4 and Chuan Zhang1,
1. Department of Endocrinology, the Second Hospital of Jilin University, Changchun 130041, Jilin, P.R. China.
2. Department of Nephrology, the Second Hospital of Jilin University, Changchun 130041, Jilin, P.R. China.
3. Department of Comparative and Experimental Medicine, Nagoya City University Graduate 24 School of Medical Sciences, Aichi 467-8601, Nagoya, Japan.
4. Institute of Basic Medical Sciences and Laboratory Animal Resource Center, University of Tsukuba, Ibaraki 305-8575, Tsukuba, Japan.

 Corresponding author: Department of Endocrinology, the Second Hospital of Jilin University, Changchun 130041, Jilin, P.R. China; E-mail:
wangs93@sina.com.

© The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/).
See http://ivyspring.com/terms for full terms and conditions.

Received: 2023.06.25; Accepted: 2023.08.22; Published: 2023.09.11

Abstract
Diabetes mellitus and its complications pose a major threat to global health and affect the quality of life
and life expectancy of patients. Currently, the application of traditional therapeutic drugs for diabetes
mellitus has great limitations and can only temporarily control blood glucose but not fundamentally cure
it. Mesenchymal stem cells, as pluripotent stromal cells, have multidirectional differentiation potential,
high self-renewal, immune regulation, and low immunogenicity, which provide a new idea and possible
development direction for diabetes mellitus treatment. Regenerative medicine with mesenchymal stem
cells treatment as the core treatment will become another treatment option for diabetes mellitus after
traditional treatment. Recently, human umbilical cord mesenchymal stem cells have been widely used in
basic and clinical research on diabetes mellitus and its complications because of their abundance, low
ethical controversy, low risk of infection, and high proliferation and differentiation ability. This paper
reviews the therapeutic role and mechanism of human umbilical cord mesenchymal stem cells in diabetes
mellitus and its complications and highlights the challenges faced by the clinical application of human
umbilical cord mesenchymal stem cells to provide a more theoretical basis for the application of human
umbilical cord mesenchymal stem cells in diabetes mellitus patients.
Keywords: umbilical cord, mesenchymal stem cells, diabetes mellitus, pluripotent, clinical application, regenerative medicine

Introduction
Diabetes mellitus (DM) is the most prevalent with a combination of impaired hypoglycaemic
metabolic disorder caused by the inability of the awareness and severe hypoglycaemic episodes (2).
pancreas to secrete insulin adequately or the body’s However, islet transplantation may be greatly limited
inability to use insulin effectively. According to the in clinical application due to a shortage of donor islets
9th edition of the International Diabetes Federation and immune rejection. Drug therapy is an important
(IDF) Atlas of Diabetes, approximately 7.002 million treatment modality for patients with T2DM (3), but its
adults aged 20–79 years will have DM worldwide by side effects (such as diarrhoea, nausea, vomiting, and
2045 (1). Type 1 diabetes mellitus (TIDM) and type 2 anaemia) and drug prices remain to be investigated.
diabetes mellitus (T2DM) are the two most common Meanwhile, persistent hyperglycaemia can cause
types of DM. Patients with T1DM are primarily chronic damage or dysfunction of the eyes, kidneys,
treated with insulin replacement therapy to alleviate heart, blood vessels, and nerves, and intervention in
absolute insulin deficiency, but may be at risk for DM and its complications and reduction of mortality
hypoglycaemia and tumourigenesis. Human islet are imminent (4, 5).
transplantation is an effective treatment for T1DM, Mesenchymal stem cells (MSCs) are widely used

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in various cell therapies because of their many potential and proliferative capacity (18). Compared
advantages, such as self-renewal capacity, multi- with dental pulp-derived mesenchymal stem cells
spectral differentiation ability, tissue damage repair, (PU-MSCs) and adipose tissue-derived mesenchymal
and lack of co-stimulatory molecules (6). The stem cells (AD-MSCs), HUC-MSCs have the strongest
abundant source of human umbilical cord efficacy in ameliorating glucose and lipid metabolism
mesenchymal stem cells (HUC-MSCs), low ethical disorders in T2DM (19). (8) Very low immunogenicity
controversy, low infection risk, high proliferation and (20). In summary, HUC-MSCs are an ideal source of
differentiation ability, and very low immunogenicity cells for cell therapy in DM.
make them uniquely advantageous for DM therapy.
Recently, studies related to the treatment of DM with Possible mechanisms of HUC-MSCs for
HUC-MSCs have rapidly developed. This review DM treatment
describes the advantages and mechanisms of MSCs for DM are cell-based therapeutic
HUC-MSCs in treating DM and the application and approaches that have shown remarkable therapeutic
research progress of HUC-MSCs in DM-related effects in DM because of their self-renewal,
complications, providing more options for managing differentiation potential, and immunosuppressive
DM and its complications. properties. Numerous studies have shown that
HUC-MSCs are a novel strategy to treat DM, and their
Source of HUC-MSCs possible mechanisms (21) include: 1) homing to the
Umbilical cord blood (UCB) is a valuable stem damaged pancreas and acting through local nutrition
cell source. MSCs can be isolated from neonatal and secretion of paracrine factors; 2) differentiation
umbilical cords by enzymatic digestion and show a into insulin-producing cells (IPCs); 3) reversal of
positive expression of classical MSC surface markers. beta-cell (β-cell) dedifferentiation, thereby alleviating
The umbilical cord comprises the umbilical artery, β-cell dysfunction and protecting islet β-cells; 4)
umbilical vein, Wharton's jelly (WJ), and external promotion of islet β-cell regeneration; 5) secretion of
amniotic epithelium surrounding the mucus anti-inflammatory cytokines and macrophage
connective tissue (7). MSCs can be isolated from phenotype regulation, thereby reducing islet β-cell
different umbilical cord parts, including the blood, inflammation; and 6) enhancing insulin sensitivity in
sub-umbilical vein endothelium, and the WJ. target tissues and improving insulin resistance (Fig.
Researchers have successfully isolated and cultured 1).
MSCs from the perivascular layer of Wharton
collagenous vessels of the human umbilical vein (8). Homing effect of HUC-MSCs
MSCs can also be isolated from non-perivascular One advantage of MSCs for DM mitigation is
areas (sub-amniotic membranes) (9). Platelet-derived their ability to home to damaged tissues and then
growth factor (PDGF) produced by human amniotic directly proliferate and differentiate to replace
cells may induce cell migration from the vascular damaged cells and repair damaged tissues. Homing is
system to the amnion (10). The human umbilical cord potentially important for recruiting MSCs to the
is a rich MSC source. injury and regeneration sites (22). MSCs homing
includes both non-systematic and systemic homing.
Advantages of HUC-MSCs In non-systematic homing, MSCs are locally
HUC-MSCs have compelling advantages in transplanted into the target tissue and then directed to
treating DM, including (1) abundant sources, easy the injury site via a chemokine gradient. In systemic
collection, and easy preservation and transportation homing, the molecular mechanisms of MSCs homing
(11); (2) easy isolation, high purity, and include initial tethering by selectins, activation by
non-tumorigenic (12); (3) high amplification potential cytokines, blockade by integrins, exudation or
(13); (4) functional stability after lyophilisation and migration using matrix remodelling agents, and
recovery (14); (5) no adverse effects of collection on extravasation toward chemokine gradients (23). In
the donor, and ethical issues are circumvented (15); 2017, HUC-MSCs labelled with 1,1'-dioctadecyl-
and (6) low probability of infection and transmission 3,3,3',3'-tetramethylindocarbocyanine perchlorate
of pathogenic microorganisms. In contrast, bone (DiI) were detected in the pancreas of T1DM mice,
marrow-derived MSCs (BM-MSCs) have a high risk of suggesting that HUC-MSCs may target and migrate to
viral infection and a significant decrease in cell damaged organs to exert therapeutic effects (24). Yin
number and proliferation/differentiation capacity et al. pre-labelled HUC-MSCs with cell membrane-Dil
with age (16, 17). (7) More primitive and proliferative (CM-Dil) to demonstrate their migration in various
differentiation capacity. Compared with BM-MSCs, tissues, thus confirming the implantation of MSCs in
HUC-MSCs have higher pancreatic differentiation the pancreatic islets of T2DM mice. This suggests that

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homing of HUC-MSCs may be closely related to tissue healing, wound healing, modulating immunity,
damage (25). Overall, HUC-MSCs may play a role in anti-inflammation, anti-apoptosis, and cytoprotection.
treating DM by homing to damaged islets. However, Recently, there has been intense interest in the
the homing rate of MSCs is low, and MSCs may exert synthesis and release of EVs by MSCs via paracrine
protective effects through other mechanisms. secretion. Human umbilical cord mesenchymal stem
cell-derived exosomes (HucMSC-exs) are nanometer-
Paracrine effects of HUC-MSCs sized and are capable of rapid diffusion across
The paracrine properties of MSCs make them a biological barriers and cell membranes. Numerous
key tissue repair option, and the paracrine effect of studies have shown that HucMSC-exs have
MSCs is achieved through the secretion of soluble anti-inflammatory, anti-apoptotic, tissue repair,
factors and release of extracellular vehicles (EVs), neuroprotective, and immunomodulatory properties,
such as exosomes and microvesicles (26). All the suggesting that HucMSC-ex may be a potential DM
factors secreted by MSCs are called the secretome and therapy. HucMSC-ex alleviates T2DM by activating
comprise various cytokines, chemokines, angiogenic the regenerative capacity of islets (31), improving
factors, and growth factors. Moreover, up to 80% of insulin sensitivity (32), reversing peripheral insulin
the therapeutic effects of MSCs are mediated by resistance, and attenuating β-cell destruction (33).
paracrine signalling (27). HUC-MSCs secrete soluble Human umbilical cord mesenchymal stem cell-
molecules such as keratinocyte growth factor (KGF), derived small extracellular vesicles (HUC-MSC-sEVs)
hepatocyte growth factor (HGF), vascular endothelial attenuated structural damage in the pancreas, kidney,
growth factor (VEGF), fibroblast growth factor (FGF), and liver of T2DM rats (34). HucMSC-ex protects
placental growth factor (PGF), monocyte chemo- β-cells from hypoxia-induced apoptosis by carrying
attractant protein 1 (MCP-1), insulin-like growth miR-21 to attenuate endoplasmic reticulum (ER)
factor 1 (IGF-1), epidermal growth factor (EGF), stress and inhibit p38 MAPK phosphorylation (35).
prostaglandin E2 (PGE2), indoleamine 2,3-deoxy- Exosome-loaded immunomodulatory biomaterials
genase (IDO), interleukin-10 (IL-10), interleukin-6 can attenuate the local immune response induced by
(IL-6), transforming growth factor-β1 (TGF-β1), nitric grafts in DM mice (36). The above studies revealed the
oxide (NO), human leukocyte antigen-G5 (HLA-G5), potential value of HucMSC-ex and miRs in DM.
tumour necrosis factor-α stimulated gene 6 (TSG-6), Overall, HUC-MSCs play a protective role against DM
and neurotrophic factors (12, 28-30). These factors by secreting soluble factors and EVs.
play a role in promoting tissue regeneration,
participating in angiogenesis, promoting ulcer tissue

Figure 1. This figure illustrates the possible mechanism of HUC-MSCs for the treatment of DM. HUC-MSCs exert beneficial effects on diabetes by differentiating into IPCs,
promoting islet β-cell regeneration, reversing β-cell dedifferentiation, reducing islet β-cell inflammation, and improving insulin resistance. IPCs insulin-producing cells.

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Differentiation of HUC-MSCs into IPCs tiation into functionally competent β-cells. Pax4, in
concert with Pdx1, Ngn3, and MAF bZIP transcription
HUC-MSCs ameliorate hyperglycaemia and
factor A (MafA), can induce the differentiation of
weight loss in DM rats by differentiating them into
HUC-MSCs into pancreatic β-like cells (pβLCs)
IPCs (37-39). HUC-MSCs induced to differentiate into
functional pancreatic β cells (63). MSCs participate in
IPCs (40, 41) express pancreatic β-cell differentiation-
the repair process by secreting various cytokines and
related genes (e.g. nestin, pancreatic duodenal
growth factors with paracrine and autocrine activities,
homeobox-1 (PDX-1), neurogenin3 (NGN3), paired
which may contribute to endogenous β-cell
box 6 (PAX6), paired box 4 (PAX4), nk2 homeobox 2
regeneration and islet structural recovery (21). Wei et
(NKX2.2), nk6 homeobox 1 (NKX6.1), glucose
al. found that HUC-MSCs protect islets from
transporter 2 (GLUT-2), and insulin (INS) genes) (42,
hypoxia-induced dysfunction (64) and secrete IGF-1
43), and promote the secretion of serum C-peptide
to exert a trophic effect on islets (65). Bao et al. found
and INS in DM rats (44, 45). Additionally, HUC-MSCs
that HUC-MSCs overexpressing tissue inhibitors of
promote the survival, function, and number of
matrix metalloproteinase (TIMP)-1 induced weight
islet-like cell clusters (46). Co-culture of HUC-MSCs
loss and hypoglycaemia and improved islet function
with T1DM rat pancreatic cells promotes survival,
and survival in T1DM mice (66). Lu et al. found that
proliferation, and induced differentiation of HUC-
HUC-MSC transplantation is safe and effective in
MSCs into IPCs (47). Furthermore, the differentiation
T1DM patients and may better protect residual β-cells
of IPCs is a very complex process, and the initial stage
(67). Hu et al. found that the combination of
of nestin preselection, appropriate induction reagents
HUC-MSCs and selegiline was effective in improving
(48), and extracellular matrix (49) are necessary for the
hyperglycaemia, promoting islet β-cell regeneration,
in vitro culture of IPCs from HUC-MSCs. PDX-1 (50,
and inhibiting islet alpha cell (α-cell) production in
51), inhibition of Notch signalling (52) and laminin
T2DM rats (68). Although the exact mechanism needs
411 (53) effectively regulate the differentiation of
to be further explored, this study may provide a new
MSCs into IPCs. Under hypoxic conditions,
therapeutic approach for DM.
UCB-MSCs also efficiently differentiate into IPCs (54,
55). Additionally, factors that effectively promote the Interaction of HUC-MSCs with various
efficacy of IPC action include Port-A catheter immune cells and cytokines
transplantation (56), suspension culture (57), and
addition of the histone deacetylase (HDAC) inhibitor HUC-MSCs and macrophage polarization
TMP269 (58). Overall, HUC-MSCs can replace DM is characterised by mild chronic inflam-
damaged islet β cells by inducing differentiation into mation, which is often accompanied by inflammatory
IPCs, which are ideal seed cells to treat DM. cell infiltration in islets. Macrophage infiltration of
islets and autoimmune destruction of β-cells are
HUC-MSCs can effectively improve islet β-cell important features of the chronic inflammatory
function process in T1DM. Macrophages may be a major
β-Cell dedifferentiation is thought to be an contributor to the development of chronic
important contributor to β-cell dysfunction in T2DM inflammation and insulin resistance in patients with
(59). Pro-inflammatory cytokines can lead to β-cell T2DM (3). UC-MSC transplantation induces an
dysfunction and de-differentiation. MSCs reduce increase in M2 macrophages in pancreatic islets,
endogenous interleukin-1b (IL-1b) production in adipose tissue, liver, and skeletal muscle. HUC-MSCs
T2DM islets by secreting IL-1Ra, thereby reducing produce anti-inflammatory mediators and growth
islet injury and reversing β-cell dedifferentiation (60). factors that suppress inflammation and improve
Additionally, it has been shown that the interleukin-1 insulin sensitivity and β-cell regeneration (25).
receptor antagonist (IL-1Ra) can also regulate the HUC-MSCs reduce insulin resistance by secreting IL-6
phenotypic transition of macrophages (61). In db/db (69) and IL-10 (70) to promote M2 macrophage
mice, early infusion of HUC-MSCs reduced β-cell polarization. MCP-1 secreted by HUC-MSCs
dedifferentiation markers, such as aldehyde synergistically regulates macrophage polarisation
dehydrogenase 1 family member A3+ (ALDH1A3+), with IL-6 (71). Additionally, low-dose decitabine may
and increased the proportion of Ins+ β cells and prolong the antidiabetic effects of MSCs and promote
Pdx1+/Ins+ cells (62). This suggests that MSCs sustainable β-cell recovery by polarising macrophages
transplantation may be a therapeutic strategy for to the M2 phenotype (72). Overall, HUC-MSCs can
protecting and restoring β-cell function in patients reduce islet β-cell inflammation by polarising
with T2DM. Additionally, the potential mechanisms macrophages to the M2 anti-inflammatory phenotype,
for the therapeutic effects of MSCs on DM may thereby alleviating islet dysfunction in patients with
involve islet regeneration, including direct differen- DM.

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HUC-MSCs and other immune cells conclusion, HUC-MSCs act as an effective treatment
MSCs not only act on innate immune cells but for T2DM by improving IR, thereby providing a
also interact with other immune cells, thus regulating potential avenue for developing novel clinical T2DM
multiple effector functions (73). MSCs regulate therapies.
antigen presentation by dendritic cells (DCs),
cytotoxicity of natural killer (NK) cells and neutrophil
HUC-MSCs and other types of diabetes
activation. MSCs induce peripheral tolerance in T cells Recently, with advances in regenerative
and exert effective tissue protection through the medicine research, HUC-MSCs may provide a new
release of anti-inflammatory, anti-apoptotic, and treatment option for other types of DM. Hu et al.
trophic molecules (74). Li et al. found that regulatory found that HUC-MSCs therapy could restore the
T cells (Treg)/T helper cell 17 (Th17) and Treg/T function of residual islet β cells in patients with
helper cell 1 (Th1) cell ratios increased significantly new-onset T1DM over a longer period. This suggests
after 4 weeks of transplantation of HUC-MSCs, while that implantation of HUC-MSCs is expected to be an
the Th17/Th1 cell ratio remained unchanged (75), effective strategy for treating new-onset T1DM (87).
suggesting that HUC-MSCs ameliorate immune Yang et al. found that HUC-MSCs reduced
disorders in T2DM by repairing Treg cells. HUC- inflammatory responses and attenuated pancreatic
MSCs can reduce blood glucose, increase C-peptide injury in rats with severe acute pancreatitis (SAP) (88).
levels, and Treg production in T2DM patients (76), Kong et al. found that HUC-MSCs ameliorated
suggesting that HUC-MSCs with powerful chronic pancreatitis in rats via the AKT-mTOR-S6K1
immunomodulatory ability are safe and effective in signalling pathway, which provides a basis for the
T2DM patients, and microencapsulated HUC-MSCs clinical application of HUC-MSCs in treating
reduce effector Th1 cells and repair the Treg/Th17 pancreatitis (89). In 2019, HucMSC-ex delivered
ratio (77), suggesting that HUC-MSCs may treat exogenous miR-145-5p to inhibit pancreatic ductal
T1DM by modulating immunity. In addition, HUC- adenocarcinoma progression, suggesting a thera-
MSCs have shown efficacy in other autoimmune peutic role of HUC-MSCs in pancreatic exocrine
diseases, such as T1DM combined with Sjogren diseases (90). Additionally, transplantation of
syndrome (SS) (78, 79). Overall, MSCs may represent HUC-MSCs can effectively alleviate weight loss
a new strategy to treat immune-mediated diseases. symptoms, reduce blood glucose levels, and improve
offspring survival in gestational diabetes mellitus
HUC-MSCs improve insulin resistance (GDM) patients (91). However, it has been shown that
Insulin resistance (IR) is one of the most common GDM adversely affects the proliferative capacity and
and important pathological features of T2DM. MSCs viability of HUC-MSCs (92). Therefore, to address this
can exert immunomodulatory and anti-inflammatory situation, it is crucial to identify conditions that
effects through paracrine effects, thereby increasing improve the survival of HUC-MSCs, reduce
insulin sensitivity and improving insulin resistance in apoptosis, and promote proliferation.
T2DM rats (80). Umbilical cord mesenchymal stem In conclusion, MSC therapy presents a novel
cell-conditioned medium (UC-MSC-CM) may approach for treating DM, displaying substantial
improve IR in C2C12 cells by improving glucose efficacy in both basic and clinical trials. HUC-MSCs
transporter 4 (GLUT4) translocation, insulin exhibit the capacity to migrate towards damaged
signalling pathways, and mitochondrial content and pancreatic islets, facilitated by homing and paracrine
function (81). HUC-MSCs also improve IR by effects, thus assuming a reparative role. Additionally,
modulating the balance between PTEN-mediated they induce differentiation into IPCs, replacing
PI3K/Akt and ERK/MAPK signalling pathways (82). impaired islet β-cells and enabling the secretion of C
UC-MSCs infusion and fasting-mimicking diet (FMD) peptide and insulin. Furthermore, they counteract
synergistically modulate the systemic inflammatory β-cell de-differentiation, thereby safeguarding
microenvironment and improve hyperglycaemia and pancreatic β-cells, and facilitate regeneration of islet
lipid metabolism disorders in T2DM mice (83). β-cells along with structural revitalization, conseq-
Glucagon-like peptide-1 (GLP-1) gene modification of uently enhancing islet β-cell functionality. Their
HUC-MSCs improves fasting glucose, IR, and β-cell impact extends to immune cells, encompassing
function in T2DM mice (84). HUC-MSCs combined macrophages, DCs, NK cells, neutrophils, and T cells,
with liraglutide can downregulate the TLR4/NF-kB thereby exerting immunomodulatory and anti-
inflammatory pathway and oxidative stress while inflammatory properties. This therapeutic modality
improving glucose metabolism and inhibiting islet also ameliorates insulin resistance by targeting
β-cell apoptosis in an ASK1/JNK/BAX pathway- insulin-responsive organs. In summary, the collective
dependent manner in T2DM rats (85, 86). In mechanisms through which HUC-MSCs operate

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synergistically culminate in an amelioration of HUC-MSCs promoted renal tubular cell proliferation

diabetic symptoms (Table. 1). Nevertheless, the and reduced apoptosis, thus exerting a protective
homing rate of MSCs remains limited, prompting the effect on the kidneys (94). Additionally, HUC-MSCs
need for further investigations to enhance their inhibited the levels of inflammatory factors IL-6,
homing rate, bolster their survival rate post- IL-1β, tumour necrosis factor-alpha (TNF-α), TGF-β,
transplantation, and optimize overall efficacy and MCP-1, and nuclear factor-κB (NF-κB) and down-
safety. Notably, contemporary research endeavors regulated the expression of fibronectin alpha-smooth
have augmented the efficacy of diabetes mellitus muscle actin (α-SMA) and collagen IV, suggesting
treatment via preemptive treatments of MSCs, that HUC-MSCs benefit podocytes under high
including hypoxic pre-conditioning. While current glucose (HG) by suppressing inflammation and
studies yield promising clinical outcomes, the full fibrosis while delaying the progression of DN (95-97).
spectrum of optimal efficacy warrants deeper Nie et al. found that HUC-MSCs decreased
exploration. malondialdehyde levels and 4-hydroxynonenal
(4-HNE) protein expression and increased the
HUMSCs and complications of T2DM antioxidant enzymes catalase (CAT) and glutathione
peroxidase (GPX) (98). HUC-MSCs attenuated the
Diabetic nephropathy
expression of TGF-β1, α-SMA, collagen I, and heat
Diabetic nephropathy (DN) is one of the most shock protein 47 (HSP47) mRNA and increased the
serious complications of DM and a major cause of expression of E-cadherin and bone morphogenetic
end-stage chronic kidney disease. HUC-MSCs act protein 7 (BMP-7) mRNA, suggesting that HUC-
mainly by promoting paracrine mechanisms, such as MSCs can prevent renal injury in DN rats via
mitogenic, anti-fibrotic, anti-inflammatory, antioxi- paracrine humoral factors (99, 100). Notably,
dant, anti-apoptotic, cytoprotective and immuno- HUC-MSCs improved renal function in mice, mainly
modulatory. HUC-MSC transplantation is expected to due to immunomodulatory effects rather than direct
be an effective therapeutic approach for preventing implantation and trans-differentiation into renal cells
and treating DN. An et al. found that HUC-MSCs (101). Overall, HUC-MSCs can improve DN through
lowered blood glucose, improved renal function and the above-mentioned mechanisms, and may be a
renal histopathological changes in DN nonhuman promising DN therapeutic strategy.
primates (93). Fang et al. found that IGF-1 secreted by

Table 1. The possible modes of action of MSCs in the treatment of diabetes are discussed in the table.
Mode of action of HUC-MSCs
Mode of action Mechanism References
Homing effects Systemic homing Initial tethering by selectins (22, 23)
Activation by cytokines
Blockade by integrins
Exudation or migration using matrix remodelling agents
Extravasation toward chemokine gradients
Non-systematic homing Directed to the injury site via a chemokine gradient.
Paracrine effects Secrete soluble molecules (KGF, HGF, VEGF, FGF, PGF, MCP-1, IGF-1, Promoting tissue regeneration and angiogenesis (12, 28-30)
EGF, PGE2, IDO, IL-10, IL-6, TGF-β1, NO, HLA-G5, TSG-6, and Promoting ulcer tissue healing and wound healing
neurotrophic factors) Modulating immunity, anti-inflammation, anti-apoptosis,
and cytoprotection.
Release of EVs, such as exosomes and microvesicles Activating the regenerative capacity of islets (31-33)
Improving insulin sensitivity
Reversing peripheral insulin resistance
Attenuating β-cell destruction
Differentiation into Induced to differentiate into IPCs Replace some damaged islet β-cells to secrete C peptide and (40, 45)
IPCs INS
Improve islet β-cell Protection of pancreatic islet beta cells Secreting IL-1Ra to reduce islet injury and reverse β-cell (60, 62)
function dedifferentiation
Promoting the regeneration of pancreatic islet beta cells Induced to differentiate into pβLCs functional pancreatic β (63)
cells
Immunomodulatory Macrophage Suppress inflammation and improve insulin sensitivity by (25, 69-71)
effects secreting IL-6 and IL-10 to promote M2 macrophage
polarization.
DCs, NK cells, neutrophil, and T cells Regulate antigen presentation by DCs (74)
Regulate cytotoxicity of NK
Regulate neutrophil activation
Induce peripheral tolerance in T cells
Improve insulin Liver, fat and skeletal muscle Improve IR in C2C12 cells and improve lipid metabolism (81, 83)
resistance disorders in T2DM mice
HUC-MSCs, Human umbilical cord mesenchymal stem cells; KGF, Keratinocyte growth factor; HGF, Hepatocyte growth factor; VEGF, Vascular endothelial growth factor;
FGF, Fibroblast growth factor; PGF, Placental growth factor; MCP-1, Monocyte chemoattractant protein 1; IGF-1, Insulin-like growth factor 1; EGF, Epidermal growth factor;
PGE2, Prostaglandin E2; IDO, Indoleamine2,3-deoxygenase; IL-10, Interleukin-10; IL-6, Interleukin-6; TGF-β1, Transforming growth factor-β1; NO, Nitric oxide; HLA-G5,

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Int. J. Med. Sci. 2023, Vol. 20 1498
Human leukocyte antigen-G5; TSG-6, Tumor necrosis factor α stimulated gene 6; EVs, Extracellular vehicles; β-cell, Beta cell; IPCs, Insulin-producing cells; INS, Insulin;
IL-1Ra, Interleukin-1 Receptor antagonist; PβLCs, Pancreatic β-like cells; DCs, Dendritic cells; NK cells, Natural killer cell; IR, Insulin resistance; T2DM, Type 2 diabetes
mellitus.

Diabetic retinopathy umbilical cord blood cells (HUCBCs) are widely

accepted to repair the central nervous system (115).
Diabetic retinopathy (DR) is a common cause of
Stem cell-rich HUCBCs can survive, migrate,
visual impairment and blindness in working-age
differentiate, and restore neurological function in the
individuals. Microangiopathy and inflammatory
ischaemic brain microenvironment of stroke rats
responses are key components of DR. Recently, MSCs
(116). Lin et al. found that CD34-immunosorted
have received increasing attention for their tissue
human umbilical cord blood haematopoietic stem
damage repair therapy, anti-inflammatory effects, and
cells (HUCB34) after hypoxic preconditioning
pro-angiogenic effects, and they offer potential
promoted neuronal progenitor cell (NPCs) homing to
options for the treatment of DR. HUC-MSCs play an
the ischaemic brain and enhanced neuronal synapse
anti-inflammatory role and inhibit retinal neuronal
regeneration (117). Chen et al. found that HUCBCs
apoptosis by upregulating the expression of
promote vascular and WM remodelling by
adiponectin (APN) and neurotrophin-4 (NT-4) and
upregulating miR-126 expression while promoting
downregulating the expression of myocardial
M2 macrophage polarisation and inducing neural
infarction-associated transcript (MIAT), IL-1β, IL-6,
repair by decreasing vascular cell adhesion
and high-sensitivity C-reactive protein (hs-CRP) (102,
molecule-1 (VCAM-1) and MCP-1 expression (118).
103). HUC-MSCs increase the number of surviving
HUCBCs increase the density of oligodendrocyte
retinal ganglion cells (RGCs) and improve neuro-
progenitors and oligodendrocytes, increase angio-
protection through a BDNF-dependent mechanism,
poietin 1 (Ang-1), expression, and decrease the
suggesting that HUC-MSCs may slow DR progression
expression of ischaemic border zone (IBZ) RAGE,
through paracrine humoral factors (104, 105).
matrix metalloproteinase 9 (MMP-9), and toll-like
Additionally, numerous studies have shown that
receptor 4 (TLR4), suggesting that HUCBCs have a
HucMSC-ex have anti-inflammatory, anti-apoptotic,
therapeutic effect on nerve repair in DM rats with
tissue repair, neuroprotective, and immunomodu-
stroke (119, 120). Therefore, MSCs therapy may be a
latory properties. Moreover, EVs are nanometer-sized
promising therapeutic option for diabetic patients
and can diffuse rapidly through the retina (106). Fu et
with central nervous system complications.
al. found that HucMSC-ex effectively prevented early
retinal vascular damage and retinal thickening, and Diabetic autonomic neuropathy
alleviated DM-induced structural damage to the Diabetic autonomic neuropathy (DAN) is a
retina (107). Li et al. found that HucMSC-derived serious and common complication of DM that has
exosomes shuffled microRNA-17-3p ameliorated the significant adverse effects on patient survival and
inflammatory response and oxidative damage in DR quality of life (121). Diabetic cystopathy (DC) is
mice by targeting STAT1, providing new insights into considered a manifestation of diabetic neuropathy,
novel targeted therapies for DR (108). In 2021, and its pathogenesis may be related to long-term
HucMSC-derived exosomes shuffled microRNA-18b hyperglycaemia, bladder wall remodelling induced
exerted anti-apoptotic and anti-inflammatory effects polyuria, and oxidative stress leading to smooth
in DR rats by mediating the MAP3K1/NF-κB axis, muscle cell and neuronal damage (122). Wu et al.
suggesting that miR-18b is critical for HucMSC-ex found that HUC-MSCs overexpressing nerve growth
treatment of DR (109). Zhang et al. found that factor (NGF) could secrete neurotrophic factors and
HucMSC-ex overexpressing miR-126 was able to cytokines in the rat spinal cord and could also
reduce hyperglycemia-induced retinal inflammation differentiate into NeuN neurones and glial fibrillary
by targeting and regulating high mobility group box 1 acidic protein (GFAP)-positive astrocytes to
(HMGB1) (110). Overall, these studies have laid a effectively prevent bladder hypertrophy and
solid foundation for HUC-MSCs in DR treatment. remodelling, thereby reversing the progression of DC
Diabetic central nervous system complications and restoring bladder function (123). Shin et al. found
that HUC-MSC transplantation improved urinary
DM is a risk factor for acute stroke and can lead
function in DM rats, which provides a rationale for
to a higher risk of ischaemic stroke and a worse
HUC-MSC treatment of DM-related detrusor
prognosis (111-113). Cerebral haemorrhage,
underactivity (DUA) (124). Wu et al. found that
neurological deficits, and white matter (WM) damage
HUC-MSC transplantation may improve diabetic
can be severe after stroke in DM mice (114).
erectile dysfunction in rats by increasing the
Inflammatory and immune responses play important
production of paracrine growth factors (VEGF),
roles in ischaemic stroke prognosis, and human

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Int. J. Med. Sci. 2023, Vol. 20 1499

endothelial nitric oxide synthase (eNOS), IGF1, and pro-inflammatory cytokines and proteases, and
basic fibroblast growth factor (bFGF) (125). In reduced levels of various growth factors (139-141).
conclusion, transplantation of HUC-MSCs may be a HUC-MSCs can self-renew, multi-directionally
new potential therapeutic option for DAN. differentiate, and secrete multiple cytokines and
growth factors, and their mechanisms to improve
Diabetic foot disease diabetic wound healing mainly include 1) promoting
Diabetic foot ulcers (DFU) are full-length lesions diabetic wound healing by differentiating into
that occur in the skin of the foot of patients with DM, keratin-forming cells (142); 2) secreting molecules
accompanied by infection and tissue destruction related to wound healing in a paracrine manner
caused by neuropathy and/or peripheral artery (VEGF, PDGF, KGF, TGF-β1, SMA, scavenger
disease (PAD) (126). DFU has a high disability and receptor class B type1 (SR-B1), and platelet endo-
mortality rate, which severely affects the quality of life thelial cell adhesion molecule-1 (PECAM-1/CD31)) to
of patients, shortens life expectancy, and imposes a promote angiogenesis (143-146); 3) regulating the
heavy socioeconomic burden (127, 128). In recent activity, function, and proliferative capacity of
years, HUC-MSCs have achieved good therapeutic vascular endothelial cells by reducing oxidative stress
effects in the treatment of DFU. Zhao et al. found that and inflammatory response, thereby promoting
HUC-MSCs specifically homed to ulcerated tissue and angiogenesis (147, 148); 4) inducing functional
promoted epithelialisation of ulcerated tissue, recovery of vascular endothelial cells by modulating
possibly by stimulating the release of cytokeratin 19 macrophage phenotype (149); and 5) stimulating
from keratin-forming cells and promoting diabetic fibroblast activity and promoting cell
extracellular matrix formation (129). Shi et al. found proliferation, collagen synthesis, and glycosamino-
that HUC-MSCs promoted wound healing in DFU glycan levels, thereby playing a role in skin wound
rats by transdifferentiating, regulating inflammation, healing play a role (150). Moreover, HUC-MSCs may
and providing growth factors that promote angio- be more effective than fibroblasts in stimulating
genesis, cell proliferation, and collagen deposition diabetic wound healing (151, 152). Additionally,
(130). Xia et al. found that HUC-MSCs prevented or HUC-MSCs accelerate wound healing in diabetic rats
cured foot ulcers in DFU rats by reversing the by increasing epidermal and dermal thickness and
neuronal structure and function by upregulating NGF density, accelerating epithelial and collagen
and promoting significant angiogenesis in the femoral regeneration, and increasing angiogenesis (153). Han
nerve-innervated gastrocnemius muscle (131). et al. found that the Wnt signalling pathway
HUC-MSCs induce angiogenesis (132, 133), promote activation promoted the proliferation and
tissue repair and regeneration (134), and reduce differentiation of HUC-MSCs, thereby facilitating the
muscle damage and apoptosis in the ischaemic hind healing of diabetic skin wounds (154). Yue et al. found
limbs of DM mice (135). Transplantation of that c-Jun overexpression promotes the proliferation
HUC-MSCs significantly improved skin temperature, and migration of HUC-MSCs in vitro and accelerates
ankle-arm pressure index, transcutaneous partial diabetic wound closure, re-epithelialization, and
pressure of oxygen, and claudication distance in angiogenesis in vivo (155). The development of new
patients with postoperative diabetic foot disease. This technologies has extensively improved the
is accompanied by a significant increase in therapeutic efficacy of HUC-MSCs. HUC-MSCs can
neovascularization and complete or gradual ulcer improve skin wound healing in diabetic mice by
healing (136). In conclusion, transplantation of combining with Pluronic F127 hydrogel (156),
HUC-MSCs may be a potential strategy for clinical tissue-engineered scaffolds (157, 158), or Cas9-AAV6
application in DFU, although its long-term effects engineering modification (159). Overall, HUC-MSC
remain to be elucidated. transplantation may have a therapeutic effect on
impaired diabetic wound healing; however, its
Impaired wound healing in DM
specific therapeutic modalities and safety need to be
Impaired wound healing is a common DM further explored.
complication. DM is associated with persistent
inflammation and a defective tissue repair response. HUC-MSCs infusion is safe and effective
Impaired angiogenesis is an important factor in for COVID-19 with diabetes
delaying chronic diabetic wound healing. Poorly
healing wounds in DM mice exhibit a persistent Currently, coronavirus disease 2019 (COVID-19)
inflammatory response, a deficiency of M2 is a serious global public health problem and is
macrophages (137, 138), a prolonged accumulation of significantly associated with an increased risk of
pro-inflammatory M1 macrophages, elevated levels of developing DM (160). At the same time, patients with
DM are at a high risk of developing severe COVID-19

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infections, have a complex disease process, and have an immunostimulatory state in MSCs, suggesting that
significantly higher mortality rates (161, 162). Severe the metabolic disease environment alters the
COVID-19 is thought to result from the hyper- immunomodulatory efficacy of healthy donor MSCs
inflammatory state and overactive immune response (173). Boland et al. found that culturing HUC-MSCs in
caused by severe acute respiratory syndrome xeno-free conditions attenuated palmitate-induced
coronavirus 2 (SARS-CoV-2) infection, as well as impairment of the immunomodulatory function of
cytokine storm and immune thrombosis. The SARS- HUC-MSCs (174). Additionally, the mode of MSCs
CoV-2 spike glycoprotein binds to angiotensin- administration affects therapeutic efficacy, with
converting enzyme 2 (ACE2), and the serine protease intravenous delivery methods being more effective
transmembrane protease serine 2 (TMPRSS2) initiates than intraperitoneal grafts (175). Local delivery causes
S proteins that can facilitate viral entry into cells, viral MSCs to cluster into "spheroids", thereby altering
replication, and cell-to-cell transmission (163). The gene expression and phenotype. In 2020, researchers
activity of ACE2 is increased in DM mice (164, 165) found that budesonide could act synergistically with
and significantly increased in patients with DM prostaglandin E2 (PGE2) produced by spheroid MSCs
treated with angiotensin-converting enzyme to inhibit T cell proliferation at the PGE2 receptors
inhibitors (ACEI) and angiotensin receptor blockers EP2 and EP4 (176). Moreover, IPCs may be
(ARB) (166), suggesting that patients with DM may be immunogenic and trigger immune responses after
at increased COVID-19 risk. transplantation into the host owing to changes in the
MSCs can achieve immunomodulation by immune microenvironment and immune cell
secreting various cytokines through paracrine infiltration, thus reducing cell survival and further
pathways or by interacting directly with the immune differentiation (177). However, encapsulation of IPCs
cells (167). ACE2 and TMPRSS2 were expressed at with alginate has been shown to avoid graft rejection,
low levels in HUC-MSCs, suggesting that HUC-MSCs which greatly improves the efficacy of allogeneic or
may have the ability to "evade" viral infection and xenogeneic MSCs in the treatment of DM (178).
thus exert immunomodulatory effects (168). Stem cell banking is the most important life
HUC-MSCs reduced the levels of inflammatory resource for human beings, which can provide
molecules associated with the COVID-19 "cytokine high-quality seed cell resources for stem cell therapy.
storm", including interferon-γ (IFNγ), IL1β, IL-6, and By establishing a standardized production process of
TNFα, and regulated upon activation of normal T cell MSCs, it can improve stem cell preparation quality
expressed and secreted factor (RANTES). and promote the sustainable development of stem cell
Additionally, no serious adverse events related to clinical applications. Actively promoting the clinical
HUC-MSC infusion have been observed (169, 170). translation of stem cell therapy and improving the
HUC-MSCs improved respiratory distress and survival rate and efficacy of HUC-MSCs after
reduced inflammatory biomarkers in patients with transplantation will become the top priority of stem
critically ill COVID-19-induced automated resources cell technology research nowadays. With the
directory service (ARDS) (171). Tao et al. found that development of technology, the field of stem cell
UC-MSCs significantly increased pulmonary static research has become a frontier hotspot. The
compliance, maintained a stable partial pressure of implantation of the bioartificial pancreas (179), the
oxygen (PaO2)/fraction of inspired oxygen (FiO2) labelling of nanoparticles (NP) (180), and the
ratio, and improved renal function in critically ill co-microencapsulation of HUC-MSCs/human
COVID-19 patients, suggesting that UC-MSCs pancreatic islet-derived progenitor cells (hIDC) (181)
transplantation may have a positive therapeutic effect may provide new tools for cellular therapy of DM.
in critically ill COVID-19 patients (172). In conclusion, Carboxylic acid-functionalized single-walled carbon
HUC-MSC therapy may be a potential treatment nanotubes (f-SWCNT-COOH) (182) and some
option for DM combined with COVID-19. cytokines (183) can increase the viability and ex vivo
expansion of hematopoietic stem cell (HSC) and/or
Opportunities and challenges hematopoietic stem progenitor cell (HSPC). These
HUC-MSCs have shown impressive results in studies provide new perspectives for developing DM
treating DM and its complications, but most studies cell transplantation therapies based on HUC-MSCs.
are still in the preclinical stage. Improving the We believe that the effectiveness of HUC-MSC
survival and efficacy of HUC-MSCs after transplanta- therapy will be greatly improved by applying
tion in a challenging metabolic environment may be advanced technologies such as gene modification,
an interesting topic in the future, as elevated nanotechnology, magnetic targeting technology, and
palmitate levels in the sera of obese and T2DM tissue engineering technology. We believe that soon,
patients lead to a shift from an immunosuppressive to HUC-MSCs may provide a better solution for the

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Figure 2. This figure illustrates the broad effect of HUC-MSCs on DM and its complications, as well as the therapeutic effect of HUC-MSCs on diabetic patients infected with
COVID-19. COVID-19: coronavirus disease 2019.

clinical treatment of DM and its complications, and research is needed to improve the homing rate,
thus can bring new hope to a greater extent in DM survival rate, efficacy, and safety of MSCs after
patients worldwide. transplantation. With the gradual maturation of
technology and theory, the fundamental treatment of
Conclusions diabetes will usher in a greater breakthrough. We
The DM epidemic and its complications pose a believe that HUC-MSCs transplantation can provide
major threat to global health, accompanied by high more options for the management of DM and its
morbidity and mortality. Currently, there are many complications and bring longer-term benefits to
ways to treat DM, such as traditional oral patients.
hypoglycaemic therapy and insulin injections, but
they can only temporarily control blood glucose levels Abbreviations
and cannot cure diabetes, and have insufficient DM: diabetes mellitus
control over diabetic complications, in addition to IDF: international diabetes federation
long-term use of hypoglycaemic drugs or insulin T1DM: type 1 diabetes mellitus
injections, which significantly reduces patient T2DM: type 2 diabetes mellitus
compliance. Recently, regenerative medicine with MSCs: mesenchymal stem cells
MSCs treatment as the core has provided new ideas HUC-MSCs: human umbilical cord
and possible development directions for DM mesenchymal stem cells
treatment. The characteristics of HUC-MSCs, such as UCB: umbilical cord blood
abundant source, less ethical controversy, lower risk WJ: wharton's jelly
of infection, higher proliferation and differentiation PDGF: platelet derived growth factor
ability, and very low immunogenicity, make them BM-MSCs: bone marrow-derived mesenchymal
stand out among MSCs of different tissue sources. We stem cells
mainly describe the application of HUC-MSCs in DM PU-MSCs: pulp-derived mesenchymal stem cells
and its complications. HUC-MSCs transplantation is AD-MSCs: adipose tissue-derived mesenchymal
expected to be an efficient and ideal treatment for DM stem cells
and its complications, and its application area will β-cell: beta cell
gradually expand (Fig. 2). Currently, HUC-MSCs DiI: 1,1'-dioctadecyl-3,3,3',3'-tetramethylindo-
therapy is still in the exploration stage, and further carbocyanine perchlorate

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Int. J. Med. Sci. 2023, Vol. 20 1502

CM-Dil: cell membrane-dil TNF-α: tumor necrosis factorTh17- alpha

EVs: extracellular vesicles NF-κB: nuclear factor-κB
KGF: keratinocyte growth factor α-SMA: alpha-smooth muscle actin
HGF: hepatocyte growth factor HG: high glucose
VEGF: vascular endothelial growth factor HNE: 4-hydroxynonenal
FGF: fibroblast growth factor CAT: catalase
PGF: placental growth factor GPX: glutathione peroxidase
MCP-1: monocyte chemoattractant protein 1 HSP47: heat shock protein 47
IGF-1: insulin-like growth factor 1 BMP-7: bone morphogenetic protein 7
EGF: epidermal growth factor DR: diabetic retinopathy
PGE2: prostaglandin E2 APN: adiponectin
IDO: indoleamine2,3-deoxygenase NT-4: neurotrophin-4
IL-10: interleukin-10 MIAT: myocardial infarction-associated
IL-6: interleukin-6 transcript
TGF-β1: transforming growth factor-β1 hs-CRP: high-sensitivity C-Reactive Protein
NO: nitric oxide RGCs: retinal ganglion cells
HLA-G5: human leukocyte antigen-G5 HMGB1: high mobility group box 1
TSG-6: tumor necrosis factor α stimulated gene 6 WM: white matter
HucMSC-ex: HUCBCs: human umbilical cord blood cells
human umbilical cord mesenchymal stem HUCB34: CD34-immunosorted human umbilical
cell-derived exosome cord blood hematopoietic stem cells
HUC-MSCs-sEVs: human umbilical cord NPCs: neuronal progenitor cells
mesenchymal stem cell-derived small extracellular VCAM-1: vascular cell adhesion molecule-1
vesicle Ang-1: angiopoietin 1
ER: endoplasmic reticulum IBZ: ischemic border zone
PDX-1: pancreatic duodenal homeobox-1 MMP-9: matrix metalloproteinase 9
NGN3: neurogenin3 TLR4: toll-like receptor 4
PAX6: paired box 6 DAN: diabetic autonomic neuropathy
PAX4: paired box 4 DC: diabetic cystopathy
NKX2.2: nk2 homeobox 2 NGF: nerve growth factor
NKX6.1: nk6 homeobox 1 GFAP: glial fibrillary acidic protein
GLUT-2: glucose transporter 2 DUA: detrusor underactivity
INS: insulin eNOS: endothelial nitric oxide synthase
HDAC: histone deacetylase bFGF: basic fibroblast growth factor
IL-1b: interleukin-1b DFU: diabetic foot ulcer
IL-1Ra: interleukin-1 receptor antagonist PAD: peripheral artery disease
MafA: MAF bZIP transcription factor A SR-B1: scavenger receptor class B type1
PβLCs: pancreatic β-like cells PECAM-1/CD31: platelet endothelial cell
TIMP: tissue inhibitors of matrix metallo- adhesion molecule-1
proteinase SARS-CoV-2: severe acute respiratory syndrome
α-cell: alpha cell coronavirus 2
DCs: dendritic cells ACE2: angiotensin converting enzyme 2
NK: cytotoxicity of natural killer cell TMPRSS2: transmembrane protease, serine 2
Treg: regulatory T cells ACEI: angiotensin converting enzyme inhibitor
Th17: t helper cell 17 ARB: angiotensin receptor blocker
Th1: t helper cell 1 IL-2R: interleukin-2R
SS: sjogren syndrome IL-8: interleukin-8
UC-MSC-CM: umbilical cord-mesenchymal stem IFNg: interferon-g
cell-conditioned medium IFNγ: interferon-γ
GLUT4: glucose transporter 4 RANTES: regulated upon activation normal T
FMD: fasting-mimicking diet cell expressed and secreted factor
GLP-1: glucagon-like peptide-1 ARDS: automated resources directory service
SAP: severe acute pancreatitis PaO2: partial pressure of oxygen
GDM: gestational diabetes mellitus FiO2: fraction of inspiration oxygen
DN: diabetic nephropathy PGE2: prostaglandin E2

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science and technology (Grant No. 3D5223990429) is 20. Wang H, Qiu X, Ni P, Qiu X, Lin X, Wu W. et al. Immunological characteristics
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Satoru Takahashi designed the study. All authors 25. Yin Y, Hao H, Cheng Y, Gao J, Liu J, Xie Z. et al. The homing of human
read and approved the final manuscript. umbilical cord-derived mesenchymal stem cells and the subsequent
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Competing Interests 26. Keshtkar S, Azarpira N, Ghahremani MH. Mesenchymal stem cell-derived
extracellular vesicles: novel frontiers in regenerative medicine. Stem cell
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