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Stem Cell Therapy for Diabetes Treatment

Article in Journal of Experimental and Basic Medical Sciences · February 2024

DOI: 10.5606/jebms.2024.1074

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Journal of Experimental and Basic Medical Sciences 2024;5(1):60-68
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Review

Stem Cell Therapy for Diabetes Treatment

Aslı Melike Ekmekçi1, Mai Abusalim1, Oytun Erbaş1

Glucose in the blood is regulated by beta (β)-cells ABSTRACT

secreted by the pancreas. Insulin plays a crucial role
Diabetes mellitus (DM) is a widespread metabolic disease
as a primary regulator of homeostasis since no other
characterized by the disruption of blood glucose regulation,
hormone is capable of reducing blood glucose levels. primarily caused by dysfunctional pancreatic beta (β)-cells.
Diabetes mellitus (DM) is characterized by β-cell For the repair of β-cells, alternative approaches such as
function loss, which leads to elevated blood glucose embryonic stem cells, mesenchymal stem cells, and induced
levels. The insulin-releasing pancreatic β-cells are pluripotent stem cells (iPSCs) are on the agenda due to
the limitations of factors such as donor deficiency in islet
destroyed or rendered ineffective, leading to DM. It cell transplantation treatment. It is aimed to produce real
is a metabolic condition that has spread worldwide. β-cells with the contributions of stem cell-based clinical
According to projections, it is estimated to reach studies conducted in recent years. In this chapter, stem
552 million cases in 2030.[1] There are two primary cell transplantation is considered an alternative stem cell-
based therapy in diabetes for insulin independence through
types: type 1 diabetes mellitus (T1DM) and type 2
various means such as β-cell differentiation and β-cell
diabetes mellitus (T2DM). The pathophysiology of repair. Current and traditional treatment methods applied
T2DM comprises the development of resistance in in Type 1 diabetes and Type 2 diabetes are not sufficient
insulin target tissues followed by β-cell malfunction to prevent the devastating damage of microvascular and
due to a mix of genetic and environmental factors, macrovascular complications. For this reason, promising
stem cell approaches have been discussed in DM as well
in contrast to T1DM, which is defined by β-cell death as its complications. This chapter focuses on the curative
leading to autoimmune dysfunction.[2] Monogenic potential of cells with excellent differentiation ability, such
diabetes, a less frequent form of the disease, is caused as embryonic, adult, and iPSCs, in DM and its complications,
by a particular gene mutation that affects pancreas which despite the discovery of insulin remain fatal.
Keywords: Beta cells, diabetes mellitus, stem cells, stem cell therapy,
development and β-cell function.[3] embryonic stem cell.
The literature demonstrates the availability of a
range of therapeutic strategies for the management
of diabetes. The most popular techniques include One promising treatment is the exchange of
diet restriction, oral antidiabetic drugs, and insulin.[4-6] β-cells via transplantation of islets of Langerhans,
yet unfortunately, the lack of donors is the primary
cause of its underuse. For this approach, human
1
ERBAS Institute of Experimental Medicine, Illinois, USA & Gebze, Türkiye pluripotent stem cells (PSCs), such as embryonic stem
cells (ESCs) and induced pluripotent stem cells (iPSCs),
Correspondence: Aslı Melike Ekmekçi. Institute of Experimental Medicine, are a crucial supply of β-cells. With further studies,
41470 Gebze-Kocaeli, Türkiye
we have come remarkably close to the original form.
E-mail: aslimelike01@gmail.com
However, the challenges of producing a fully mature
Cite this article as: Ekmekçi AM, Abusalim M, Erbaş O. Stem Cell Therapy for
Diabetes Treatment. JEB Med Sci 2024;5(1):60-68. β-cell remain.[7] This has the potential to be a real
cure for T1DM and possibly T2DM and MD. Islet cell
doi: 10.5606/jebms.2024.1074 transplantation (ICT) has been associated with less
progression of microvascular complications such as
Received : November 3, 2023
Accepted : November 12, 2023 diabetic nephropathy (DNP), diabetic neuropathy (DN),
Published online : February 26, 2024 diabetic retinopathy (DR), and others.[8] In different
©2024 Journal of Experimental and Basic Medical Sciences. All rights reserved. research with a three-year follow-up, ICT was superior
Stem Cell Therapy for Diabetes Treatment 61

to intensive medical therapy in terms of improving million people with diabetes worldwide continue to
hemoglobin A1c and slowing the progression of DR.[9] suffer from catastrophic consequences such as DNP,
Despite its ability to save lives, insulin often does not DN, and DR.[20]
halt the development of end-stage microvascular
Diabetes occurs when the pancreatic cells
complications in patients, thus, patients still face
responsible for insulin secretion become dysfunctional
diabetes fatal consequences despite the development
or produce insufficient insulin, the body does not
of insulin. Stem cell-based alternative therapy has
respond to the produced insulin, and glucose builds
eventually become a candidate for high interest
up in the blood. As a result of this inability to manage
over injected insulin as an important approach for
glucose, diabetes-related micro-, and macrovascular
diabetes treatment. Nonetheless, further research is
effects occur. Thirst, polyphagia, weight changes,
needed to overcome various clinical challenges, such
polyuria, and blurred vision are common symptoms
as donor shortages, and to determine its feasibility.
of diabetes. In advanced cases, hyperglycemia with
ketoacidosis is likely to occur.[21-24]
THE RELATIONSHIP BETWEEN STEM
CELLS AND DIABETES PLURIPOTENT STEM CELLS AND
Transplantation of insulin-producing cells has DIABETES
enabled stem cell repair of pancreatic β-cells.[10,11]
Scientists highly value the pluripotent state of
Under the normal conditions and signaling, stem
ESCs, and it is for that, that they are being studied
cells have the astounding ability to self-renew
for their use in a variety of medical conditions,
and differentiate into specialized cells such as
including diabetes.[25] Through differentiation and
lymphocytes, hepatocytes, leukocytes, erythrocytes,
established development, ESCs are viewed as a
myocytes, nerve cells, and muscle cells.[12]
great source for the production of islet cells capable
As cell sources, stem cells are typically classified of producing insulin. Although challenging when
as ESCs or adult stem cells (ASCs). While ASCs are rare considered, it is possible that ESCs might be made
stem cells found in almost all major organs that are to differentiate into pancreatic islet cells, which then
referred to as multipotent cells due to their limited could be transplanted into the area of concern in
ability to differentiate, ESCs -also known as PSCs- on diabetic patients, thus preventing β-cell deficiency.
the other hand, are differentiated from the embryo’s In the past, mouse ESCs (mESCs) have been used for
inner cell mass and have the ability to differentiate this approach. Researchers have generated replicas
into various germ cell line.[13] from genetically altered and drug-selected mESCs
that can secrete insulin. Following monitoring, these
Adult stem cells are commonly found in medical
cells were implanted into diabetic mice and improved
applications. For instance, for the successful treatment
hyperglycemia.[26–31] Aside from mESCs, another
of leukemia and other hematological tumors, bone
group utilized human ESCs (hESCs) for the same
marrow transplantation employs hematopoietic stem
purpose.[32,33]
cells (HSCs) from donor marrow. In a similar manner to
HCSs, ASCs not only can multiply but also differentiate Cells co-expressing pancreatic and duodenal
into various blood cells, whereas mesenchymal stem homeobox 1 (PDX1) and NK6 homeobox protein 1
cells (MSCs) promote the formation of fat, bone, and (NKX6.1) in the developing human embryo show
cartilage.[14,15] In recent years, remarkable progress multipotent pancreatic bud and stem progenitors
has been made in the generation of functional that subsequently produce insulin-secreting β-cells.[34]
β-cells from human stem cell populations. This
Key transcription factors (TFs) are highly expressed
strategy describes the path that PSCs take during
in pancreatic progenitor cells and β-cells involved in
embryogenesis, from definitive endoderm formation
insulin secretion. Co-expression of PDX1 and NKX6.1
to pancreatic endoderm, endocrine progenitors, and
has been shown to be essential for the production of
ultimately islets of Langerhans.
mono-hormonal, glucose-sensitive β-cells.[35,36]
Ethical concerns make investigating the prospect of
Specifically, NKX6.1 is a crucial marker regulating
regenerating insulin-secreting cells problematic.[16-18]
β-cell maturation and functionality.[35,37] Researchers
Scientists are attempting to employ several have reported varying degrees of success with regard
types of stem cells to treat a wide range of medical to ESCs and islet generation. As a result, many issues
ailments.[19] Despite these advances, more than 400 have been encountered, including cell homogeneity,
62 JEB Med Sci

immaturity of differentiated cells, low numbers of In rats with high-fat diet-induced T2DM, BM-MSC
cells that produce insulin, and inadequate insulin transplantation activated insulin receptor substrate,
sensitivity to glucose.[30,32,33,38,39] On the other hand, as and reduced hyperglycemia. It was discovered that
neither C-peptide nor intracellular insulin is produced glucose transporter type 4 (GLUT4) translocation and
after the cells are cultivated in an insulin-free medium, expression had increased.[69]
several research groups claim that these cells are not Mesenchymal stem cells have demonstrated
insulin-producing cells at all.[40-42] therapeutic effects on islet cell recovery and
The first cell line to be used for in vitro produce glycemic control in animal models. Clinical practice
β-cells were ESC cells. A procedure has been created has been affected by these findings. The literature
by one group to transform mESCs into definitive, contains clinical research on MSC therapy in T2DM
completely pure, endodermal cell lines. [16] It patients.[70-78] Nevertheless, there is still a long way
demonstrated the production of pancreatic endocrine to go for a definitive and routine approach to stem
hormone-producing cells containing insulin and cell-based treatment of T2DM.
C-peptide.[43] As a result, they were able to produce Recent research has demonstrated that VEGF
insulin from these cells in the human islet interval, is crucial to the development of vascular damage
yet were unable to produce it in response to glucose. in DR and has suggested that blocking VEGF is a
Later on, this response was achieved by a different useful strategy for managing the condition. The
group. Pluripotent stem cells have been proven reduction of VEGF production by MSC injection in
to have drawbacks, including a significant risk of a hypoxic environment by the reductase enzyme
tumorigenesis, immunological rejection, and ethical inhibitor atorvastatin has been proven.[79-85] Moreover,
controversies.[18,44-46] These considerations explain the studies indicate that BM-HSCs provide better visual
reason why the clinical use of ESCs is still unclear. activity.[86]
Numerous molecular similarities are shared between
iPSCs and ESCs. Therefore, by obtaining specific Epithelial progenitor cells (EPCs) generated
iPSCs from diabetics, the ethical and immunological from mouse BM-MSCs and human MSCs have
rejection concerns and moral questions associated been demonstrated in animal models to stimulate
neovascularization and enhance DR.[87-89]
with ESC transplantation have not emerged.[47-54]
These findings might make iPSCs a promising choice Patients with T1DM and T2DM may develop foot
for cellular replacement therapy in T1DM in the future. ulcers and require amputations as a result of DN, one
of the most prevalent consequences of DM. When
STEM CELL TREATMENT FOR T2DM hyperglycemia rises over time, DN develops into
a chronic condition.[90,91] Among the reasons linked
Type 2 diabetes mellitus is characterized by to the occurrence of DN are dysregulated glucose
insulin resistance and reduced insulin secretion. levels, metabolic variables, oxidative stress, elevated
Treatment includes diet, oral antidiabetics, and glycolysis hemoglobin levels, and poor blood velocity
the use of external insulin.[55-64] Patients with T2DM due to free radical buildup.[91,92] Besides, prolonged
who regularly take insulin eventually acquire insulin elevated blood glucose levels also promote the
resistance, and existing therapies do not completely creation of advanced glycation end products
solve this issue.[65] Although transplanting pancreatic (AGEs), which, after binding to their receptors, start
islet cells is seen to be a viable strategy, obstacles like an inflammatory reaction and enhance oxidative
a paucity of donors and ethical concerns have limited stress, which further causes Schwann cells to
its use. In order to increase the lowered insulin levels deteriorate. Subsequently, any oxidation-mediated
in patients, stem cells such BMSCs, ADSCs, ESCs, and loss of function in these cells, which govern nerve
iPSCs can develop into beta- and comparable cells regeneration as well as neuron insulation, increases
capable of producing insulin.[45,66] DN in diabetes patients.[93-98]
Patients with T2DM who received a combination of Diabetic nephropathy, a microvascular
intrapancreatic bone marrow infusion and hyperbaric complication of DM, is one of the most common causes
oxygen therapy experienced improvements in of end-stage chronic kidney disease and is associated
glycemic control and C-peptide levels as well as a with high mortality.[99-101] Matrix molecule-producing
reduction in their need for insulin.[67] After receiving podocytes in the glomerular basal membrane are
a BMSCs injection, T2DM patients improved in the damaged in DNP, resulting in proteinuria, fibrosis,
same way.[68] and renal failure. Self-regeneration of damaged
Stem Cell Therapy for Diabetes Treatment 63

podocytes is limited, and the proteinuria condition POTENTIAL OF STEM CELLS: THEIR
worsens due to the negative effect on the glomerular IMPACT ON MACROVASCULAR AND
barrier.[102]
BEYOND
Proteinuria, fibrosis, and dysfunction of proximal
Atherosclerosis is a macrovascular condition
tubular epithelial cells (PTECs) together with
that is common in DM patients. Stroke, myocardial
increased tubulointerstitial inflammation are all infarction, and vascular disease are among the risks
signs of decreased renal function.[103] The negative that have been linked to persistently elevated blood
features of PTECs, such as inflammation, are increased sugar levels.[114,115] Depletion EPCs and the presence
by prolonged hyperglycemia, AGEs, and glycated of cells like CD133 and CD34 are reliable indicators
albumin.[104] of arterial disease. Moreover, reduced EPC numbers
The renin-angiotensin system activation, synthesis have been identified as a potential new indicator of
of different growth factors, and excessive cytokine peripheral artery disease in DM.[116–118]
production are only a few of the several routes Vascular stem cells, which may identify EPCs,
whereby AGEs are hypothesized to be implicated in are being researched as a potential therapy for the
the pathophysiology of DNP.[105] By preventing the macrovascular problems of diabetes. In one study,
production of pro-inflammatory cytokines, blocking it was demonstrated that vascular progenitor cells
inducible nitric oxide synthase, and encouraging developed from human vascular smooth muscle cells
parenchymal cell proliferation, MSCs can improve into vascular networks.[119] In vivo testing of EPCs’
renal healing.[106,107] To simulate DNP characteristics, capacity to create vascular networks was successful.
iPSCs were developed into podocytes in many The same CD133+ subset from which mesenchymal
studies.[108,109] progenitor cells (MPCs) are produced may also be
a candidate for this vascular job.[120,121] Intravenous
The paracrine action of renal trophic factors
injection of MPCs slowed cardiac remodeling and
released by MSCs in DNP was the subject of one
enhanced myocardial function in a diabetic animal
investigation. Animals with diabetes brought on by
investigation employing a cardiomyopathy model,
a high-fat diet and streptozotocin received MSCs.
with a substantial increase in matrix metalloproteinase
It was found that both therapies had ameliorative (MMP)-2 activity and a decrease in MMP-9.[122]
effects.[110] A significant decrease in blood glucose
levels was observed in MSC-treated diabetic mice. Considering in terms of long-term implications
Furthermore, albuminuria was reduced, and glomeruli in DM, chronic hyperglycemia is known to cause
were histologically normal in these animals. On the endothelial dysfunction, subsequently causing issues
other hand, in diabetic mice without MSC treatment, including vascular network damage in the target
glomerular enlargement was found to be present. organs. The ability of progenitor cells from diabetic
Thus, MSC administration appeared to prevent the animals to restore vascular homeostasis has been
regeneration of beta-pancreatic islets and kidney demonstrated in various experiments.[123,124] This
damage in diabetic animals. According to the results finding implies that the number of stem cells decreases
of the study, MSC transplantation is recommended with the formation of a deficit of major stem cells in
diabetes. The use of these formerly mentioned two
as a treatment for T1DM.[111] In addition to that, by
stem cells to correct vascular dysfunction and restore
reducing podocyte loss and promoting the release of
vascular function still requires further research before
bone morphogenetic protein-7, MSCs reduced fibrosis
a clear prescription can be made. Nonetheless, the
and glomerulosclerosis. They thereby contributed to
use of stem cells to treat macrovascular problems
the regeneration and protection of DNP.[112]
appears promising.
The injection of BM-MSC enhanced renal function
In conclusion, diabetes is a metabolic condition
and controlled the levels of insulin, heme oxygenase-1, that is widespread across the world. Due to damage
AGEs, and glucose in the blood.[113] The results of the to the pancreas’ β-cells, it is characterized by insulin
research show that stem cell-based treatments, such loss and impaired insulin sensitivity. Diabetes and
as MSCs, are successful in treating DNP, despite its consequences continue to endanger human life
their limitations due to the consequences mentioned despite the discovery of insulin. Although ICT has
previously. been tested by researchers as an alternate therapy,
the lack of donors still poses problems in practice.
Furthermore, the first stem cells employed in the stem
64 JEB Med Sci

cell strategy for diabetes were ESCs. Yet, iPSCs have We There Yet? Cells. 2021 Jan 19;10:191.
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risk as well as ethical questions. Mesenchymal stem RJ, et al. Reduced progression of diabetic microvascular
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