Corresponding Author: Deby
Susanti Vinski
E-mail: [email protected]
INTRODUCTION
Therapeutic of Mesenchymal Stem Cells in Diabetes
In recent years,
diabetes mellitus has become one of the biggest health problems in the whole
world (S. Gao et al., 2022). It was estimated that approximately 463 million
adults worldwide suffer from diabetes in 2019, while it is estimated that by
2030 there will be 578 million people with diabetes (Saeedi et al., 2019). Diabetes is a major risk factor for stroke and
ischemic heart disease, which together represent high rates of mortality and
morbidity in adult patients (Lozano et al., 2012). Diabetes is also the leading cause of blindness and
chronic kidney disease in adults (Garofalo et
al., 2015); (Esteves et al.,
2008). For the prevention of diabetes
complications, improving glycemic control is essential. Type 2 diabetes mellitus (DMT2) accounts for 90% to
95% of diabetes mellitus cases. DMT2 occurs as a result of a combination of
dysfunction of insulin-producing pancreatic beta cells and insulin resistance (Raz et al., 2013). Initial treatment of DMT2 generally involves oral
antidiabetic drugs. However, over time, insulin becomes necessary for glycemic
control as the disease progresses. Currently, available therapeutic regimens
can improve hyperglycemia and temporarily improve insulin sensitivity in target
organs. However, these treatments cannot reverse insulin resistance as well as
disease progression and pancreatic beta cell dysfunction (Inzucchi, 2002).
However, none of
the available therapies modulate the course of the disease. Animal studies have
shown that glucagon-like peptide 1 (GLP 1) receptor agonists and dipeptidyl
peptidase IV (DPP IV) inhibitors lead to improved pancreatic beta cell
function. However, the improvement of beta cell function has not been confirmed
in humans (Sasaki et al., 2015); (H. Y. Kim et al.,
2014). Ideal therapy options for DMT2 may be strategies to
improve peripheral insulin resistance while promoting pancreatic beta cell
regeneration (Zang et al., 2017). Cell-based therapies have emerged as next-generation
drugs to address the complex pathophysiology of DMT2 (Volarevic et
al., 2011); (Cho et al.,
2018); (Dom�nguez-Bendala
et al., 2012). Mesenchymal stem cells (MSCs) have shown therapeutic
effects in animal studies as well as in clinical studies, opening the door to
new methods for treating DMT2. MSCs could self-renew and differentiate into
mesenchymal lineages, such as hydrogenic, adipogenic, and osteogenic lineages
in vitro. MSCs show low immunogenicity due to moderate expression of major
histocompatibility complex (MHC) class I and the absence of MHC class III as
well as costimulatory molecules on the cell surface (Y.-L. Si et al., 2011) (Yi Zhang et al., 2014). In addition, a variety of growth factors, cytokines,
and exosomes secreted by MSCs play an essential role in the regulation of
insulin sensitivity as well as pancreatic beta-cell dysfunction (Sivanathan et al.,
2015); (Su et al., 2019). Previous studies have shown that MSCs could exert
certain anti-diabetic effects, which is supported by evidence that multiple
infusions of MSCs can reverse hyperglycemia instead of a single infusion (Hao et al., 2013); (R. Jiang et al., 2011). This study aims to explain and analyze the effective
treatment of diabetes mellitus by Mesenchymal Stem Cells with respect to
traditional therapy based on oral anti-diabetic drugs. As well as to study its
regularly consistent properties.
METHOD
Patient�s data are collected regularly and recorded in
the patient�s notation book regarding the personal data and medical history.
Since stem cells can be utilized for almost all medical follow up complaints,
the use of stem cells is commonly based on the patient's own selection.
a.
There
are options to use the stem cell or other other kind of treatment handlings.
b.
Stem
cells consist of living cells which are maintained and cared for in
"CELLTECH STEM CELL and BANKING Laboratory" in a "cryo
tank" with a temperature of -1900C (below zero Celsius degree), carried
out by "close system" or "open system".
c.
Both
conditions are owned by �Celltech Stem Cell and Banking Laboratory. The main
concentration still relies on the source from Umbilical Cord and Umbilical Cord
Blood.
d.
Closed
System is also called a quantum process. These two methods are implemented at
the CELLTECH STEM CELL Laboratory." Stem cells are stored in vials
containing 20 million cells or more. The closed system is more efficient and
sterile because it runs automatically and quickly, in a well closed system away
from human interventions.
e.
A closed system is also
known as a "quantum stem cell".
f.
Provisioning is related to
the type and severity of disease and the quantity of cells that is required.
Dosis
a.
Based
on the patient's body weight multiplied by 1 million cells, is the requirements
dosis basically used. For a body weight e.g.of 70 kg, (1 X 70 million) cells
are required. The allogeneic trait of stem cells opens the possibility to
replace or increase the number of cells and regenerate to restore the number of
damaged cells. Its allogeneic properties can replace any cell in the target
location of recovery. The dose obviously depends on the number of damaged cells
and replacing it. In general, a package of 20 million cells is minimally
effective. More may be needed for more severe conditions.
b.
In
general, at least 6 months later, an inspection of its condition and
effectiveness needs to be carried out
c.
On
this occasion, treatment for diseases such as Praderwili syndrome, and Autism,
as well as other several others, have been
d.
successfully
treated.
RESULT AND DUSCUSSION
Mesenchymal Stem Cells
Mesenchymal stem
cells are pluripotent progenitor cells that can differentiate into osteoblasts,
adipocytes, chondrocytes, and other cell types of mesodermal origin (N. Kim & Cho,
2013). These cells have a high ability for self-renewal,
the ability of immunological regulation, low immunogenicity, and have an
essential role in clinical cell therapy. MSCs originate from different sources
and were first isolated from bone marrow (Vining & Mooney,
2017). Research has since shown that MSCs can be isolated
from various human tissues such as urine, menstrual blood, gingiva, synovium,
umbilical cord, and adipose tissue (Packer, 2018); (Kasoju et al., 2017). MSCs are good for transplantation due to their low
immunogenicity. After transplantation, MSCs can chemoattract near damaged
tissues and secrete various anti-inflammatory and growth factors to promote the
repair of damaged tissues (Jadalannagari &
Aljitawi, 2015). However, mesenchymal tumor cells and MSCs have many
identical phenotypes of stem genes, suggesting that some early tumor cells
originate from MSCs (Galie et al., 2008). The clinical application of MSCs has been limited by
factors revealed in studies showing that MSCs promote tumorigenesis through
immunological regulation, vascularization, and the promotion of tumor
interstitial remodeling (Yu et al., 2008); (Bagley et al., 2009). However, it was discovered that exosomes extracted
from an MSC culture medium have a repair function like MSCs and do not have the
risk of tumor formation (Timmers et al., 2008); (Cosenza et al., 2018).
MSCs are the
most used stem cells in the human body because they have been easily isolated
for many years. Since 2012, MSCs have been used clinically to treat various
diseases such as Crohn's disease, graft-versus-host disease, and knee
osteoarthritis. Type 1 diabetes mellitus is an autoimmune disease where immune
cells attack the beta cells of the pancreatic islets of Langerhans. However,
type 2 diabetes mellitus is thought to be a disease associated with insulin
resistance, although recent research has shown that the disease is associated
with immunological dysfunction. Therefore, MSC therapy may be a useful
treatment for type 1 and type 2 diabetes mellitus. In preclinical studies as
well as clinical studies, MSC transplantation in diabetic patients has shown
significant improvement in diabetes with no adverse effects (Dang et al., 2017).
The Mechanisms of MSC Therapy
Therapeutic
efficacy for DMT2 was hypothesized decades ago. However, the mechanisms of MSCs
have not yet been fully elucidated. Therefore, several potential mechanisms of
MSCs in DMT2 are described here (S. Gao et al., 2022).
Pancreatic Beta Cells Regeneration
MSCs promote
insulin production, which facilitates the regeneration of endogenous beta cells
of pancreatic islets. Previous studies have shown that MSCs can differentiate
into beta cells or insulin-producing cells in vitro (El-Sherbiny et al.,
2020); (Ghoneim et al., 2020); (L.-B. Chen et al.,
2004). In addition, a growing body of evidence suggests
that limited transdifferentiation of infused MSCs can occur in vivo to
facilitate the process of pancreatic regeneration as well as ameliorate
hyperglycemia in DMT2 models (S. Gao et al., 2022). In mice, in addition to streptozotocin-induced
increased insulin production 42 days after intravenous hBM-MSC injection, many
transplanted cells migrated into ductal structures as well as islet structures,
while only a minority of transplanted cells were labeled with insulin (Hess et al., 2003). MSCs can stimulate beta cell proliferation and
trigger endogenous insulin production, transdifferentiation of MSCs into beta
cells and transplant engraftment may not significantly contribute to pancreatic
function restoration (S. Gao et al., 2022).
MSCs have shown
the potential for repair through the secretion of various cytokines and growth
factors, including interleukin 6 (IL6), transforming growth factor β
(TGF-β), and vascular endothelial growth factor (VEGF), which participate
through autocrine and paracrine action. to lead to the improvement of islet
function (Caplan & Dennis,
2006) as well as the facilitation of the vascularization
process (Park et al., 2010). Some studies have linked the potential of MSCs for
islet repair to the apoptotic effects of MSCs. It has been demonstrated that
BM-MSCs can reduce islet cell apoptosis because reduced caspase 3 cleavage in
vivo was observed after MSC treatment (Borg et al., 2014). In addition, the anti-apoptotic effect of MSCs was
proven in a study where the regulation of reactive oxygen species (ROS) was
reduced, as well as superoxide ions, nitric oxide, caspase 8, caspase 3, and
p53, as well as the regulation of Bcl2 under hypoxic conditions (Chandravanshi &
Bhonde, 2017). BM-MSCs could attenuate endoplasmic reticulum
stress-induced apoptosis by Myc overexpression via cell-cell interaction or
stromal cell factor 1 (He et al., 2018).
In addition,
MSCs can also enhance the formation of autophagosomes by cleaning damaged
mitochondria and increasing insulin secretion (K. Zhao et al., 2015). Mitochondria are essential for energy production,
cell apoptosis, and signaling, and their function is important in many diseases
such as ischemia, diabetes, aging, and inflammation. Studies have shown that
MSC-mediated mitochondrial transfer is essential support for rescuing injured
cells and restoring mitochondrial function (Yuan et al., 2021); (Gomzikova et al.,
2021). MSC mitochondria can be transferred to beta cells
when under hypoxic conditions for replenishment (Rackham et al., 2020). Therefore, the rate of insulin secretion, as well as
the rate of oxygen consumption in islet cells, are improved after culturing
with MSCs. This indicates that mitochondrial transfer can potentially respond
to and alleviate oxidative and hypoxic stress resulting from excessive ROS
production in damaged mitochondria (Rackham et al., 2020). Mitochondria have an essential role in energy
metabolism, and therefore their intercellular transfer can partially explain
the therapeutic mechanism of MSCs in improving the regeneration of beta cells.
In addition, studies have postulated that the donation of mitochondria by MSCs
can prevent other complications that occur in diabetes, such as inflammation
and diabetic nephropathy (Konari et al., 2019); (Planat-Benard et al.,
2021); (Yuan et al., 2021).
MSC for Alleviation of Insulin Resistance
Insulin
resistance is a hallmark of DMT2 and describes the failure of cells to respond
to insulin during disease progression. Intravenous injection of BM-MSCs
increases GLUT expression and upregulates insulin receptor substrate 1 (IRS-1)
phosphorylation as well as AKT in insulin target tissues (Y. Si et al., 2012). This suggests that MSCs could alleviate insulin
resistance in T2DM patients (Si et al., 2012). MSCs inhibit the E3 ligase
Mitsugumin 53 (MG53) which promotes ubiquitinoylation of IRS-1 in skeletal
muscle (Wei et al., 2008). Skeletal muscle accounts for 70% to 80% of
insulin-stimulated glucose disposal, while inhibition of the IRS-1 ubiquitin
pathway may be key to alleviating insulin resistance (Shulman et al., 1990). Insulin resistance in Metabolic
Dysfunction-Associated Fatty Liver Disease (MAFLD) and other subsequent liver
diseases is associated with excessive production of inflammatory mediators as
well as their downstream signaling molecules. Here, evidence suggests that the
NOD-like receptor protein 3 (NLRP3) inflammasome plays an essential role in
obesity-induced insulin resistance (Esser et al., 2014). MSCs applied for the treatment of DMT2 showed that
the formation of NLRP3 was inhibited through the regulation of the immune
response of MSCs, leading to the improvement of GLUT4 and IRS-1 function in
liver cells (Sun et al., 2017).
Exosomes are
extracellular vesicles on the nanoscale and have the potential for tissue
regeneration and damage repair. In vivo experiments showed the therapeutic
effects of intravenously injected MSC exosomes on reducing blood glucose levels
and restoring IRS-1 phosphorylation as well as AKT signaling pathways in
insulin target tissues (Sun et al., 2017). It has been confirmed that exosomal miR-29b-3p can
regulate cellular insulin sensitivity with the help of sirtuin-1 (Su et al.,
2019), which is a class III histone deacetylase deeply involved in the
regulation of genomic stability, apoptosis, and gene expression. This suggests
that histone modification associated with insulin resistance is a potential
treatment approach for MSCs. In addition, insulin resistance can be improved by
reducing ROS< removal of dysfunctional mitochondria as well as alleviating endoplasmic
reticulum stress (Bi et al., 2018).
Hepatic Metabolic Homeostasis and MSCs
DMT2 is
associated with liver dysfunction where approximately 57% to 80% of baboons
suffering from DMT2 also suffer from MAFLD. The relationship between DMT2 and
MAFLD is bidirectional and complex because the characteristics and metabolic
syndromes are similar, such as glucose tolerance, oxidative stress, and lipid
accumulation in the liver (Anstee et al., 2013). Intravenous MSC therapy can lead to a significant
reduction in a panel of biochemical markers of liver function disorders caused
by a high-fat diet, such as aspartate aminotransferase (AST), alanine aminotransferase
(ALT), lactate dehydrogenase (LDH), and alkaline phosphatase (AKP). This
suggests that MSCs can improve liver function in DMT2 patients (Ezquer et al., 2011). The main regulators of lipid metabolism are PPARs,
which help control fatty acid balance, beta-oxidation, and adipogenesis. In
mice on a high-fat diet, after the introduction of MSC, PPAR-alpha was
increased while PPAR-gamma was decreased in the liver. This suggests that the
PPAR signaling pathway is modulated by MSCs, which has an impact on liver
metabolism (C.-W. Lee et al.,
2017).
Oxidative stress
caused by mitochondrial dysfunction leads to a metabolic imbalance in the liver
(Wei et al., 2008). The glutathione/oxidative glutathione (GSH/GSSG)
ratio was decreased, while the amount of superoxide dismutase, inversely
proportional to systemic ROS levels, was increased after MSC treatment (W. Jiang et al., 2018); (Ho et al., 2012). This leads to the assumption that MSC therapeutic
effect is largely related to metabolic homeostasis. Treatment with MSC
conditioned medium showed similar effects, indicating that paracrine effects
have a significant contribution to the repair process in DMT2 (Nagaishi et al., 2014). Intravenously injected MSC resides in the liver for
five days after administration and remains in the liver for 15 days after
treatment. Bioactive factors such as APOM and IGFBP2 secreted by MSCs paracrine
increase insulin sensitivity and reduce lipid accumulation in hepatocytes via
PI3K-AKT activation (Yuanyuan Zhang et al.,
2021).
Regulation of Systemic Inflammation and MSCs
The pathogenesis
of insulin resistance is associated with obesity, where chronic low-grade
inflammation and activation of the immune system are involved (Esser et al., 2014). Overexpression of inflammatory cytokines such as
IL1β, IL6, and TNF-α is therefore associated with the pathogenesis of
metabolic syndromes including MAFLD, atherosclerosis, and insulin resistance.
Abnormal changes in tissue and peripheral immune cells as well as their
regulatory function always accompany the development of diabetes, which
suggests that immune cells such as T cells, natural killer cells, and
macrophages simultaneously participate in the progression of DMT2 (Esser et al., 2014). MSCs have an immunomodulatory effect on B
lymphocytes, T cells, natural killer cells, and dendritic cells through
para-kinetic effects that include the secretion of extracellular vesicles,
growth factors, anti-inflammatory mediators, cytokines, chemokines, and enzymes
(J. Chen et al., 2021); (Hashemian et al.,
2015). MSC activation is subject to stimulation by many
inflammatory cytokines, including interferon-γ (INF-γ) and
TNF-α, which switch to an immunosuppressive phenotype inducing the
secretion of soluble factors that mediate immunomodulatory activities such as
IL10, indoleamine-pyrrole 2,3-dioxygenase (IDO, hepatocyte growth factor (HGF),
and prostaglandin E2 (PGE2) (Shrestha et al., 2021); (F. Gao et al., 2016). The paracrine immunomodulatory properties of MSCs
are mediated by different signaling pathways such as the Rap1/NF-κB
pathway (Ding et al., 2018). However, until now, the precise mechanism of
MSC-based immunomodulation is not fully understood, although MSCs are used to
treat immune-mediated disorders(Ma et al., 2014) (Singer & Caplan,
2011) which includes diabetes (S. Gao et al., 2022).
The results of
experiments carried out so far have shown in an animal model with diabetes that
the inflammatory status contributes to the modification of the pancreatic
microenvironment, and MSC treatment promotes the proliferation of regulatory T
cells to ensure long-term immunoregulatory effects (Boumaza et al., 2009). Th2 cytokines (IL13 and IL10) secreted by regulatory
T cells seem to play an essential role in the survival and activation of beta
cells through anti-inflammatory effects, where the definitive mechanism of
action is still unknown (Anne-Marie Madec et al., 2009). Mobilization of MSCs
by inflammatory factors in specific microenvironments has been demonstrated,
indicating that MSCs can induce the switch of macrophages to an
anti-inflammatory phenotype to alleviate insulin resistance in DMT2 patients (Yin et al., 2018)(Z. Xie et al., 2016). Classically activated macrophages (M1) can stimulate
MSCs to overexpress MCP-1 and IL6, which converts M1 to an alternatively
activated M2 phenotype. In the meantime, the expression of IL-4R is enhanced in
macrophages, which makes them sensitive to the IL4 stimulus. MSCs can reduce
systemic inflammatory cytokines to impair the action of insulin receptors as
well as the corresponding downstream signaling pathways by preventing the
formation of NLRP3 in the liver and adipose tissue (Sun et al., 2017). TNF-α and IL-1β secreted by DMT2 islets
can stimulate MSCs to secrete IL-1Ra, while this can potentially lead to
attenuation of islet inflammation (L. Wang et al., 2020).
Efficacy and Safety of MSC Therapy in Patients with DMT2
A pilot study in
China showed that transplantation of placenta derived MSCs in patients with
long-term DMT2 is easy, safe, and potentially effective (R. Jiang et al., 2011). 10 patients with DMT2 whose duration was greater
than or equal to three years participated in the research, glucose was poorly
controlled in these patients, and they were dependent on insulin. The study
participants were brought closer to real clinical conditions because they had
comorbidities that often occur in diabetics, such as vascular complications,
kidney disease, and heart disease (R. Jiang et al., 2011). Patients received an average of 1.35 * 106 kg of
placental stem cells during three separate treatments with one-month intervals
between therapeutic infusions (R. Jiang et al., 2011). HbA1c and insulin dose measurements six months after
MSC treatment showed a trend of improvement for all patients. After treatment
with MSCs, the release of insulin and C-peptide was improved (R. Jiang et al., 2011). According to a meta-analysis (El-Badawy &
El-Badri, 2016), patients with DMT2 may benefit from MSC therapy.
Another meta-analysis (Li et al., 2021) also showed that patients with diabetes may benefit
from MSC therapy. A meta-analysis (Li et al., 2021) included 10 studies with 239 patients with diabetes.
Compared to percentile levels, there were significant changes in F-CP, PBG,
FBG, HbA1C as well as insulin requirements in diabetic patients after MSC
therapy (Li et al., 2021). Another analysis showed that MSC therapy has a role
in glucose control in DMT2 patients (Ranjbaran et al.,
2021).
In diabetic
animals, human MSCs or islet-like cells derived from human MSCs have been
successfully transplanted (Ho et al., 2012); (J. Kim et al., 2012). Transplantation of MSCs in animals with diabetes
leads to a decrease in the level of glucose in the animals' blood. MSC infusion
can improve blood glucose homeostasis in animals with DMT2 and DMT1. After
infusion of MSCs, there was a reduction in blood glucose levels for several
days to two weeks, where the reduction was sustained from 20 days to 10 weeks
after treatment (Ho et al., 2012)(Ammar et al., 2015)(Zhou et al., 2015) (R. H. Lee et al.,
2006). Glycemic effects can be improved by multiple MSC
transplantations (R. H. Lee et al.,
2006)(Ho et al., 2012). After seven administrations of MSC therapy, glucose
levels are significantly normalized (Ho et al., 2012). Insulin-producing cells (IPCs) derived from MSCs are
effective for the treatment of diabetes. MSC-derived IPC cells have many
characteristics as true pancreatic beta cells including insulin production,
C-peptide expression, pancreatic beta cell-specific gene expression, and the
ability to respond to glucose �(Seyedi et al., 2016)(Gabr et al., 2013)(Seyedi et al., 2016) (Dang et al., 2015). IPCs transplanted into the kidney capsule (Kadam et al., 2010); (Hu et al., 2012) and liver (Timmers et al., 2008) led to a decrease in glucose levels three days after
treatment, while normalization occurred after more than nine weeks from
treatment or until graft removal (Kadam et al., 2010) (Timmers et al., 2008) while some results showed that IPC transplantation
did not lower glucose levels (Hu et al., 2012).
A meta-analysis (Rahim et al., 2018) that included 11 studies of stem cell therapy
involving 363 T2DM patients showed that stem cell treatment improved HbA1C, and
daily insulin requirements, and induced the specified variables. However, stem
cell therapy had a negative effect on C-peptide (Rahim et al., 2018). A meta-analysis (Rahim et al., 2018) revealed 20 different reported adverse effects of
stem cell therapy, where fever was the most frequently reported with an
incidence rate of 0.14%. In addition, patients rarely reported contusion,
muscle strain, hematuria, viral gastroenteritis as well as folliculitis
complications, the incidence rate of which was 0.02% (Rahim et al., 2018). Another study (Mathur et al., 2023) showed that treating patients with DMT2 with MSC
therapy led to a reduction in the dose of antidiabetic drugs over a period of
12 months. The effective dose of MSC therapy ranged from 1 * 106 cells/kg to
3.7 * 106 cells/kg (Mathur et al., 2023). After the treatment, the level of HbAc1 decreased by
an average of 32%, while the level of glucose in the blood was reduced by an
average of 45%. C-peptide levels in patients were reduced by 38% in two trials
and increased by 36% in four trials. No serious side effect (Mathur et al., 2023)s were noted in any of the trials (Mathur et al., 2023).
MSC Therapy for DMT2 Clinical Studies
DMT2 occurs
because of inflammation and immunological dysfunction, which are most likely
essential factors for the development of insulin resistance in this disease.
MSC therapy is expected to effectively cure DMT2 as well as ameliorate insulin
resistance in humans as was the case in animal studies (Huang et al., 2021)(H.-J. Kim et al.,
2018)(M. Wang et al., 2018) (Deng et al., 2018). al., 2018). Studies published so far have confirmed
that MSC therapy can effectively reduce HbA1c, PBG, and FBG, improve insulin
resistance, and reduce insulin requirements. During the follow-up period, MSC
therapy was shown to have a significant effect in clinical trials. Adverse
effects that occurred because of MSC therapy in clinical trials are nausea,
fever, vomiting, subcutaneous hematoma, minor hypoglycemia, and headache.
However, all symptoms were alleviated after symptomatic treatment and without side
effects and serious complications. However, previous studies have had a
follow-up period of only 12 months, and therefore longer studies are needed to
assess long-term complications and side effects. Although there are still many
challenges, according to the current results, MSC therapy represents a
potential method for DMT2 and promises new ways to treat diabetes (Huang et al., 2021).
The efficacy of
MSCs for the treatment of DMT2 was demonstrated by the publication of a
clinical study (A. Bhansali et al.,
2009) where B-MSCs were used and transplanted into the
pancreas of 10 patients suffering from DMT2. Patients were followed for six
months after treatment (A. Bhansali et al.,
2009). Seven out of 10 patients in the study reduced their
insulin requirements by more than 50%, while of these seven, two patients were
able to stop using insulin completely at day seven and day 41 after B-MSC
therapy (A. Bhansali et al.,
2009). In all patients, there was a significant reduction
in the need for insulin, an increase in C-peptide, and an improvement in HbA1c (A. Bhansali et al.,
2009). Subsequently, PD-MSCs were used in 10 patients in a
pilot phase I clinical trial where patients were administered three separate
intravenous doses of PD-MSCs at one-month intervals (R. Jiang et al., 2011). Follow-up tests were performed three months after
the last MSC dose (R. Jiang et al., 2011). In all patients treated with PD-MSC, there was a
significant decrease in HbA1c, a decrease in daily insulin doses, and an
increase in C-peptide levels (R. Jiang et al., 2011).
A randomized,
prospective, single-blind, and placebo-controlled study was conducted to
evaluate the safety and efficacy of B-MSC therapy in patients with DMT2 (A. Bhansali et al.,
2014). 21 patients participated in the research (A. Bhansali et al.,
2014), of which 11 patients received B-MSC therapy, and 10
received placebo therapy. Additional tests were performed three, six, and 12
months after the end of treatment. There was a significant improvement in
C-peptide levels and insulin dose between cases and controls (A. Bhansali et al.,
2014). Insulin requirement after B-MSC therapy was reduced
by more than 50% while HbA1c values were below 7% (A. Bhansali et al.,
2014). Another placebo-randomized controlled trial �(S. Bhansali et al.,
2017)examined the efficacy of autologous BM-MSCs compared
to bone marrow-derived mononuclear cells (BM-MNCs). 30 patients participated in
the study, of which 10 received a placebo, 10 BM-MSC, and 10 patients were
treated with BM-MNC (S. Bhansali et al.,
2017). There was a significant reduction in daily insulin
requirements in the BM-MSc group 12 months after the end of treatment. In the
BM-MNC group, after 12 months, the daily need for insulin was reduced and there
was a significant increase in C-peptide levels (S. Bhansali et al.,
2017). The reduction in daily insulin requirement was
greater in patients from the BM-MNC group compared to patients from the BM-MSC
group, while the BM-MNC group also showed increased sensitivity to insulin
after treatment (S. Bhansali et al.,
2017).
The described
studies showed that transplantation of MSCs leads to the alleviation of the
metabolic burdens that occur due to DMT2. The studies have shown that MSCs have
the ability to significantly reduce daily insulin requirements (A. Bhansali et al.,
2014); (S. Bhansali et
al., 2017) (A. Bhansali et
al., 2009); (R. Jiang et
al., 2011), to reduce HbA1c levels (A. Bhansali et al.,
2009); Jiang et al., 2011), as well as to increase
C-peptide levels (A. Bhansali et al.,
2009). However, further studies are needed to better
understand the efficacy of this therapy, as well as the mechanisms through
which MSC transplantation may lead to improvement in DMT2 patients (Cho et al.,
2018). In a rat model of DMT2, MSC therapy leads to a
reduction in blood glucose levels and effective mitigation of hyperglycemia (Hao et al., 2013) (M. Xie et al., 2017)(Z. Xie et al., 2016)(Y. Zhao et al., 2013) (Y. Si et al., 2012). Several mechanisms have been found to be involved in
the reduction that occurs in patients with DMT2, including improved insulin
sensitivity in peripheral tissues as well as the promotion of pancreatic beta
cell function. Insulin sensitivity is thought to be improved as a result of
increased GLUT4 expression as well as increased levels of phosphorylated IRS1
and AKT in target tissues. AKT and IRS1 represent part of the insulin signal
transduction pathway to promote GLUT4 translocation and glucose uptake. The
ability of MSCs to improve hyperglycemia may be short-lived because so far the
reduced blood glucose levels have been transient after MSC treatment. A single
infusion of MSCs leads to a reduction of hyperglycemia for four weeks, after
which hyperglycemia returns to the state before MSC treatment (Y. Si et al., 2012).
Another trial (Hao et al., 2013) also showed that the effects of MSC therapy lasted
only two to three weeks even after serial infusions of MSC therapy. Therefore,
additional studies are needed to determine the sustainability of MSC treatment
in DMT2 patients, as well as to clarify the exact mechanisms of MSC therapy.
However, the downside of animal studies is that animal models do not reflect
the true pathological state of DMT2 that occurs in humans (A. Bhansali et al.,
2014). More human clinical studies are needed to determine
the potential side effects of MSC treatments. In one study (A. Bhansali et al.,
2009), side effects noted were nausea in six out of 10
patients and vomiting in one out of 10 patients. In two patients from the study (A.
Bhansali et al., 2014), there was a sudden drop in hemoglobin
that was corrected within a month. However, another study (R. Jiang
et al., 2011) did not record any adverse effects of MSC
therapy, while improving heart and kidney function after MSC therapy was
observed. However, although minimal side effects were generally reported,
clinical studies only followed patients for 12 months and involved only a small
number of patients. Further studies are necessary that will include a larger
population of patients, and a longer period of follow-up of patients after the
end of treatment, to determine the efficacy and safety of MSC therapy in
patients with DMT2. The individual outcomes of the studies conducted so far
have given promising results. However, due to the different methodologies used
in the studies, it is difficult to compare the obtained results (Cho et al.,
2018).
Case Study
MSCs were
cultured in the laboratory to develop islet cells. Four patients with T2DM
participated in this case study. The average age of the patients was 62.5, of
which two were women and two were men. After MSC therapy, all patients
experienced a decrease in blood glucose and HbA1c levels.
Table 1. HbA1c in patients with
DMT2 after MSC therapy
|
Patient
|
Age
|
Sex
|
HbA1c (1) %
|
HbA1c (2) %
|
HbA1c (3) %
|
|
A
|
68
|
Female
|
6.4
|
6.1
|
|
|
B
|
56
|
Male
|
6.4
|
5.7
|
|
|
C
|
56
|
Male
|
5.8
|
5.7
|
5.5
|
|
D
|
70
|
Female
|
8.5
|
7.5
|
|
Table 2. Glucose levels after MSC therapy
|
Patient
|
Age
|
Sex
|
Glucose (1) mg/dL
|
Glucose (2) mg/dL
|
Glucose (3) mg/dL
|
|
A
|
68
|
Female
|
107
|
96
|
|
|
B
|
56
|
Male
|
107
|
95
|
|
|
C
|
56
|
Male
|
95
|
89
|
82
|
|
D
|
70
|
Female
|
189
|
173
|
|
Risks of Intravenous Administration of MSC Therapy
The
therapeutic effects of MSCs are greatly influenced by the delivery route of MSC
therapy. The most frequently used way of introducing MSC therapy in clinical
studies and research with animals is intravenous injection. A bioluminescence
system is used to monitor the in vivo biodistribution of MSCs. Impoverished
cell survival was activated after the majority of MSCs were trapped in
pulmonary capillaries and were eliminated within a few hours after injection in
the tail vein of mice (Schrepfer et al., 2007). However, during long-term follow-up, the fluorescence signal in
the lungs gradually disappeared, and therefore the fate of MSCs in the lungs is
controversial (de Witte et al., 2018). As a potential safety issue in cellular therapies, microthrombi
occur due to blockages of the pulmonary capillaries. Intravenous infusion of
MSCs leads to a decrease in the blood flow rate in the pulmonary capillaries,
which can lead to the formation of thrombus in the blood vessels (M�kel� et al., 2015). To address this issue, heparin was mixed with the cell
suspension during systemic injection (Liao et al., 2017). In addition, MSCs were treated with a hypertonic solution before
introduction to reduce cell size (Leibacher et al., 2017). There are suggestions that the size of MSCs will gradually
increase with extended passage of culture (Leibacher et al., 2017), and this suggests that infusion of low-passage MSCs will reduce
microthrombi formation (S. Gao et al., 2022).
Numerous
adverse effects of MSC therapy in DMT2 patients have been reported in previous
studies. Some even unwanted events can be interpreted because of disease
progression after cell therapy that did not have a sufficient therapeutic
effect. In three patients with age-related macular degeneration, vision loss
occurred as a negative reaction to adipose-derived MSC therapy (Kuriyan et al., 2017). MSC therapy in another study did not by itself lead to
full-thickness recovery of ulcerated skin after it was applied topically (Maksimova et al., 2022); (Baranovskii et al., 2022). The benefit-risk ratio and patient safety
are the most important factors in clinical practice. Therefore, all adverse events are monitored in clinical trials
with DMT2 patients and MSC treatment. Potential risks of MSC therapy include
adverse events in the upper respiratory tract and lungs (intravenous injection
causing infused cells to pass through the lungs), acute immunological and
allergic adverse events, as well as the formation of unwanted tissue and injury
caused by the puncture. Acute immunological and allergic adverse events were
not (Estrada et al., 2008); (A. Bhansali et al., 2009); (A. Bhansali et al., 2014); (Liu et al., 2014); (Hu et al., 2012); (Sood et al., 2015); (R. Jiang et al., 2011); (Kong et al., 2014); (Skyler et al., 2015); (Thom et al., 2006); (Wu et al., 2014); (Y. Zhao et al., 2013).
Although the
formation of unwanted tissue was not found, it should be evaluated during
long-term follow-up of patients. Studies (Wu et al., 2014); (A. Bhansali et al., 2009); (Liu et al., 2014) reported a low incidence of punctate hemorrhage, subcutaneous
injection site hematoma, and post-traumatic pain after MSC transplantation,
respectively. Moderate and relapsing fever with spontaneous remission after
transvenous MSC transplantation has been reported in 13.6% to 22.2% of patients
(Kong et al., 2014); (Liu et al., 2014). After MSC transplantation, patients experienced transient
self-limiting nausea, headache, vomiting, upper respiratory tract infection,
and abdominal pain (A. Bhansali et al., 2009); (Skyler et al., 2015); (Liu et al., 2014). Low hypoglycemia occurred frequently in patients who continued
to use antidiabetic drugs after MSC therapy, while severe hypoglycemia was not
reported (Zang et al., 2017).
CONCLUSION
This
study confirms the trust on the therapeutic power of stem cells for diabetes
mellitus and strongly provided consistent traits on other dysfunctions with
Prader-Willi syndrome and autism tests conducted in the previous quarter� before. Another opportunity gained with this
study was the support of the quantum closed system machine that successfully
cultivated the healthy stem cell product outputs to be applied to this study.� Based on the results of this study, the
management of the clinic decided to escalate the capacity and quality of the
stem cell culture machines and the experts of manpower in the near future.
REFERENCES
Ammar, H. I., Sequiera, G. L., Nashed, M. B., Ammar, R. I.,
Gabr, H. M., Elsayed, H. E., Sareen, N., Rub, E. A.-E., Zickri, M. B., &
Dhingra, S. (2015). Comparison of adipose tissue-and bone marrow-derived
mesenchymal stem cells for alleviating doxorubicin-induced cardiac dysfunction
in diabetic rats. Stem Cell Research & Therapy, 6(1), 1�14.
Anstee, Q. M., Targher, G., & Day, C. P. (2013).
Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis.
Nature Reviews Gastroenterology & Hepatology, 10(6), 330�344.
Bagley, R. G., Weber, W., Rouleau, C., Yao, M., Honma, N.,
Kataoka, S., Ishida, I., Roberts, B. L., & Teicher, B. A. (2009). Human
mesenchymal stem cells from bone marrow express tumor endothelial and stromal
markers. International Journal of Oncology, 34(3), 619�627.
Baranovskii, D. S., Klabukov, I. D., Arguchinskaya, N. V,
Yakimova, A. O., Kisel, A. A., Yatsenko, E. M., Ivanov, S. A., Shegay, P. V,
& Kaprin, A. D. (2022). Adverse events, side effects and complications in
mesenchymal stromal cell-based therapies. Stem Cell Investigation, 9.
Bhansali, A., Asokumar, P., Walia, R., Bhansali, S., Gupta,
V., Jain, A., Sachdeva, N., Sharma, R. R., Marwaha, N., & Khandelwal, N.
(2014). Efficacy and safety of autologous bone marrow-derived stem cell
transplantation in patients with type 2 diabetes mellitus: a randomized
placebo-controlled study. Cell Transplantation, 23(9), 1075�1085.
Bhansali, A., Upreti, V., Khandelwal, N., Marwaha, N., Gupta,
V., Sachdeva, N., Sharma, R. R., Saluja, K., Dutta, P., & Walia, R. (2009).
Efficacy of autologous bone marrow�derived stem cell transplantation in
patients with type 2 diabetes mellitus. Stem Cells and Development, 18(10),
1407�1416.
Bhansali, S., Dutta, P., Kumar, V., Yadav, M. K., Jain, A.,
Mudaliar, S., Bhansali, S., Sharma, R. R., Jha, V., & Marwaha, N. (2017).
Efficacy of autologous bone marrow-derived mesenchymal stem cell and
mononuclear cell transplantation in type 2 diabetes mellitus: a randomized,
placebo-controlled comparative study. Stem Cells and Development, 26(7),
471�481.
Bi, S., Nie, Q., Wang, W., Zhu, Y., Ma, X., Wang, C., Zhang,
B., Li, H., Zhang, Q., & Chen, G. (2018). Human umbilical cord mesenchymal
stem cells therapy for insulin resistance: a novel strategy in clinical
implication. Current Stem Cell Research & Therapy, 13(8), 658�664.
Borg, D. J., Weigelt, M., Wilhelm, C., Gerlach, M., Bickle,
M., Speier, S., Bonifacio, E., & Hommel, A. (2014). Mesenchymal stromal
cells improve transplanted islet survival and islet function in a syngeneic
mouse model. Diabetologia, 57, 522�531.
Boumaza, I., Srinivasan, S., Witt, W. T., Feghali-Bostwick,
C., Dai, Y., Garcia-Ocana, A., & Feili-Hariri, M. (2009). Autologous bone
marrow-derived rat mesenchymal stem cells promote PDX-1 and insulin expression
in the islets, alter T cell cytokine pattern and preserve regulatory T cells in
the periphery and induce sustained normoglycemia. Journal of Autoimmunity,
32(1), 33�42.
Caplan, A. I., & Dennis, J. E. (2006). Mesenchymal stem
cells as trophic mediators. Journal of Cellular Biochemistry, 98(5),
1076�1084.
Chandravanshi, B., & Bhonde, R. R. (2017). Shielding
engineered islets with mesenchymal stem cells enhance survival under hypoxia. Journal
of Cellular Biochemistry, 118(9), 2672�2683.
Chen, J., Zheng, C.-X., Jin, Y., & Hu, C.-H. (2021).
Mesenchymal stromal cell-mediated immune regulation: a promising remedy in the
therapy of type 2 diabetes mellitus. Stem Cells, 39(7), 838�852.
Chen, L.-B., Jiang, X.-B., & Yang, L. (2004).
Differentiation of rat marrow mesenchymal stem cells into pancreatic islet
beta-cells. World Journal of Gastroenterology: WJG, 10(20), 3016.
Cho, J., D�Antuono, M., Glicksman, M., Wang, J., &
Jonklaas, J. (2018). A review of clinical trials: mesenchymal stem cell
transplant therapy in type 1 and type 2 diabetes mellitus. American Journal
of Stem Cells, 7(4), 82.
Cosenza, S., Toupet, K., Maumus, M., Luz-Crawford, P.,
Blanc-Brude, O., Jorgensen, C., & No�l, D. (2018). Mesenchymal stem
cells-derived exosomes are more immunosuppressive than microparticles in
inflammatory arthritis. Theranostics, 8(5), 1399.
Dang, L. T.-T., Bui, A. N.-T., Pham, V. M., Phan, N. K.,
& Van Pham, P. (2015). Production of islet-like insulin-producing cell
clusters in vitro from adiposederived stem cells. Biomedical Research and
Therapy, 2, 1�9.
Dang, L. T.-T., Phan, N. K., & Truong, K. D. (2017).
Mesenchymal stem cells for diabetes mellitus treatment: new advances. Biomedical
Research and Therapy, 4(1), 1062�1081.
de Witte, S. F. H., Luk, F., Sierra Parraga, J. M., Gargesha,
M., Merino, A., Korevaar, S. S., Shankar, A. S., O�Flynn, L., Elliman, S. J.,
& Roy, D. (2018). Immunomodulation by therapeutic mesenchymal stromal cells
(MSC) is triggered through phagocytosis of MSC by monocytic cells. Stem
Cells, 36(4), 602�615.
Deng, Z., Xu, H., Zhang, J., Yang, C., Jin, L., Liu, J.,
Song, H., Chen, G., Han, W., & Si, Y. (2018). Infusion of adipose‑derived mesenchymal stem cells inhibits skeletal muscle
mitsugumin 53 elevation and thereby alleviates insulin resistance in type 2
diabetic rats. Molecular Medicine Reports, 17(6), 8466�8474.
Ding, Y., Liang, X., Zhang, Y., Yi, L., Shum, H. C., Chen,
Q., Chan, B. P., Fan, H., Liu, Z., & Tergaonkar, V. (2018). Rap1
deficiency-provoked paracrine dysfunction impairs immunosuppressive potency of
mesenchymal stem cells in allograft rejection of heart transplantation. Cell
Death & Disease, 9(3), 386.
Dom�nguez-Bendala, J., Lanzoni, G., Inverardi, L., &
Ricordi, C. (2012). Concise review: mesenchymal stem cells for diabetes. Stem
Cells Translational Medicine, 1(1), 59�63.
El-Badawy, A., & El-Badri, N. (2016). Clinical efficacy
of stem cell therapy for diabetes mellitus: a meta-analysis. PloS One, 11(4),
e0151938.
El-Sherbiny, M., Eladl, M. A., Ranade, A. V., Guimei, M.,
& Gabr, H. (2020). Functional beta-cells derived from umbilical cord blood
mesenchymal stem cells for curing rats with streptozotocin-induced diabetes
mellitus. Singapore Medical Journal, 61(1), 39.
Esser, N., Legrand-Poels, S., Piette, J., Scheen, A. J.,
& Paquot, N. (2014). Inflammation as a link between obesity, metabolic
syndrome and type 2 diabetes. Diabetes Research and Clinical Practice, 105(2),
141�150.
Esteves, J., Laranjeira, A. F., Roggia, M. F., Dalpizol, M.,
Scocco, C., Kramer, C. K., Azevedo, M. J., & Canani, L. H. (2008). Fatores
de risco para retinopatia diab�tica. Arquivos Brasileiros de Endocrinologia
& Metabologia, 52, 431�441.
Estrada, E. J., Valacchi, F., Nicora, E., Brieva, S., Esteve,
C., Echevarria, L., Froud, T., Bernetti, K., Cayetano, S. M., & Velazquez,
O. (2008). Combined treatment of intrapancreatic autologous bone marrow stem
cells and hyperbaric oxygen in type 2 diabetes mellitus. Cell
Transplantation, 17(12), 1295�1304.
Ezquer, M., Ezquer, F., Ricca, M., Allers, C., & Conget,
P. (2011). Intravenous administration of multipotent stromal cells prevents the
onset of non-alcoholic steatohepatitis in obese mice with metabolic syndrome. Journal
of Hepatology, 55(5), 1112�1120.
Gabr, M. M., Zakaria, M. M., Refaie, A. F., Ismail, A. M.,
Abou-El-Mahasen, M. A., Ashamallah, S. A., Khater, S. M., El-Halawani, S. M.,
Ibrahim, R. Y., & Uin, G. S. (2013). Insulin-producing cells from adult
human bone marrow mesenchymal stem cells control streptozotocin-induced
diabetes in nude mice. Cell Transplantation, 22(1), 133�145.
Galie, M., Konstantinidou, G., Peroni, D., Scambi, I.,
Marchini, C., Lisi, V., Krampera, M., Magnani, P., Merigo, F., & Montani,
M. (2008). Mesenchymal stem cells share molecular signature with mesenchymal
tumor cells and favor early tumor growth in syngeneic mice. Oncogene, 27(18),
2542�2551.
Gao, F., Chiu, S. M., Motan, D. A. L., Zhang, Z., Chen, L.,
Ji, H. L., Tse, H. F., Fu, Q.-L., & Lian, Q. (2016). Mesenchymal stem cells
and immunomodulation: current status and future prospects. Cell Death &
Disease, 7(1), e2062�e2062.
Gao, S., Zhang, Y., Liang, K., Bi, R., & Du, Y. (2022).
Mesenchymal stem cells (MSCs): a novel therapy for type 2 diabetes. Stem
Cells International, 2022.
Garofalo, C., Iazzetta, N., Camocardi, A., Pacilio, M.,
Iodice, C., Minutolo, R., De Nicola, L., & Conte, G. (2015). Anti-diabetics
and chronic kidney disease. Giornale Italiano Di Nefrologia: Organo
Ufficiale Della Societa Italiana Di Nefrologia, 32(5).
Ghoneim, M. A., Refaie, A. F., Elbassiouny, B. L., Gabr, M.
M., & Zakaria, M. M. (2020). From mesenchymal stromal/stem cells to
insulin-producing cells: progress and challenges. Stem Cell Reviews and
Reports, 16, 1156�1172.
Gomzikova, M. O., James, V., & Rizvanov, A. A. (2021).
Mitochondria donation by mesenchymal stem cells: current understanding and
mitochondria transplantation strategies. Frontiers in Cell and Developmental
Biology, 9, 653322.
Hao, H., Liu, J., Shen, J., Zhao, Y., Liu, H., Hou, Q., Tong,
C., Ti, D., Dong, L., & Cheng, Y. (2013). Multiple intravenous infusions of
bone marrow mesenchymal stem cells reverse hyperglycemia in experimental type 2
diabetes rats. Biochemical and Biophysical Research Communications, 436(3),
418�423.
Hashemian, S. J., Kouhnavard, M., & Nasli-Esfahani, E.
(2015). Mesenchymal stem cells: rising concerns over their application in
treatment of type one diabetes mellitus. Journal of Diabetes Research, 2015.
He, Y., Zhang, D., Zeng, Y., Ma, J., Wang, J., Guo, H.,
Zhang, J., Wang, M., Zhang, W., & Gong, N. (2018). Bone marrow-derived
mesenchymal stem cells protect islet grafts against endoplasmic reticulum
stress-induced apoptosis during the early stage after transplantation. Stem
Cells, 36(7), 1045�1061.
Hess, D., Li, L., Martin, M., Sakano, S., Hill, D., Strutt,
B., Thyssen, S., Gray, D. A., & Bhatia, M. (2003). Bone marrow�derived stem
cells initiate pancreatic regeneration. Nature Biotechnology, 21(7),
763�770.
Ho, J. H., Tseng, T.-C., Ma, W.-H., Ong, W.-K., Chen, Y.-F.,
Chen, M.-H., Lin, M.-W., Hong, C.-Y., & Lee, O. K. (2012). Multiple
intravenous transplantations of mesenchymal stem cells effectively restore
long-term blood glucose homeostasis by hepatic engraftment and β-cell
differentiation in streptozocin-induced diabetic mice. Cell Transplantation,
21(5), 997�1009.
Hu, J., Li, C., Wang, L., Zhang, X., Zhang, M., Gao, H., Yu,
X., Wang, F., Zhao, W., & Yan, S. (2012). Long term effects of the
implantation of autologous bone marrow mononuclear cells for type 2 diabetes
mellitus. Endocrine Journal, 59(11), 1031�1039.
Huang, Q., Huang, Y., & Liu, J. (2021). Mesenchymal stem
cells: an excellent candidate for the treatment of diabetes mellitus. International
Journal of Endocrinology, 2021.
Inzucchi, S. E. (2002). Oral antihyperglycemic therapy for
type 2 diabetes: scientific review. Jama, 287(3), 360�372.
Jadalannagari, S., & Aljitawi, O. S. (2015). Ectodermal
differentiation of wharton�s jelly mesenchymal stem cells for tissue
engineering and regenerative medicine applications. Tissue Engineering Part
B: Reviews, 21(3), 314�322.
Jiang, R., Han, Z., Zhuo, G., Qu, X., Li, X., Wang, X., Shao,
Y., Yang, S., & Han, Z. C. (2011). Transplantation of placenta-derived
mesenchymal stem cells in type 2 diabetes: a pilot study. Frontiers of
Medicine, 5(1), 94�100.
Jiang, W., Tan, Y., Cai, M., Zhao, T., Mao, F., Zhang, X.,
Xu, W., Yan, Z., Qian, H., & Yan, Y. (2018). Human umbilical cord
MSC-derived exosomes suppress the development of CCl 4-induced liver injury
through antioxidant effect. Stem Cells International, 2018.
Kadam, S. S., Sudhakar, M., Nair, P. D., & Bhonde, R. R.
(2010). Reversal of experimental diabetes in mice by transplantation of
neo-islets generated from human amnion-derived mesenchymal stromal cells using
immuno-isolatory macrocapsules. Cytotherapy, 12(8), 982�991.
Kasoju, N., Wang, H., Zhang, B., George, J., Gao, S.,
Triffitt, J. T., Cui, Z., & Ye, H. (2017). Transcriptomics of human
multipotent mesenchymal stromal cells: retrospective analysis and future
prospects. Biotechnology Advances, 35(4), 407�418.
Kim, H.-J., Li, Q., Song, W.-J., Yang, H.-M., Kim, S.-Y.,
Park, S.-C., Ahn, J.-O., & Youn, H.-Y. (2018). Fibroblast growth factor-1
as a mediator of paracrine effects of canine adipose tissue-derived mesenchymal
stem cells on in vitro-induced insulin resistance models. BMC Veterinary
Research, 14, 1�10.
Kim, H. Y., Hwang, J.-I., Moon, M. J., & Seong, J. Y.
(2014). A novel long-acting glucagon-like peptide-1 agonist with improved
efficacy in insulin secretion and β-cell growth. Endocrinology and
Metabolism, 29(3), 320�327.
Kim, J., Park, S., Kang, H. M., Ahn, C. W., Kwon, H. C.,
Song, J. H., Lee, Y. J., Lee, K. H., Yang, H., & Baek, S. Y. (2012). Human
insulin secreted from insulinogenic xenograft restores normoglycemia in type 1
diabetic mice without immunosuppression. Cell Transplantation, 21(10),
2131�2147.
Kim, N., & Cho, S.-G. (2013). Clinical applications of
mesenchymal stem cells. The Korean Journal of Internal Medicine, 28(4),
387.
Konari, N., Nagaishi, K., Kikuchi, S., & Fujimiya, M.
(2019). Mitochondria transfer from mesenchymal stem cells structurally and
functionally repairs renal proximal tubular epithelial cells in diabetic
nephropathy in vivo. Scientific Reports, 9(1), 5184.
Kong, D., Zhuang, X., Wang, D., Qu, H., Jiang, Y., Li, X.,
Wu, W., Xiao, J., Liu, X., & Liu, J. (2014). Umbilical cord mesenchymal
stem cell transfusion ameliorated hyperglycemia in patients with type 2
diabetes mellitus. Clinical Laboratory, 60(12), 1969�1976.
Kuriyan, A. E., Albini, T. A., Townsend, J. H., Rodriguez,
M., Pandya, H. K., Leonard, R. E., Parrott, M. B., Rosenfeld, P. J., Flynn Jr,
H. W., & Goldberg, J. L. (2017). Vision loss after intravitreal injection
of autologous �stem cells� for AMD. New England Journal of Medicine, 376(11),
1047�1053.
Lee, C.-W., Hsiao, W.-T., & Lee, O. K.-S. (2017).
Mesenchymal stromal cell-based therapies reduce obesity and metabolic syndromes
induced by a high-fat diet. Translational Research, 182, 61�74.
Lee, R. H., Seo, M. J., Reger, R. L., Spees, J. L., Pulin, A.
A., Olson, S. D., & Prockop, D. J. (2006). Multipotent stromal cells from
human marrow home to and promote repair of pancreatic islets and renal
glomeruli in diabetic NOD/scid mice. Proceedings of the National Academy of
Sciences, 103(46), 17438�17443.
Leibacher, J., Dauber, K., Ehser, S., Brixner, V., Kollar,
K., Vogel, A., Spohn, G., Sch�fer, R., Seifried, E., & Henschler, R.
(2017). Human mesenchymal stromal cells undergo apoptosis and fragmentation
after intravenous application in immune-competent mice. Cytotherapy, 19(1),
61�74.
Li, Y., Wang, F., Liang, H., Tang, D., Huang, M., Zhao, J.,
Yang, X., Liu, Y., Shu, L., & Wang, J. (2021). Efficacy of mesenchymal stem
cell transplantation therapy for type 1 and type 2 diabetes mellitus: a
meta-analysis. Stem Cell Research & Therapy, 12(1), 273.
Liao, L., Shi, B., Chang, H., Su, X., Zhang, L., Bi, C.,
Shuai, Y., Du, X., Deng, Z., & Jin, Y. (2017). Heparin improves BMSC cell
therapy: anticoagulant treatment by heparin improves the safety and therapeutic
effect of bone marrow-derived mesenchymal stem cell cytotherapy. Theranostics,
7(1), 106.
Liu, X., Zheng, P., Wang, X., Dai, G., Cheng, H., Zhang, Z.,
Hua, R., Niu, X., Shi, J., & An, Y. (2014). A preliminary evaluation of
efficacy and safety of Wharton�s jelly mesenchymal stem cell transplantation in
patients with type 2 diabetes mellitus. Stem Cell Research & Therapy,
5(2), 1�9.
Lozano, R., Naghavi, M., Foreman, K., Lim, S., Shibuya, K.,
Aboyans, V., Abraham, J., Adair, T., Aggarwal, R., & Ahn, S. Y. (2012).
Global and regional mortality from 235 causes of death for 20 age groups in
1990 and 2010: a systematic analysis for the Global Burden of Disease Study
2010. The Lancet, 380(9859), 2095�2128.
Ma, S., Xie, N., Li, W., Yuan, B., Shi, Y., & Wang, Y.
(2014). Immunobiology of mesenchymal stem cells. Cell Death &
Differentiation, 21(2), 216�225.
M�kel�, T., Takalo, R., Arvola, O., Haapanen, H.,
Yannopoulos, F., Blanco, R., Ahvenj�rvi, L., Kiviluoma, K., Kerkel�, E., &
Nystedt, J. (2015). Safety and biodistribution study of bone marrow�derived
mesenchymal stromal cells and mononuclear cells and the impact of the
administration route in an intact porcine model. Cytotherapy, 17(4),
392�402.
Maksimova, N. V, Michenko, A. V, Krasilnikova, O. A.,
Klabukov, I. D., Gadaev, I. Y., Krasheninnikov, M. E., Belkov, P. A., &
Lyundup, A. V. (2022). Mesenchymal stromal cell therapy alone does not lead to
complete restoration of skin parameters in diabetic foot patients within a
3-year follow-up period. BioImpacts: BI, 12(1), 51.
Mathur, A., Taurin, S., & Alshammary, S. (2023). The
Safety and Efficacy of Mesenchymal Stem Cells in the Treatment of Type 2
Diabetes-A Literature Review. Diabetes, Metabolic Syndrome and Obesity,
769�777.
Nagaishi, K., Ataka, K., Echizen, E., Arimura, Y., &
Fujimiya, M. (2014). Mesenchymal stem cell therapy ameliorates diabetic
hepatocyte damage in mice by inhibiting infiltration of bone marrow�derived
cells. Hepatology, 59(5), 1816�1829.
Packer, M. (2018). The Alchemist�s nightmare: Might
mesenchymal stem cells that are recruited to repair the injured heart be
transformed into fibroblasts rather than cardiomyocytes? Circulation, 137(19),
2068�2073.
Park, K.-S., Kim, Y.-S., Kim, J.-H., Choi, B., Kim, S.-H.,
Tan, A. H.-K., Lee, M.-S., Lee, M.-K., Kwon, C.-H., & Joh, J.-W. (2010).
Trophic molecules derived from human mesenchymal stem cells enhance survival,
function, and angiogenesis of isolated islets after transplantation. Transplantation,
89(5), 509�517.
Planat-Benard, V., Varin, A., & Casteilla, L. (2021).
MSCs and inflammatory cells crosstalk in regenerative medicine: concerted
actions for optimized resolution driven by energy metabolism. Frontiers in
Immunology, 12, 626755.
Rackham, C. L., Hubber, E. L., Czajka, A., Malik, A. N.,
King, A. J. F., & Jones, P. M. (2020). Optimizing beta cell function
through mesenchymal stromal cell-mediated mitochondria transfer. Stem Cells,
38(4), 574�584.
Rahim, F., Arjmand, B., Shirbandi, K., Payab, M., &
Larijani, B. (2018). Stem cell therapy for patients with diabetes: a systematic
review and meta-analysis of metabolomics-based risks and benefits. Stem Cell
Investigation, 5.
Ranjbaran, H., Mohammadi Jobani, B., Amirfakhrian, E., &
Alizadeh‐Navaei, R. (2021). Efficacy of mesenchymal stem cell therapy on
glucose levels in type 2 diabetes mellitus: A systematic review and meta‐analysis.
Journal of Diabetes Investigation, 12(5), 803�810.
Raz, I., Riddle, M. C., Rosenstock, J., Buse, J. B.,
Inzucchi, S. E., Home, P. D., Del Prato, S., Ferrannini, E., Chan, J. C. N.,
& Leiter, L. A. (2013). Personalized management of hyperglycemia in type
2 diabetes: reflections from a Diabetes Care Editors� Expert Forum. Am
Diabetes Assoc.
Saeedi, P., Petersohn, I., Salpea, P., Malanda, B.,
Karuranga, S., Unwin, N., Colagiuri, S., Guariguata, L., Motala, A. A., &
Ogurtsova, K. (2019). Global and regional diabetes prevalence estimates for
2019 and projections for 2030 and 2045: Results from the International Diabetes
Federation Diabetes Atlas. Diabetes Research and Clinical Practice, 157,
107843.
Sasaki, S., Miyatsuka, T., Matsuoka, T., Takahara, M.,
Yamamoto, Y., Yasuda, T., Kaneto, H., Fujitani, Y., German, M. S., &
Akiyama, H. (2015). Activation of GLP-1 and gastrin signalling induces in vivo
reprogramming of pancreatic exocrine cells into beta cells in mice. Diabetologia,
58, 2582�2591.
Schrepfer, S., Deuse, T., Reichenspurner, H., Fischbein, M.
P., Robbins, R. C., & Pelletier, M. P. (2007). Stem cell transplantation:
the lung barrier. Transplantation Proceedings, 39(2), 573�576.
Seyedi, F., Farsinejad, A., Nematollahi-Mahani, S. A.,
Eslaminejad, T., & Nematollahi-Mahani, S. N. (2016). Suspension culture
alters insulin secretion in induced human umbilical cord matrix-derived
mesenchymal cells. Cell Journal (Yakhteh), 18(1), 52.
Shrestha, M., Nguyen, T. T., Park, J., Choi, J. U., Yook, S.,
& Jeong, J.-H. (2021). Immunomodulation effect of mesenchymal stem cells in
islet transplantation. Biomedicine & Pharmacotherapy, 142,
112042.
Shulman, G. I., Rothman, D. L., Jue, T., Stein, P., DeFronzo,
R. A., & Shulman, R. G. (1990). Quantitation of muscle glycogen synthesis
in normal subjects and subjects with non-insulin-dependent diabetes by 13C
nuclear magnetic resonance spectroscopy. New England Journal of Medicine,
322(4), 223�228.
Si, Y.-L., Zhao, Y.-L., Hao, H.-J., Fu, X.-B., & Han,
W.-D. (2011). MSCs: biological characteristics, clinical applications and their
outstanding concerns. Ageing Research Reviews, 10(1), 93�103.
Si, Y., Zhao, Y., Hao, H., Liu, J., Guo, Y., Mu, Y., Shen,
J., Cheng, Y., Fu, X., & Han, W. (2012). Infusion of mesenchymal stem cells
ameliorates hyperglycemia in type 2 diabetic rats: identification of a novel
role in improving insulin sensitivity. Diabetes, 61(6), 1616�1625.
Singer, N. G., & Caplan, A. I. (2011). Mesenchymal stem
cells: mechanisms of inflammation. Annual Review of Pathology: Mechanisms of
Disease, 6, 457�478.
Sivanathan, K. N., Rojas-Canales, D. M., Hope, C. M.,
Krishnan, R., Carroll, R. P., Gronthos, S., Grey, S. T., & Coates, P. T.
(2015). Interleukin-17A-induced human mesenchymal stem cells are superior
modulators of immunological function. Stem Cells, 33(9), 2850�2863.
Skyler, J. S., Fonseca, V. A., Segal, K. R., &
Rosenstock, J. (2015). Allogeneic mesenchymal precursor cells in type 2
diabetes: a randomized, placebo-controlled, dose-escalation safety and
tolerability pilot study. Diabetes Care, 38(9), 1742�1749.
Sood, V., Mittal, B. R., Bhansali, A., Singh, B., Khandelwal,
N., Marwaha, N., & Jain, A. (2015). Biodistribution of 18F-FDG-labeled
autologous bone marrow�derived stem cells in patients with type 2 diabetes
mellitus: exploring targeted and intravenous routes of delivery. Clinical
Nuclear Medicine, 40(9), 697�700.
Su, T., Xiao, Y., Xiao, Y. E., Guo, Q. I., Li, C., Huang, Y.,
Deng, Q., Wen, J., Zhou, F., & Luo, X.-H. (2019). Bone marrow mesenchymal
stem cells-derived exosomal MiR-29b-3p regulates aging-associated insulin
resistance. ACS Nano, 13(2), 2450�2462.
Sun, X., Hao, H., Han, Q., Song, X., Liu, J., Dong, L., Han,
W., & Mu, Y. (2017). Human umbilical cord-derived mesenchymal stem cells
ameliorate insulin resistance by suppressing NLRP3 inflammasome-mediated
inflammation in type 2 diabetes rats. Stem Cell Research & Therapy, 8,
1�14.
Thom, S. R., Bhopale, V. M., Velazquez, O. C., Goldstein, L.
J., Thom, L. H., & Buerk, D. G. (2006). Stem cell mobilization by
hyperbaric oxygen. American Journal of Physiology-Heart and Circulatory
Physiology.
Timmers, L., Lim, S. K., Arslan, F., Armstrong, J. S.,
Hoefer, I. E., Doevendans, P. A., Piek, J. J., El Oakley, R. M., Choo, A.,
& Lee, C. N. (2008). Reduction of myocardial infarct size by human
mesenchymal stem cell conditioned medium. Stem Cell Research, 1(2),
129�137.
Vining, K. H., & Mooney, D. J. (2017). Mechanical forces
direct stem cell behaviour in development and regeneration. Nature Reviews
Molecular Cell Biology, 18(12), 728�742.
Volarevic, V., Arsenijevic, N., Lukic, M. L., &
Stojkovic, M. (2011). Concise review: mesenchymal stem cell treatment of the
complications of diabetes mellitus. Stem Cells, 29(1), 5�10.
Wang, L., Liu, T., Liang, R., Wang, G., Liu, Y., Zou, J.,
Liu, N., Zhang, B., Liu, Y., & Ding, X. (2020). Mesenchymal stem cells
ameliorate β cell dysfunction of human type 2 diabetic islets by reversing
β cell dedifferentiation. EBioMedicine, 51.
Wang, M., Song, L., Strange, C., Dong, X., & Wang, H.
(2018). Therapeutic effects of adipose stem cells from diabetic mice for the
treatment of type 2 diabetes. Molecular Therapy, 26(8), 1921�1930.
Wei, Y., Rector, R. S., Thyfault, J. P., & Ibdah, J. A.
(2008). Nonalcoholic fatty liver disease and mitochondrial dysfunction. World
Journal of Gastroenterology: WJG, 14(2), 193.
Wu, Z., Cai, J., Chen, J., Huang, L., Wu, W., Luo, F., Wu,
C., Liao, L., & Tan, J. (2014). Autologous bone marrow mononuclear cell
infusion and hyperbaric oxygen therapy in type 2 diabetes mellitus: an
open-label, randomized controlled clinical trial. Cytotherapy, 16(2),
258�265.
Xie, M., Hao, H. J., Cheng, Y. U., Xie, Z. Y., Yin, Y. Q.,
Zhang, Q., Gao, J. Q., Liu, H. Y., Mu, Y. M., & Han, W. D. (2017).
Adipose-derived mesenchymal stem cells ameliorate hyperglycemia through
regulating hepatic glucose metabolism in type 2 diabetic rats. Biochemical
and Biophysical Research Communications, 483(1), 435�441.
Xie, Z., Hao, H., Tong, C., Cheng, Y., Liu, J., Pang, Y., Si,
Y., Guo, Y., Zang, L., & Mu, Y. (2016). Human umbilical cord-derived
mesenchymal stem cells elicit macrophages into an anti-inflammatory phenotype
to alleviate insulin resistance in type 2 diabetic rats. Stem Cells, 34(3),
627�639.
Yin, Y., Hao, H., Cheng, Y., Zang, L., Liu, J., Gao, J., Xue,
J., Xie, Z., Zhang, Q., & Han, W. (2018). Human umbilical cord-derived
mesenchymal stem cells direct macrophage polarization to alleviate pancreatic
islets dysfunction in type 2 diabetic mice. Cell Death & Disease, 9(7),
760.
Yu, J. M., Jun, E. S., Bae, Y. C., & Jung, J. S. (2008).
Mesenchymal stem cells derived from human adipose tissues favor tumor cell
growth in vivo. Stem Cells and Development, 17(3), 463�474.
Yuan, Y., Yuan, L., Li, L., Liu, F., Liu, J., Chen, Y.,
Cheng, J., & Lu, Y. (2021). Mitochondrial transfer from mesenchymal stem
cells to macrophages restricts inflammation and alleviates kidney injury in
diabetic nephropathy mice via PGC-1α activation. Stem Cells, 39(7),
913�928.
Zang, L., Hao, H., Liu, J., Li, Y., Han, W., & Mu, Y.
(2017). Mesenchymal stem cell therapy in type 2 diabetes mellitus. Diabetology
& Metabolic Syndrome, 9, 1�11.
Zhang, Yi, Cai, W., Huang, Q., Gu, Y., Shi, Y., Huang, J.,
Zhao, F., Liu, Q., Wei, X., & Jin, M. (2014). Mesenchymal stem cells
alleviate bacteria‐induced liver injury in mice by inducing regulatory
dendritic cells. Hepatology, 59(2), 671�682.
Zhang, Yuanyuan, Gao, S., Liang, K., Wu, Z., Yan, X., Liu,
W., Li, J., Wu, B., & Du, Y. (2021). Exendin-4 gene modification and
microscaffold encapsulation promote self-persistence and antidiabetic activity
of MSCs. Science Advances, 7(27), eabi4379.
Zhao, K., Hao, H., Liu, J., Tong, C., Cheng, Y., Xie, Z.,
Zang, L., Mu, Y., & Han, W. (2015). Bone marrow-derived mesenchymal stem
cells ameliorate chronic high glucose-induced β-cell injury through
modulation of autophagy. Cell Death & Disease, 6(9), e1885�e1885.
Zhao, Y., Jiang, Z., Zhao, T., Ye, M., Hu, C., Zhou, H., Yin,
Z., Chen, Y., Zhang, Y., & Wang, S. (2013). Targeting insulin resistance in
type 2 diabetes via immune modulation of cord blood-derived multipotent stem
cells (CB-SCs) in stem cell educator therapy: phase I/II clinical trial. BMC
Medicine, 11, 1�13.
Zhou, Y., Hu, Q., Chen, F., Zhang, J., Guo, J., Wang, H., Gu,
J., Ma, L., & Ho, G. (2015). Human umbilical cord matrix-derived stem cells
exert trophic effects on β-cell survival in diabetic rats and isolated
islets. Disease Models & Mechanisms, 8(12), 1625�1633.
