REVIEW ARTICLE Diabetes Management

Promising hope, treatment of diabetes

with a stem cell
Amira Ragab El Barky*, Ehab Mostafa Mohamed Ali & Tarek Mostafa Mohamed

ABSTRACT
Diabetes mellitus represents a serious global health problem. It is a widespread disease that’s
affecting many millions of people worldwide. One of the main effects is the decrease in β-cell
mass, which is ubiquitous in most of all patients with type 1 diabetes. The management of
diabetes without any side effects is still a challenge. Stem cell therapy holds a great promise
for the repair of injured tissues and organs. It is one of the most promising therapies for
diabetes mellitus. So, this article review aimed to educate the role of MSCS in diabetes.

GRAPHICAL ABSTRACT

Stem cell therapy for diabetes treatment

Introduction people that gain diabetes which will jump more

than 592 million [4]. Diabetes is implicated
Diabetes is a global health matter which
in numerous complications, for example,
characteristic of hyperglycemia, which prompts
retinopathy, neuropathy, kidney disease and
the reproduction of free radicals, hence oxidative
peripheral vascular disease [5]. Different
stress occur [1]. DM generated from the
pathogenic processes are implicated in the
destruction of the pancreatic beta cell which
advancement of diabetes, the t processes differ
causes decrease insulin secretion, defects of
from complete destruction of the pancreatic
insulin receptor and hence affects their action
β-cell to the oddity of insulin actions [2,3].
or it arises from a combination of them [2]. The
chronic hyperglycemia, which arises according to Stem cell therapy holds a great promise for the
diabetes, can cause severe damage, dysfunction repair of injured tissues and organs. It is one
and failure of various organs [3]. It is expected of the most promising therapies for diabetes
that by the year 2035, there will be numerous mellitus [6]. Transplanted islet tissue very

Chemistry Department, Biochemistry Division, Tanta University, Tanta, Egypt

*Author for correspondance: [email protected]

Diabetes Manag (2017) 7(3), 272–279 ISSN 1758-1907 272

REVIEW ARTICLE El Barky, Ali, Mohamed

KEYWORDS carefully mimics the physiology of the wasted Mesenchymal stem cells will grow and
islets and patients no longer need daily insulin differentiate according to their environment.
■■ diabetes injections. This review article aims to elucidate In vivo, when injected into the pancreas, it is
■■ stem cell the potential role of Mesenchymal Stem Cell predictable that MSCs can differentiate to create
■■ mesenchymal stem cell (MSCs) in controlling damages of vital tissues in pancreatic cells with exocrine and endocrine
diabetes. functions. Thus, transplantation of MSCs from
bone marrow stem cells can repair the pancreas in
ABBREVIATIONS its role to provide paracrine effects and other cell
Mesenchymal Stem Cell (MSCs)
■■ DM: Diabetes Mellitus differentiation effects [15]. Bone marrow stem
Stem cells are unspecialized cells that have the cells can differentiate into cells that can secrete
■■ IPCs: Insulin-Producing ability of self-renovation and differentiation insulin in-vitro [16,17], but Bartholomew et al.
Cells in response to the suitable signal [7]. MSCs were not able to confirm this finding.
■■ STZ: Streptozotocin are bone marrow cells, different from the
hematopoietic stem cells, which possess The pancreas is an organ that has limited ability
■■ TBARS: Thiobarbituric to proliferate [18]. However, these MSCs cells
Acid Reactive an extensive proliferative and capability to
differentiate into many different cell types, can proliferate and differentiate in-vitro [19]. The
Substances use of growth factors in differentiation processes
including osteocytes, adipocytes, chondrocytes,
■■ MSCs: Mesenchymal has been studied. Most of the growth factors are
myocytes, cardiomyocytes, and neurons [8]. The
Stem Cell pleiotropic and changes motility, proliferation,
greatest number of MSCs is found in neonates
than it is reduced during the lifespan to about morphogenesis and survival of cells [20].
one-half at the age of 80 [9]. Much different design has been utilized to
stimulate the differentiation of Insulin Producing
Stem cells and diabetes mellitus Cells (IPCs) from stem cells in-vitro. These
designs have participated in the differentiation
Insulin therapy has extremely improved the procedure by using special medium, a variety of
quality of life in patients with diabetes, especially induction and different growth factors, such as
in individuals with type 1 diabetes. However, the vitamin derivatives for example, nicotinamide
method is inaccurate and does not completely [21], GLP-1, which is an anti-diabetic agent
control the minute-to-minute variation in in β-cell expansion, function, propagation and
systemic blood glucose [10]. Because of these neogenesis [22], and nourished ES cells with
shortcomings, research has been directed towards all-trans retinoic acid [23], betacellulin, activin
establishing cells based therapies that circumvent A [24].
the need for exogenous insulin delivery by
conventional injection or most modern pump In T1DM rats, MSC was capable of
technology [11,12]. differentiating to create pancreatic insulin-
producing cells, releasing insulin and improving
Stem cells generate unbelievable interest in diabetic symptoms [25,26].
repairing failing tissues and organs [12]. The
stem cell remedy has become a good concept to Those insulin-producing pancreatic beta cells
create insulin-producing cells for patients with express the multiple genes that related to the
type I [13]. Langerhans islets have their own development or function of pancreatic beta cells,
glucose sensor, produce and release insulin in including high expression of pancreatic and
response to glucose, preserve normoglycaemia duodenal homeobox 1, insulin, and glucagon
and function. Therefore, β-cell replacement by [26], and were capable of releasing insulin in a
islet cell transplantation can prevent diabetes. glucose-dependent manner that led to refinement
The two types of clinical islet cell transplants diabetic state in STZ-induced diabetes in nude
which have been completed include allogeneic mice [26]. Transplantation of MSCs into STZ-
islet cell transplantation for the remedy of type 1 induced diabetes in C57Bl/6 mice prompts
diabetes and autologous islet cell transplantation achieving normal blood glucose level and prevents
for the protection of surgical diabetes after glycosuria. This was accompanied by improved
a total pancreatectomy. Allogeneic islet cell renal function tests and pancreatic histology of
transplantation has several hurdles such as regeneration of normal beta-pancreatic islets
unstable outcomes of islet isolation. The side [27]. In diabetic NOD mice, the injection of
effects which may arise from immunosuppressant MSC has the ability to reduce the diabetogenic
and demand to multiple people for transplant T cells to penetrate pancreatic beta cell islets and
the pancreas make it very difficult [14]. thus preventing the β-cell destruction [28].

273 Diabetes Manag (2017) 7(3)

 Promising hope, treatment of diabetes Review Article

There is a mutual action of MSC’s in co- culturing, then they differentiated to create
transplantation with pancreatic islets which pancreatic Insulin Secreting Cells (ISC) on day
resulted in amended graft morphology and 14, they quantified by using a hemocytometer
improved revascularization indicating that and tested for sterility, viability and insulin
possible trophic factors secreted by MSCs are secreting markers such as Pax-6, Ipf-1, and Isl-1
helping islet engraftment [29]. Furthermore, by immunofluorescence. The prepared inoculum
multiple intravenous (IV) injection of MSCs was then mixed with Hematopoietic Stem Cells
to a rodent model of T2DM resulted in (HSC) generated from 100-ml cultured BM
normal blood glucose levels, which kept stable which was aspirated on day 9 [35]. A combined
for approximately more than two months cell inoculum of the ISC and HSC was infused as
after infusion. Moreover, serum insulin and described previously into the portal circulation,
C-peptide levels were restored back to normal thymus and into the subcutaneous tissue [35].
levels after MSC injection and pancreatic islets Ten patients suffering from diabetes with mean
were repaired [30]. age 20.2, suffering from diabetes, approximately
8.1 years ago were subjected to MSCs infusion,
the results showed that MSCs treatment have
Previous and recent studies on stem cells
not any side effects to all of diabetic patients. All
treatment
of the patients had improvement in C-peptide,
On a study by Aziz et al. [31] they derived Hb1Ac, blood sugar levels and exogenous insulin
MSCs from the bone marrow of male albino demand. After 3 months of MSCs infusions,
rats, they characterized MSCs morphologically GAD antibodies were analyzed and it showed a
and by CD29 marker and they infused MSCs significant reduction [36].
(5 × 106 cell/rat) into STZ-induced diabetes
In a study by Gabr et al. [37], Bone Marrow
female rats. Diabetic female rats which received
Aspirates (BMA) were collected in an
MSCs displayed a significant decrease in serum
anticoagulant heparin falcon tube from six
glucose levels and a significantly increased
consenting donors (TABLE 1). The BMA were
serum insulin levels as compared with the STZ
diluted 1:1 with low glucose Dulbecco’s modified
non-treated group. Moreover, cardiovascular
Eagle’s medium, 10% fetal bovine serum. After
performance was also improved in the STZ/
3 days, the non-adherent cells were removed.
MSC group as compared with the STZ non-
The remaining adherent MSCs was cultured to
treated group [31]. Moreover, they stated
80% confluence before passaging with trypsin.
that MSCs improve the kidney function and
At passage 3, MSCs were differentiated to
concluded that MSC are capable of improving
create pancreatic insulin-producing cells. The
the kidney function and regenerating kidney
ability of differentiated cells was established
tissues in diabetic nephropathy rats most
normoglycaemia in diabetic nude mice was
probably through their paracrine action via
examined by their implantation in the renal sub
different growth factors such as VEGF, TGFβ
capsular space. The sera of diabetic mice that
& TNFα and anti-apoptotic action via bcl2 and
treated with IPCs contained human insulin and
Bax genes (TABLE 1) [32].
c-peptide but measly levels of mouse insulin.
Human cord blood, which derived from healthy BM-MSCs from diabetic and nondiabetic
donors and all of them were checked for any human subjects could be differentiated without
pathogenic antigen antibodies and only that are genetic manipulation to form IPCs that, when
free were used for isolating human cord blood- transplanted, could maintain euglycemia in
derived stem cells CB-SCs. They concluded that diabetic mice for 3 months [37].
T1D patients have realized an improvement of
EL Barky et al. [6] derived MSCs from bone
metabolic control and also, showed a significant
marrow of white male albino rats. MSCs were
reduction in an autoimmunity which lasts
distinguished morphologically and by CD –ve 34
several months after a single treatment and
and CD +ve 105. They were then differentiated
stated that the improvement may be achieved
into IPCs and both of them were infused into
with more than one dose. Notably, reversal of
the independently tail vein of STZ-induced
autoimmunity, leads to regeneration of islet
diabetes in rats (TABLE 1). They reported
β-cells and improvement of metabolic control in
that both MSC and IPCs therapy significantly
long-standing T1D subjects [33].
improved the body weight, S. Insulin, α-amylase,
MSC was generated from 10-gram adipose tissue adiponectin, creatinine, total cholesterol, TAG,
[34]. MSC was harvested on day 10 after MSCs IL-6, TNF-α and liver L-MDA and glycogen

274
REVIEW ARTICLE El Barky, Ali, Mohamed

Table 1. Sources and dosage of stem cell.

Experimental
Route of
Source Dosage models of Diabetic history After stem cell infusions Reference
administration
diabetes
Improved voiding function was
noted in ADSCs-treated rats
Diabetic animal group as compared with phosphate-
had modest reduction buffered saline-treated
Tail vein injection, of plasma insulin, rats. Though some ADSCs
Adipose Tissue Type II, female
3 × 106 autologous Detrusor at the significantly higher differentiated into smooth
Derived Stem Cells sprague-dawley [68]
ADSCs in 0.5 mL PBS time of repeat plasma glucose level, muscle cells, paracrine pathway
(ADSCs) rats (8 weeks old)
laparotomy and more dyslipidemia seems to play the main role in
relative to the control this process, thus resulting in
group. the reduction of apoptosis and
preservation of ‘‘suburothelial
capillaries network.
Blood glucose levels
(fasting and 2 h Plasma glucose level (fasting
post prandial) were and 2 h post prandial) was
Bone marrow significantly increased significantly decreased after
• 200,000 MSC cells.
mesenchymal stem after aloxan injection. transplantation of MSCs and
• 200,000 Pancreatic Wistar rats Intraperitoneally [15]
cells, pancreatic On the other hand PSCs. Moreover, C peptide and
Cells (PSCs)
cells both C-peptide insulin level was significantly
and insulin levels increasing after transplantation
were significantly of MSCs and PSCs
decreased.
MSCs treated group significantly
There was an
reduced elevated serum glucose
incredible increase
level. Also, both MSCs and
in the serum glucose
• Bone marrow IPCs treated group showed a
levels and a significant
mesenchymal significant increase in serum
1 × 105 MSCs cell/rat decrease in the serum
stem cells Type I, Wistar rats Tail vein injection insulin levels after six weeks of [6]
1 × 105 IPCs cell/rat insulin level in the
• Insulin Producing the experiment as compared
STZ-induced diabetes
Cells (IPCS) to the STZ-induced diabetes
groups as compared
group but it didn't reach the
to the control normal
normal value as compared to
group.
the control normal group.
The blood glucose levels were
Patients were All had normal lowered at second weeks
Human umbilical
type II diabetes laboratory findings and needed to reduce the
cord blood stem 1.5×107 cell Corpus cavernosa [69]
complicated with except diabetes medication doses from one
cells (hUCBSCs)
impotencies mellitus related one month in insulin and three
months in hypoglycemic agent
Bone marrow- Type1, Diabetic MSC therapy significantly
Intravenous Diabetic nephropathy
derived nephropathy improved 24 h urinary albumin,
10 cells per rat
6
injection in rat with blood glucose [32]
mesenchymal stem female albino serum urea, creatinine and
tail vein >200 mg/dl.
cells rats glucose levels.
The blood glucose levels of the
diabetic mice implanted with
Human bone • 1 million The diabetic mice
Renal the differentiated clusters of
marrow-derived undifferentiated Diabetic nude had blood glucose
subcapsular cells were normalized within few [37]
mesenchymal stem MSCs mice levels exceeded 16.5
space days, whereas those receiving
cells • 1,000 IPC clusters mmol/L.
no cells or undifferentiated cells
remained hyperglycemic.

levels in STZ-induced diabetes model and Mechanism action of MSCs in diabetes

concluded stem cells, which have the ability to
Diabetes Mellitus (DM) is metabolic, endocrine
differentiate into insulin-producing cells (IPCs),
disorder worldwide; it is usually accompanied
would provide a potentially free source of islet
by diverse complications such as, retinopathy,
cells for transplantation and mitigate the major
neuropathy, nephropathy and cardiovascular
limitations of availability and allogeneic rejection.
disease [38]. It is a major public health problem
Therefore, stem cell therapy is becoming the
throughout the world and is the leading cause of
most favorable therapy for DM [6].
global mortality [39].

275 Diabetes Manag (2017) 7(3)

 Promising hope, treatment of diabetes Review Article

Type-I is an autoimmune disorder with Bone marrow mesenchymal stem cells (BM-
complete destruction of the pancreatic β-cells so MSCs) can be utilized to originate insulin-
it characterized by insulin deficiency and requires producing cells [55]. BM-MSCs have a special
insulin injection for its treatment [2,3] whereas interest because patients with diabetes mellitus
Type-II is insulin resistance and it can manage who incidentally receive a bone marrow
by the administration of synthetic drugs [40]. transfusion can improve β-cell function [56].
Also, it’s lowering apoptotic factors, such as IL-
Both Type-I and Type-II diabetes are
1β so; it can lower apoptosis [57]. Mesenchymal
considerable public health concern with
stem cells have an immunosuppressive effect [58],
numerous complications, leading to a constant
anti-inflammatory and immunomodulatory
increase in treatment costs [41]. Several distinct
characteristics [59].
types of diabetes mellitus exist and are caused
by a complex interaction of genetics and Chen et al. [60] stated that MSCs could
environmental factors [42]. successfully differentiate in vitro to create
pancreatic β-like cells. These cells were
Oxidative stress results in macro and micro
morphologically identical to the pancreatic
vascular complications exerting toxicities on
beta cells. Moreover, they could also transcript,
different vital organs in the patient with diabetes
translate and excrete insulin. Mesenchymal stem
[43]. Oxidative stress is produced by the formation
cells can be converted to create pancreatic insulin-
of advanced glycation end product which has
producing cells and their potential therapeutic
a strong role with the diabetic complications
remedy for diabetes builds on the differentiation
[44]. Free radicals resulted in oxidative stress-
capacity [61]. When BMSCs at 3rd passage
mediated injury and enhanced program β-cell
70%-80% confluent, they were differentiated to
death [45]. It also reacts with polyunsaturated
create pancreatic insulin producing cells by using
fatty acids, which exist in the membrane and
cockatiel of a growth factor for example, activin
cause lipid peroxidation [46]. The high level of
A, β-fibroblast and epidermal growth factor, 2-
lipid peroxidation marker, Thiobarbituric Acid
mercaptoethanol, nicotinamide and high glucose.
Reactive Substances (TBARS), in the diabetes
Processing BMSCs with insulin-promoting
is conceded is an indication of the deficiency of
factors such as nicotinamide, high glucose
the antioxidant [47]. MSC has a beneficial effect
induction and growth factors such as activin A
on glycemic via a direct differentiation of cells
and GLP-1 can convert them to pancreatic beta
able to producing insulin, or through an indirect
cells and produce insulin. Nicotinamide, which
effect on secretion of immune modulators, which
is a poly (ADP-ribose) synthetase inhibitor,
prevent endogenous T cells from destruction
is a well-known inducer to differentiate stem
pancreatic β-cell, or other which still unknown
cells into pancreatic beta cells and can protect
factors, that have an effect on insulin secretion or
cells from glucotoxicity-induced by exposure to
action (FIGURE 1) [48].
high glucose [62]. Moreover, Tang et al. [62]
MSCs were able to differentiate to create theorized high glucose concentration is a strong
pancreatic insulin producing cells in STZ- inducer of pancreatic islet differentiation. But
T1DM animal models, secreting insulin and Sun et al. [61] stated that using media with high
relief, diabetic complication, These insulin- glucose concentration only cannot differentiate
producing cells express multiple genes such as bone marrow MSCs to create insulin producing
duodenal home box 1, insulin, and glucagon cells. Activin A, which is a member of the
and were able to secrete insulin that responsible transforming growth factor-beta super-family,
for decrease glucose level and hence ameliorate can adjust neogenesis of β-cells in rats and
diabetes in STZ- nude mice [49]. stimulate ESCs to create insulin producing cells
[63-65].
Some trophic factors, such as vascular endothelial
growth factor [50], ciliary neurotropic factor, Neshati et al. [64] reported that MSCs can be
Von Willebrand factor [51], and Il-6 [52], can be differentiated to create pancreatic beta cells by
released by MSCs and have the ability to prolong using media contain high glucose concentration,
islets’ life. Scuteri [53] confirmed that MSCs can nicotinamide and 2-mercaptoethanol.
provide long survival for Langerhans islets and Furthermore, Mohamed et al. [65] reported that
they also endow in creating Pdx1. Therefore, the low glucose medium concentrations can use for
utilization of stem cells is becoming the most cell expansion and for differentiation to create
promising therapy for DM [54]. pancreatic insulin producing cells. The medium

276
REVIEW ARTICLE El Barky, Ali, Mohamed

MSCs can simultaneously treat

hyperglycemia through

A direct effect

Differentiation to cells capable of

producing insulin

An indirect effect
Secretion of immunomodulatory
which prevents endogenous T-cells
from eliciting pancreatic β-cell
Other Effects
destruction

Which influence insulin secretion

or action?

Figure 1: The mechanism of action of MSCs in diabetes.

was replaced with high glucose, which considers Highlights

the first step of differentiation processes. The
• Diabetes mellitus is a metabolic disorder,
second step of differentiation MSCS to create
affecting many millions of people
pancreatic insulin producing cells is done
worldwide.
through treating both β-mercaptoethanol and
nicotinamide as promoting factors [66,67]. • DM generated from the destruction
Conclusion of the pancreatic beta cell or insulin
resistance.
This review article has displayed some of the main
• Stem cell therapy holds a great promise
roles of MSCs as a novel therapy for diabetes.
Stem cell therapy has generated incredible interest for the repair of injured tissues and
for failing tissues, organs repair and regeneration. organs.
Bone marrow Mesenchymal Stem Cells (MSCs) • Stem cell is one of the most promising
can be used to create pancreatic beta cells, thus therapies for diabetes mellitus.
patients no longer require multiple daily insulin
injections. Transplantation of MSCs could reform Transplanted islet tissue very carefully mimics
the pancreas in its role to provide paracrine effects the physiology of the wasted islets, and patients
and other cell differentiation effects. no longer need daily insulin injections.

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