Mesenchymal Stem Cell Therapy in Type 2 Diabetes Mellitus Zang 2017
Mesenchymal Stem Cell Therapy in Type 2 Diabetes Mellitus Zang 2017
Mesenchymal Stem Cell Therapy in Type 2 Diabetes Mellitus Zang 2017
Abstract
Type 2 diabetes mellitus (T2DM), which is characterized by the combination of relative insulin deficiency and insulin
resistance, cannot be reversed with existing therapeutic strategies. Transplantation of insulin-producing cells (IPCs)
was once thought to be the most promising strategy for treating diabetes, but the pace from the laboratory to clinical
application has been obstructed due to its drawbacks. Mesenchymal stem cells (MSCs) harbor differentiation poten-
tial, immunosuppressive properties, and anti-inflammatory effects, and they are considered an ideal candidate cell
type for treatment of DM. MSC-related research has demonstrated exciting therapeutic effects in glycemic control
both in vivo and in vitro, and these results now have been translated into clinical practice. However, some critical
potential problems have emerged from current clinical trials. Multi-center, large-scale, double-blind, and placebo-
controlled studies with strict supervision are required before MSC transplantation can become a routine therapeutic
approach for T2DM. We briefly review the molecular mechanism of MSC treatment for T2DM as well as the merits and
drawbacks identified in current clinical trials.
Keywords: Mesenchymal stem cells, Type 2 diabetes mellitus, Insulin resistance
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Zang et al. Diabetol Metab Syndr (2017) 9:36 Page 2 of 11
of this therapeutic strategy [11, 12]. The identification of by key transcription factors such as Pdx-1, Ngn-3, Neu-
stem cells that possess the potential to differentiate into roD1, Pax4, and Pax6 [36]. Correct reprogramming of
insulin-producing cells (IPCs), improve pancreatic regen- cells to activate these pathways is necessary for induc-
eration, and ameliorate insulin resistance offers an alter- ing differentiation of MSCs into IPCs. Chen et al. first
native to islet cell transplant. obtained incompletely differentiated IPCs expressing
Transplantation of IPCs was once considered to be the insulin and nestin by culturing rat BM-MSCs in serum-
most promising treatment approach for DM. However, free medium in the presence of a high glucose concen-
suitable sources of IPCs free of ethical conflicts and lack- tration, nicotinamide, and β-mercaptoethanol [37]. Since
ing immunogenicity or tumorigenicity have not been then, modified protocols with different stimulating agents
established. In addition, there were apprehensions about have been applied to improve the differentiation and effi-
the clinical efficacy of this approach due to the potential cacy; however, results in vivo have not been encourag-
for cell exhaustion in vivo [13–16]. All of these obstacles ing [38, 39]. Moriscot et al. first induced differentiation
have slowed the pace with which this approach could of human BM-MSCs into IPCs using adenoviral vectors
have transitioned from the laboratory to the clinical set- coding for mouse Pdx-1 and Xie induced human BM-
ting. In recent years, mesenchymal stem cells (MSCs) MSCs into IPCs using a three-step differentiation proto-
derived from different adult tissues have attracted signifi- col (the addition of Activin A as the differentiating agent
cant attention for the treatment of DM. MSCs are known was the final step), and the resulting cells had the capac-
to promote the regeneration of pancreatic islet beta cells, ity to release insulin in a glucose-dependent manner [40,
protect endogenous pancreatic islet beta cells from apop- 41]. Chandra et al. [35] reported the generation of IPC
tosis, and ameliorate insulin resistance of peripheral tis- aggregates from murine adipose tissue-derived stem
sues by providing a supportive niche microenvironment cells, and these cells yielded numerous secretory granules
driven by the secretion of paracrine factors or the depo- within the cell cytoplasm after 10-day in vitro culture.
sition of extracellular matrix [17–22]. Not surprisingly, Calcium alginate-encapsulated IPCs, when transplanted
MSCs are now being intensively investigated for their into streptozotocin-induced diabetic mice, restored
efficacy and safety in both animals and humans. MSCs normoglycemia within 2 weeks. Some researchers have
from different sources are known to exhibit unique char- recently indicated that UC-MSCs, especially Wharton’s
acteristics. Bone marrow-derived MSCs (BM-MSCs) jelly-derived MSCs (WJ-MSCs), which are easy to source
have been extensively investigated for their potential with and culture, can be successfully differentiated into IPCs.
regard to immunomodulation and tissue repair as well as Some comparative studies have also demonstrated that
the generation of IPCs via various differentiation proto- WJ-MSCs have superior differentiation potential towards
cols [23–27]. Interestingly, umbilical cord-derived MSCs a mature beta cell phenotype as compared to BM-MSCs
(UC-MSCs) express embryonic markers and endoder- [42]. Chao et al. successfully differentiated WJ-MSCs into
mal lineage markers. UC-MSCs have higher similarity to IPCs through a stepwise culture protocol using neuron-
embryonic stem cells (ESCs) than other commonly used conditioned medium in vitro and proved that the differ-
MSCs such as BM-MSCs and also have superior potential entiated IPCs exhibit typical beta cell functions in vivo
to differentiate into IPCs [28]. The ease of procurement, [43]. Tsai et al. injected undifferentiated WJ-MSCs
low immunogenicity with allogeneic sources, painless expressing green fluorescent protein (GFP) into non-
procedures for donors, and capacity for IPC differentia- obese diabetic (NOD) mice and observed co-localization
tion make UC-MSCs an appealing alternative source of of human C-peptide and GFP in the pancreas, indicating
stem cells for treating T2DM [29, 30]. In addition, adi- that WJ-MSCs differentiated into IPCs in vivo [44]. Wu
pose tissue, placenta, amnion, and dental pulp have also et al. compared the differentiation potential of WJ-MSCs
been reported as alternative sources for cell therapy in and BM-MSCs. The results showed that both stem cell
diabetes. These MSCs can be induced to differentiate into types were able to form islet-like clusters in a medium
physiologically competent functional IPCs, which may containing nicotinamide, activin, hepatocyte growth fac-
provide a source of alternative islets for cell replacement tor, exendin-4, and pentagastrin. The expression of Pdx-
therapy [31–35]. 1, insulin secretion, and mRNA expression of insulin and
C-peptide in differentiated WJ-MSCs were greater rela-
Molecular mechanism of action of MSCs tive to levels in differentiated BM-MSCs [42].
Differentiation into IPCs However, the short-term survival time of the differen-
The potential to differentiate into IPCs was first consid- tiated cells, which resulted from the usage of stimulat-
ered to be the primary mechanism by which MSCs ame- ing agents and adenoviral vectors in the differentiation
liorate hyperglycemia in T2DM (Fig. 1). Differentiation of process limited their application. Direct transplantation
the endocrine compartment of the pancreas is controlled of MSCs was once thought to be the most effective way
Zang et al. Diabetol Metab Syndr (2017) 9:36 Page 3 of 11
Fig. 1 Diagram explaining the mechanism by which MSCs act on type 2 diabetes. MSCs exert beneficial effects on type 2 diabetes through differ-
entiation into IPCs, promotion of islet cell regeneration, protection of endogenous islet cells and amelioration of insulin resistance. IPCs insulin-pro-
ducing cells, IGF-1 insulin-like growth factor-1, VEGF vascular endothelial growth factor, PDGF platelet-derived growth factor, IRS-1 insulin receptor
substrate-1, PI3K phosphoinositide 3-kinase
to avoid this unwanted consequence. In fact, transplant- Whether the restoration of euglycemia was due to MSC
ing undifferentiated human placenta-derived MSCs or differentiation still remains controversial.
biocompatible macrocapsules with differentiated IPCs
under the kidney capsules of STZ-induced diabetic mice, Promoting the regeneration of pancreatic islet beta cells
both resulted in a reduction of hyperglycemia and res- In addition to the capacity to differentiate into IPCs,
toration of normoglycemia 15 days post transplantation MSCs also promote the regeneration of endogenous
[34]. Transplanted MSCs were preferentially located in pancreatic islet beta cells by migrating to the injured
the damaged pancreatic tissue of diabetic mouse mod- islet cells. The MSCs participate in the repair processes
els. However, as only a small fraction of donor insulin- by secreting a variety of cytokines and growth factors
positive cells was found in the pancreas, they could that have both paracrine and autocrine activities [17].
not completely account for the renewal of the islet cells Significant endogenous beta-cell regeneration and islet
[13]. Ianus et al. observed significant regeneration of architecture restoration has been observed after single
adult beta cells in diabetic mice after transplantation of or multiple infusions of MSCs [18, 19]. This effect might
BM-MSCs, despite only 1.7–3% of islet beta cells being have been mediated by the secretory effects of MSCs, as
of bone marrow origin [14]. Lechner et al. found no sig- the conditioned medium from cultured MSCs had the
nificant trans-differentiation of BM-MSCs into pancre- same capacity to regulate blood glucose in diabetic mice
atic beta cells in vivo (among >100,000 beta cells, only [20]. Lee et al. found that MSCs migrated to the islets of
two beta cells were potentially from donors) [15]. Choi streptozocin (STZ)-induced diabetic mice where they
et al. reported that the GFP-labeled cells were found in promoted tissue repair primarily by creating a microen-
the islets after bone marrow transplantation, but none of vironment that allowed endogenous cells to proliferate
these cells expressed insulin [16]. This information led to and regain their normal function [21]. The paracrine fac-
the thought that the differentiated islet progenitors were tors, such as vascular endothelial growth factor (VEGF)-
not the source of the regenerated pancreatic beta cells. alpha, insulin-like growth factor (IGF)-1, platelet-derived
Zang et al. Diabetol Metab Syndr (2017) 9:36 Page 4 of 11
growth factor (PDGF)-BB, and angiopoietin-1, also play MSCs have been reported to promote islet survival
an integral role in the process of cell regeneration [22]. against hypoxia and oxidative stress [54]. In the study
In Fox-01 ablation mice, a number of dedifferentiated by Chdravanshi et al. [54], after 48 h of direct contact
beta cells were reprogrammed into alpha cells, which co-culture with Wharton’s jelly-derived MSCs, islet
resulted in insulinopenia with hyperglucagonemia in cells exhibited higher viability and reduced apoptosis
early T2DM [45]. Another study provided circumstan- as compared with their controls without co-culture.
tial evidence that the phenomenon of beta-cell repro- In addition to amplified expression of anti-inflamma-
gramming into alpha cells occurs in humans [46]. In the tory cytokines like TGF-β and TNF-α and lower levels
mouse model of acute pancreatitis with severe defects in of pro-inflammatory cytokines, co-cultured islet cells
beta cells, islet alpha-cells converted directly into beta revealed reduced levels of reactive oxygen species,
cells to compensate for their absence, which resulted in nitric oxide, and super oxide ions, suggesting the pro-
the restoration of beta-cell function [47]. All these results tective effect of MSCs on islet cells against oxidative
indicated that islet alpha cells have an inherent potential stress-mediated cellular injuries. Given that oxidative
for spontaneous reprogramming into beta cells. When stress injury induced by hyperglycemia is recognized
Arx is aberrantly expressed in mature beta cells, conver- as a major etiological factor in the development of dia-
sion of beta cells into glucagon-producing cells occurs betes, further investigation of the antioxidant capacity
in adult mice [48]. Ectopic expression of Pax4 can force of MSCs for the promotion of islet survival may vali-
mature endocrine alpha cells to function like beta cells date the utility of MSC co-transplantation with islet
and reverse the consequences of STZ-mediated DM [49]. transplantation. Autophagy is a common intracellu-
However, such a spontaneous regeneration response was lar degradation process by which eukaryotes maintain
observed only in the case of extreme injury or beta-cell intracellular homoeostasis via degradation and recy-
ablation, which is usually not the case in humans. Our cling of damaged organelles and toxic proteins [55].
unpublished studies demonstrated that MSC infusion Autophagy plays an indispensable role in a variety of
was sufficient to promote trans-differentiation of alpha diseases, such as neurodegenerative disorders and car-
cells into beta cells. In mice with STZ-induced T2DM, diovascular diseases. Basal autophagy is essential for
intravenous infusion of allogeneic BM-MSCs resulted in maintaining the architecture and function of pancreatic
the appearance of considerable insulin/glucagon double islet beta cells. Both the deficiency and enhancement of
hormone-positive cells followed by restoration of beta- autophagy play a role in the pathogenesis of T2DM [56–
cell mass and dramatic amelioration of hyperglycemia. 59]. In a recent study, Zhao et al. found that co-culture
The intriguing conversion from alpha cell to beta cell can with BM-MSCs significantly alleviated the glucotoxicity
provide a revolutionary paradigm for treating DM via of INS-1 cells that had been induced by prolonged expo-
MSC infusion. sure to high glucose. Glucose toxicity in INS-1 cells was
characterized by decreased cell viability, increased cell
Protection of endogenous pancreatic islet beta cells apoptosis, and impaired basal insulin secretion and glu-
In addition to their regenerative properties, MSCs have cose-stimulated insulin secretion. A later study showed
also demonstrated an immunoregulatory capacity. MSCs that the protective effect of BM-MSCs on the INS-1
are also known as immunoprivileged cells because of the cells was mediated by promotion of autophagosome and
low intracellular expression of class II major histocom- autolysosome formation, which was considered to be a
patibility (MHC) proteins and co-stimulatory molecules symbol of autophagy [60]. Another study indicated that
[50, 51]. As the main effectors of the adaptive immune UC-MSCs improve wound healing in DM by inducing
response, T lymphocytes play a prominent role in auto- autophagy [61]. All these results provide evidence sup-
immune disease and transplant rejection. Some studies porting enhancement of autophagy by MSCs as an ideal
have demonstrated that MSCs suppress the proliferation strategy for the treatment of T2DM.
of T lymphocyte by inhibiting the energy metabolism of
the T cell population, promoting T-cell tolerance, or by Amelioration of insulin resistance
inducing proliferation of regulatory T-cell populations Dysfunction of insulin-producing pancreatic islet beta
[52]. Moreover, MSCs also inhibited the proliferation of cells and insulin resistance co-exist in T2DM. Therefore,
B cells and stopped a variety of immune cell functions, the mechanism underlying MSC treatment of DM in the
including cytokine secretion and cytotoxicity of T and experiments described above could not be adequately
natural killer (NK) cells, B cell maturation [53], and anti- explained solely by the potential ability of MSCs to pro-
body secretion. The immunosuppressive effects of MSCs mote pancreatic islet beta-cell function. Si et al. for the
attenuated the autoimmune processes that lead to the first time found that BM-MSC transplantation alleviated
destruction of pancreatic beta cells. hyperglycemia in rats with high-fat diet/STZ-induced
Zang et al. Diabetol Metab Syndr (2017) 9:36 Page 5 of 11
T2DM by activating the insulin receptor substrate questions about MSCs and insulin resistance remain
(IRS)-1 signaling pathway. This resulted in increased unanswered, these results shed new light on the effects
translocation and expression of GLUT-4, which further of autologous MSCs on obesity-related insulin resistance
resulted in BM-MSC–mediated amelioration of insulin in T2DM.
resistance in peripheral insulin target tissues [18]. Inter-
estingly, infusion of MSCs during the early phase (7 days) Clinical application of MSC transplantation for the
could restore β-cell function, ameliorate the destruction treatment of T2DM
of pancreatic islets, promote recruitment of MSCs to the In animal models, MSC treatment demonstrated excit-
damaged tissues, and reduce insulin resistance, whereas ing therapeutic effects on glycemic control by restoring
infusion in the late phase (21 days) merely ameliorated islet function and ameliorating insulin resistance. These
insulin resistance, suggesting a reasonable therapeutic results have now been translated into clinical practice.
time window in the early phase of diabetes [18]. Follow- A total of 96 registered phase I/II clinical studies among
ing this intriguing finding, Hughey et al. had a serendipi- T2DM patients can be found with the clinical trials reg-
tous discovery that glucose uptake in peripheral tissues, istry (http://www.clinicaltrials.gov). Thirteen papers
including skeletal muscle and adipose tissue, was elevated evaluating the clinical effects of MSC treatment in the
in MSC-treated mice with myocardial infarction. Fur- management of T2DM have been published, although
thermore, enhanced glucose uptake in these tissues was these include only four randomized, placebo-controlled
associated with improved insulin signaling as assessed by studies (Table 1).
Akt phosphorylation and the expression of GLUT-4 [62].
However, the mechanism by which MSCs ameliorated Clinical efficacy
insulin resistance could not be understood completely. As the clinical efficacy of MSC treatment for T2DM is
Insulin resistance is now considered to be closely a major concern, HbA1c reduction and insulin require-
related to systemic chronic low-grade inflammation. ments were frequently used as measures to assess the
Cytokines and chemokines, such as tumor necrosis fac- efficacy of MSC treatment for T2DM. In 2008, Estrada
tor alpha (TNF-α) and interleukin-1 beta (IL-1β), pro- et al. [69] first found that combination therapy with
duced by adipose tissue macrophages (ATMs) in an BM-MSC transplantation and hyperbaric oxygen ther-
M1 pro-inflammatory state have been identified as cru- apy (HOT) effectively reduced H bA1c levels in patients
cial effectors in the initiation of inflammation and the with T2DM for up to 1 year. In 2009, Bhansali et al.
development [63] of insulin resistance. However, an [70] demonstrated that the insulin requirements of 7
anti-inflammatory subset called M2, or alternatively out of 10 patients decreased by 75%, and three patients
activated macrophages, have been shown to play a role were able to discontinue insulin after a single BM-MSC
in preventing insulin resistance [64]. MSCs have been transplantation. Bhansali et al. [71] reported that 9 out
shown to exert anti-inflammatory effects by promoting of 11 patients (82%) achieved the primary end point of
M2 polarization in skin wounds and rhabdomyolysis- a 66.7% decrease in their insulin requirement. Together,
induced kidney injury, both in vitro and in vivo [65, 66]. these results proved that MSC transplantation should
Our research team recently confirmed that UC-MSCs be evaluated further for treatment of T2DM. However,
alleviate insulin resistance in T2DM rats by repro- the question about the duration of the effectiveness of
gramming classically activated macrophages (M1, pro- MSC treatment was raised simultaneously. Wang et al.
inflammatory) into an alternatively activated phenotype found that HbA1c levels decreased transiently as early as
(M2, anti-inflammatory). Further analysis showed that 1 month; however, HbA1c levels did not decline continu-
M1-stimulated UC-MSCs increased expression of IL-6. ously until the subsequent follow-up. The same phenom-
IL-6 upregulated IL4R expression, promoted phospho- enon was also observed in two other clinical trials carried
rylation of STAT6 in macrophages, and ultimately repro- out by Liu et al. and Hu et al.; HbA1c decreased in first
grammed macrophages into an M2 phenotype [67]. In 3 months and 1 year, but gradually increased in the next
addition, conditioned media from adipose tissue-derived 9 months and 2 years, respectively [72, 73]. Currently,
MSCs reversed insulin resistance in insulin-resistant cell this is a matter of concern for the development of use of
models, as evidenced by restored insulin and stimulated MSCs in the management of T2DM.
glucose uptake, via up-regulation of the GLUT4 gene Whether this poor response is due to route of adminis-
and reductions in IL-6 and plasminogen activator inhibi- tration of MSCs remains to be ascertained. On the other
tor-1 (PAI-1) gene expression [68]. Other results showed hand, more studies have proved that biological activ-
that UC-MSCs alleviate insulin resistance in rats with ity factors, such as VEGF, IGF-1, and β-FGF, secreted
T2DM by regulating the expression of NLRP3 inflamma- by MSCs can regulate the local microenvironment of
some in peripheral insulin target tissues. Although many the damaged tissue, inhibit cell apoptosis, improve the
Table 1 Summary of MSC-based therapies for type 2 diabetes
No Stem cell Randomized Mean dose Mode Follow-up Assessment of beta-cell Assessment Publication
type placebo-control of injected of injection period function of insulin
study cells/kg sensitivity
Zang et al. Diabetol Metab Syndr (2017) 9:36
immune defense system, and promote tissue regenera- that multiple injections of stem cells may produce a more
tion and revascularization. Systemic infusion of MSCs durable effect. Further research is needed to explore the
was believed to be superior to local injection because cumulative therapeutic effect of multiple MSC injections
the therapeutic effects of MSCs were mainly derived with short intervals.
from their secretory effects rather than their differen- The dosage of MSC infusions is another uncertain
tiation effect. Furthermore, systemic infusion not only issue. Various factors may influence the selection of the
reduces trauma but is also more convenient, especially treatment dose, such as the type of MSCs, route of cell
for patients requiring repeated administration. Although delivery, viability and purity of MSCs, and condition of
solid evidence from a rat model of diabetes suggested the patient [80]. In current clinical studies, the mean
selective localization of BrdU-labeled MSCs into the dose of injected cells ranges from 1 × 106 to 2.6 × 107/
pancreas after MSC infusion through the tail vein [74], kg of bodyweight due to the use of different cell types
how the route of administration affects the clinical effi- and counting methods [81]. Dose-dependent therapeu-
cacy of MSCs remains unclear. To address this ques- tic effects of MSC infusion have been reported in ani-
tion, Sood et al. infused 18F-FDG–labeled BM-MSCs mal experiments [82]. Similarly, a direct correlation was
via either the peripheral intravenous route or targeted found between the number of allogeneic MSCs applied
routes into the superior pancreaticoduodenal artery and and the therapeutic outcomes in treating type 2 diabe-
splenic artery. Positron emission tomography (PET) was tes. In a randomized, placebo-controlled, dose-escalation
used to track the homing and retention of the MSCs. The study, patients with type 2 diabetes inadequately con-
results showed that the best homing of MSCs in the pan- trolled with oral antidiabetic agents received allogeneic
creas was observed when cells were infused in the supe- BM-MSCs at a dose of 0.3 × 106, 1.0 × 106, or 2.0 × 106/
rior pancreaticoduodenal artery. No discernible homing kg. At week 12, the target HbA1c <7 mg/dL was achieved
of MSCs was observed in the intravenous route group; by 33% of the patients who received the 2.0 × 106/kg dose
cells infused via the intravenous route first entered in and 13.3% of those who received the 0.3 × 106/kg dose
the lung fields and then migrated and gained access to [83]. With only scattered evidence showing the benefits
the systemic circulation. They also found that the clini- of a high dosage of MSCs, further research is still needed
cal efficacy (HbA1c reduction and insulin requirement) of to determine an appropriate cell dose that is most effec-
cells delivered via the intravenous route was inferior to tive but still safe in a well-designed, dose-escalating clini-
that of cells delivered via the pancreaticoduodenal artery cal trial.
and the splenic artery [75]. Thus, the authors concluded HOT can promote stem cell mobilization and
that the intravenous route was the least effective route endothelial progenitor cell release by increasing the
for stem cell infusion. As the study had a small sample concentration of carbon monoxide synthase [84]. It was
size, this conclusion needs to be verified in larger scale hypothesized that the combination of HOT and MSC
investigations. transplantation can have a synergistic effect. Estrada
The next question about single versus multiple injec- et al. and Wang et al. proved that the combined strategy
tions also needed consideration. A few animal studies of HOT and MSCs led to reductions in HbA1c levels and
have compared the therapeutic effects of multiple MSC insulin requirement [69], while no interaction between
injections versus a single injection on diabetes [18, 19, HOT and BM-MSC infusion was observed by Wu et al.
76]. The results reveal that the beneficial effect of a single [85].
infusion of MSCs for ameliorating hyperglycemia is per- However, until now, there had been no studies compar-
haps maintained only for a period not exceeding 4 weeks ing the clinical efficacy of different sources of MSCs, pos-
[18]. However, currently there is no consensus on the sibly due to the lack of universally accepted criterion for
optimal time or interval of MSC infusion due to a lack defining MSC phenotypes and functional properties.
of direct comparisons of single versus multiple injections
in diabetes patients. Considering a single administration Evaluation of islet function
of MSCs may not be enough to maintain a therapeutic Improvement in islet function was regarded as the pri-
effect over a long period of time, a number of clinical mary mechanism of action of MSCs in the treatment
studies have been carried out using multiple MSC injec- of T2DM. Fasting levels of C-peptide, glucagon-stim-
tions, typically 2–4 times with 2- to 12-week intervals ulated C-peptide, or C-peptide area under the curve
[71, 77–79]. Bhansali et al. administered a second injec- (AUCC-pep), and homeostatic model assessment of beta-
tion of MSCs via the antecubital vein 12 weeks after the cell function (HOMA-β) have been used as evaluation
first injection via the transfemoral route into the superior indices in various clinical studies. As fasting C-peptide is
pancreaticoduodenal artery. This resulted in a further the most convenient and effective indicator, it was evalu-
reduction of insulin dose requirements [71], suggesting ated in all 13 published clinical studies [69–73, 75, 77,
Zang et al. Diabetol Metab Syndr (2017) 9:36 Page 8 of 11
78, 83–87] and the results obtained have been encourag- and the need for exogenous insulin injection [50]. In
ing. The functional capacity of islet cells in early phase a clinical trial carried out by Kong et al., fasting blood
insulin secretion and reservation were also assessed. glucose (FBG) and postprandial blood glucose (PBG) of
Glucagon-stimulated C-peptide was found to be signifi- patients in the intervention group reduced significantly
cantly increased in MSC-treated cases compared with reduced after transvenous UC-MSC transfusion, whereas
controls [71], and the area under the curve for C-pep- there was no significant increase in C-peptide levels. The
tide (AUCC-pep) increased 43.8% from baseline following results implied that UC-MSCs might have the capacity
MSC implantation [85]. In contrast to these favorable to restore insulin sensitivity in tissues to an extent that
outcomes, Skyler et al. and Kong et al. found that an further corrected hyperglycemia [78]. Unfortunately,
increase in fasting C-peptide levels was not detectable these two studies did not assess insulin resistance. As
after transvenous MSC transplantation [78, 83]. Wang the experiments indicated that MSCs had the poten-
et al. demonstrated that fasting C-peptide increased sig- tial of ameliorating insulin resistance, which might have
nificantly from baseline at 3 months after intrapancre- contributed to the long-term glycemic control of T2DM
atic MSC transfusion, but was similar to baseline levels in vivo and in vitro, indices evaluating insulin resistance
at later time points [78, 83]. Similar results were also should be measured in future clinical trials to elucidate
observed in clinical studies by Liu et al. and Hu et al. [72, the fundamental mechanism of the effects of the MSCs.
73]. Liu et al. found that fasting C-peptide progressively Our recent results showed that insulin requirements
increased with the peak value achieved at 6 months, and decreased by 50% and GIR significantly improved by
a slight decrease later at 12 months [72]. Hu et al. also 6 months after multiple intravenous injections of UC-
reported an improvement in C-peptide levels at 1 year MSCs in T2DM patients with poor glycemic control. This
after MSC implantation, but later there was a decreasing result confirmed that UC-MSCs reduce hyperglycemia in
trend in C-peptide levels over the following 2 years [73]. T2DM patients in part by ameliorating insulin resistance
Longer disease duration, older age, poor islet function of peripheral tissue.
and other complications of T2DM were associated with
a less conducive microenvironment for transplanted Adverse events
cells. Under these circumstances, there was only a short- Patient safety and the risk to benefit ratio continue to
term recovery of islet cell function and a negative impact be the most important considerations in clinical prac-
on the long-term clinical efficacy of transplanted MSCs. tice Therefore, adverse events were monitored in all of
the clinical trials evaluating MSC treatment for T2DM.
Evaluation of insulin resistance Potential risks of MSC treatment included pulmonary
Unlike promoting islet function, amelioration of insu- and upper respiratory adverse events (intravenous injec-
lin resistance using MSC treatment had not been given tion that leads to infused cells passing through the lungs),
adequate attention in either animal experiments or acute allergic and immunologic adverse events, and
clinical trials. Homeostatic model assessment of insu- damage caused by puncture and unwanted tissue forma-
lin resistance (HOMA-IR) has been commonly used tion. No acute allergic and immunologic adverse events
to evaluate the insulin resistance in peripheral tissues; were reported in all 13 studies [69–73, 75, 77, 78, 83–87]
however, glucose infusion rate (GIR) has been associated Unwanted tissue formation also was not found, but needs
with implementation difficulties. Bhansali et al. found to be assessed over long-term follow-up. A low incidence
that intrapancreatic BM-MSC transplantation did not of punctural hemorrhage, posttraumatic pain, and subcu-
improve HOMA-IR results [70]. Significant improve- taneous hematoma at the injection site following intra-
ment in HOMA-IR levels transplantation at 6 months, pancreatic MSC transplantation was reported by Wu
but not at 12 months was observed in a group receiving et al., Liu et al., and Bhansali et al., respectively [70, 72,
combined transvenous and intrapancreatic MSC [71]. 85]. Mild and moderate fever with spontaneous remis-
Liu et al. showed that fasting serum C-peptide and 2-h sion after transvenous MSC transplantation was reported
postprandial C-peptide levels were decreased to dif- in 13.6–22.2% of patients [72, 78]. Transient self-limiting
ferent degrees 1 month after intrapancreatic WJ-MSC nausea, vomiting, headache, abdominal pain, and upper
transplantation in subjects receiving insulin therapy, respiratory tract infection occasionally occurred after the
along with a reduction in their insulin requirements at MSC transplantation [70, 72, 83]. Minor hypoglycemia
the respective time points. The most probable explana- resulting from the use of anti-diabetic drugs was com-
tion for this contradictory phenomenon was that infused mon, whereas severe hypoglycemia was not frequently
WJ-MSCs rapidly improved general insulin resistance, reported as the patients were closely monitored by the
leading to a reduction in endogenous insulin secretion sponsors in the follow-up period.
Zang et al. Diabetol Metab Syndr (2017) 9:36 Page 9 of 11
Conclusions HWD and MYM assisted with the presentation of findings and assisted with
drafting and revising the manuscript. All authors read and approved the final
Results available from animal and human studies are manuscript.
encouraging, and MSC therapy may represent a new
paradigm for optimizing glycemic control in T2DM. Author details
1
Department of Endocrinology, Chinese PLA General Hospital, Beijing 100853,
However, many issues remain unresolved. Animal China. 2 Department of Molecular Biology, Institute of Basic Medicine, College
experiments demonstrated that MSCs relieve hypergly- of Life Science, Chinese PLA General Hospital, Beijing 100853, China.
cemia by differentiating into IPCs, improving pancre-
Acknowledgements
atic regeneration, promoting the conversion of alpha None.
cells to beta cells, and ameliorating insulin resistance.
As the animal models used for such experiments do Competing interests
The authors declare that they have no competing interests.
not truly represent T2DM patients, the fundamen-
tal mechanisms involved in the improvement in beta Availability of data and materials
cell function and/or insulin sensitivity require further All data generated or analysed during this study are included in this published
article.
investigation. To make new cell therapy-based strate-
gies a clinical reality, it is fundamentally necessary to Funding
identify sources of MSCs that do not have any ethical Work in the author’s laboratory is supported by the National Basic Science and
Development Program [2012CB518103] and the 863 Projects of Ministry of
conflicts. Maximal efficacy and durable therapeutic Science and Technology of China [2013AA020105].
effects along with minimal side effects are preferable
for a particular therapeutic application. Duration of Publisher’s Note
DM, residual beta-cell function, and the severity of Springer Nature remains neutral with regard to jurisdictional claims in pub-
complications (which reflect the microenvironment lished maps and institutional affiliations.
conditions) will affect treatment efficacy. Thus, the Received: 17 February 2017 Accepted: 5 May 2017
method of selection of appropriate patients for this
treatment needs to be determined. In addition, the
ideal route of administration of stem cells, whether
targeted or peripheral, should be identified. In the tar-
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