Journal of Life Science and Biomedicine  
J Life Sci Biomed, 9 (4): 102-108, 2019  
License: CC BY 4.0  
ISSN 2251-9939  
Review on: regenerative medicine, tissue  
engineering and stem cell therapy in  
diabetes mellitus  
Mastewal BIRHAN1  
College of Veterinary Medicine and Animal science, Department Veterinary Paraclinical Studies, University of Gondar, Ethiopia  
Corresponding author’s Email: ; ORCID: 0000-0002-0984-5582  
Review Article  
PII: S225199391900016-9  
Introduction. In view of the recent success in pancreatic islet transplantation, interest in treating  
diabetes by the delivery of insulin-producing β-cells has been renewed. Because differentiated  
pancreatic β-cells cannot be expanded significantly in vitro, β-cell stem or progenitor cells are seen as a  
potential source for the preparation of transplantable insulin-producing tissue. In addition to  
embryonic stem (ES) cells, several potential adult islet/β-cell progenitors, derived from pancreas, liver,  
and bone marrow, are being studied. To date, none of the candidate cells has been fully characterized or  
is clinically applicable, but pancreatic physiology makes the existence of one or more types of adult islet  
stem cells very likely. It also seems possible that pluripotential stem cells, derived from the bone  
marrow, contribute to adult islet neogenesis. Aim. In future studies, more stringent criteria should be  
met to clonally define adult islet/β-cell progenitor cells. If this can be achieved, the utilization of these  
cells for the generation of insulin-producing β-cells in vitro seems to be feasible in the near future. This  
review will focus on the potential of adult tissue-derived stem cells, in lieu of embryo-derived stem cells,  
for the treatment of diabetes. We discuss the role of adult islet stem/progenitor cells in normal  
physiology, highlight possible candidate cells isolated to date, and describe different approaches for  
stem cell-based therapy.  
06 June 2019  
15 July 2019  
25 July 2019  
Embryonic Stem Cells,  
Pancreatic Islet,  
Diabetes is a syndrome characterized by an absolute or relative β-cell deficiency in terms of mass (type 1  
diabetes mellitus, T1DM) [1]. In contrast, in type 2 diabetes (T2DM) insulin deficiency, while, due in part to loss  
of functional, responsive β-cells, is not absolute, but relative to the impaired insulin signalling present in this  
disorder [2], or pancreas is unable to produce insulin, whereas type 2 (adult onset diabetes) is caused due to  
insulin resistance of the cells [3].  
Once insulin resistance develops in several tissues, insulin-stimulated glucose disposal is decreased and  
adipocytes release many free fatty acids (FFAs). Furthermore, increased FFAs inhibit the insulin action on liver,  
resulting in increased gluconeogenesis in the hyperglycemic state [4]. The International Diabetes Federation  
estimates that up to 95% of the 380 million people worldwide who are suffer from type 2 diabetes [5]. It is  
harder to treat and typically occurs in adults as a result of excess weight or hormonal imbalances [6]. Type 2  
diabetes mellitus has become an epidemic, and virtually no physician is without patients who have the disease  
Several pathogenic processes are involved in the development of diabetes. These range from autoimmune  
destruction of the pancreatic β-cells with consequent insulin deficiency to abnormalities that result in  
resistance to insulin action [8]. In the long term effects of diabetes mellitus include progressive development of  
the specific complications of retinopathy with potential blindness, nephropathy that may lead to renal failure,  
or neuropathy with risk of foot ulcers, amputation, Charcot joints, and features of autonomic dysfunction,  
including sexual dysfunction. People with diabetes are at increased risk of cardiovascular, peripheral vascular  
and cerebrovascular disease [9].  
Over the years several sources of stem cells have been claimed to cater to the need of insulin producing  
cells. These include human embryonic stem cells, induced pluripotent stem cells, human perinatal tissues such  
as amnion, placenta, umbilical cord and postnatal tissues involving adipose tissue, bone marrow, blood  
monocytes, cord blood, dental pulp, endometrium, liver, labia minora dermis-derived fibroblasts and pancreas  
Citation: Birhan M. 2019. Review on: regenerative medicine, tissue engineering and stem cell therapy in diabetes mellitus. J. Life Sci. Biomed. 9(4): 102-108;  
Treatment of Type 2 diabetes is complicated by several factors inherent to the disease process, typically,  
insulin resistance, hyperinsulinemia, impaired insulin secretion, reduced insulin-mediated glucose uptake and  
utilization [11]. It is well-known that exercise and diet control are helpful to manage glucose level at initial stage  
[12]. A novel therapeutic approach to reduce pancreatic β-cells are dysfunctional or altogether absent in diabetic  
patients, replacement of these cells has become the major target of stem cell research in diabetes [13]. There are  
a number of different sources of stem cells and the most investigated types of stem cells for DM treatment are:  
Embryonic stem cells [14], induced pluripotent stem cells of induced pluripotent stem cells [15], germ cell  
derived stem cells, and mesenchymal stem cells [16].  
But, in addition to these therapeutic of DM either in-vivo or in-vitro approaches, the most important  
problem is choosing the best type of progenitor cell. Tissue Engineering is an interdisciplinary discipline  
addressed to create functional three-dimensional (3D) tissues combining scaffolds, cells and/or bioactive  
molecules. Tissue engineering/regenerative medicine strategies require interaction and integration with tissue  
and cells through incorporation of appropriate physical and cellular signals. Therefore, inclusion of modifying  
factors such as biologically active proteins and DNA are critical to success [17].  
This review will be included to establish a novel tissue engineering approach for diabetes mellitus (DM) by  
fabricating a tissue sheet composed of pancreatic islet cells for in vivo transplantation [18]. One alternative to  
organ or tissue transplantation is to use a renewable source of cells. Stem cells are clonogenic cells capable of  
both self-renewal and multiline age differentiation [19]. This review will discuss the current evidence and  
strategy behind these stem cell sources, as well as the advantages and disadvantages of each [13]. Therefore,  
treatment strategies for DM should be aimed at restoring beta cell mass and/or function, in addition to  
improving insulin sensitivity. The aim of this review is to give an overview of the existing knowledge of current  
experimental strategies in the treatment of DM covered by tissue engineering and regenerative medicines [20].  
Current and future cell-based therapies of DM  
The methods for generating pancreatic beta-cells include a method of creating pancreatic beta-cells in  
vitro and implanting them into the body and a method of regenerating pancreatic beta-cells in the body via  
gene introduction or the administration of differential proliferation factors to the body. Moreover, the number  
of pancreatic beta-cells is also low in type 2 diabetes, caused by the compounding factors of insulin secretory  
failure and insulin resistance; therefore, if pancreatic beta-cells can be regenerated in a living body, then a  
further amelioration of the pathology can be expected. The development of pancreatic beta-cell-targeting  
regenerative medicine can lead to the next generation of diabetes treatment [21].  
Curative therapy for diabetes mellitus mainly implies replacement of functional insulin producing  
pancreatic β cells, with pancreas or islet-cell transplants. However, shortage of donor organs spurs research  
into alternative means of generating β cells from islet expansion, encapsulated islet xenografts, human islet  
cell-lines, and stem cells. Stem-cell therapy here implies the replacement of diseased or lost cells from progeny  
of pluripotent or multipotent cells. Both embryonic stem cells (derived from the inner cell mass of a blastocyst)  
and adult stem cells (found in the postnatal organism) have been used to generate surrogate β cells or otherwise  
restore β-cell functioning [22]. Cell therapies with human embryonic and adult stem cells have emerged as an  
alternative management for various diseases. These cells were able to proliferate and differentiate into various  
cell types including those bearing a phenotype of insulin-secreting β-cells [23].  
Stem cells  
Stem cells possess an exceptional quality to replenish itself and to produce any specialized cell types under  
appropriate microenvironment. A rapidly dividing stem cell produces two new cells, each having two choices  
depending upon the requirement of the organism. Thus, a newly produced cell either may remain as a stem cell  
or it may undergo further differentiation to become a more specialized cell with specific function [24]. The stem  
cells have the potential to become any type of specialized cell such as a myocyte, blood cell, hepatocyte and  
brain cell (Figure 1).  
Embryonic stem cells  
Many cell signaling and epigenetic factors involved in the differentiation process are still unknown,  
although the presence of markers such as PDX1, Isl1, and Foxa2 are indicative of pancreatic β-cells. The exact  
composite and temporal progression of transcription factors present in pancreatic cells is important for  
Citation: Birhan M. 2019. Review on: regenerative medicine, tissue engineering and stem cell therapy in diabetes mellitus. J. Life Sci. Biomed. 9(4): 102-108;  
identification, as many of these factors are seen in different combinations in other cell lineages. The  
differentiation process is meant to mimic the embryological development of the pancreas [13].  
Pancreatic and duodenal homeobox 1 (Pdx1) is a transcription factor that regulates the embryonic  
development of the pancreas and the differentiation toward β cells. Previously, we have shown that exposure of  
mouse embryonic stem cells (mESCs) to high concentrations of diethylenetriamine nitric oxide adduct (DETA-  
NO) triggers differentiation events and promotes the expression of Pdx1. Here we report evidence that Pdx1  
expression is associated with release of polycomb repressive complex 2 (PRC2) and P300 from its promoter  
region [25].  
Figure 1. Self-renewal and differentiation potential of the stem cells [26].  
Tissue restoration is the process whereby multiple damaged cell types are replaced to restore the  
histoarchitecture and function to the tissue. Several theories, have been proposed to explain the phenomenon of  
tissue restoration in amphibians and in animals belonging to higher order [27].  
A profound knowledge of the development and differentiation of pancreatic tissues, especially islets of  
Langerhans, is necessary for developing regenerative therapy for severe diabetes mellitus. A recent  
developmental study showed that PTF-1a is expressed in almost all parts of pancreatic tissues, in addition to  
PDX- 1 PDXI, a well-known transcription factor that is essential for pancreas development [28]. Tissue  
engineering may use one of three basic strategies: isolated cells or cell substitutes, tissue inducing substances,  
or cells placed within matrices. For the purposes of IDD, the first approach is already being applied in islet  
transplantation. Since β-cells do not significantly expand in cell number in vivo the second approach of a tissue  
inducing substitute is considerably more challenging. Alternatively, it has been reported that exocrine pancreas  
tissue can be induced to take on a β-cell phenotype through metaplasia so a similar approach could be  
envisioned to target those cells [29].  
Mesenchymal stem cells  
Curative therapy for diabetes mellitus mainly implies replacement of functional insulin-producing  
pancreatic β cells, with pancreas or islet-cell transplants. However, shortage of donor organs spurs research  
into alternative means of generating β cells from islet expansion, encapsulated islet xenografts, human islet  
cell-lines, and stem cells. Stem-cell therapy here implies the replacement of diseased or lost cells from progeny  
of pluripotent or multipotent cells. Both embryonic stem cells (derived from the inner cell mass of a blastocyst)  
and adult stem cells (found in the postnatal organism) have been used to generate surrogate β cells or otherwise  
restore β-cell functioning [22].  
Originally identified by Friedenstein et al. in 1976 [30] as a fibroblast-like cell population capable of  
generating osteogenic precursors, the mesenchymal stromal cells derived from the bone marrow (BM) are a  
Citation: Birhan M. 2019. Review on: regenerative medicine, tissue engineering and stem cell therapy in diabetes mellitus. J. Life Sci. Biomed. 9(4): 102-108;  
rare, heterogeneous, stromal population of multipotent non-haematopoietic progenitor cells with the capacity  
to differentiate into multiple mesenchymal lineages, including bone, fat and cartilage. Due to this characteristic,  
Caplan [31] dubbed them “mesenchymal stem cells” (MSCs), which has been recently changed by a consensus  
statement recommendation to “multipotent mesenchymal stromal cells” [32]. Other studies have identified  
pluripotent cells capable of differentiation along endodermal and neurectodermal lineages, including neurons,  
hepatocytes and endothelial cells [33], [34]. Such stem cells, isolated from BM, have been referred to as  
“multipotent adult progenitor cells” (MAPCs), “marrow-isolated adult multilineage inducible cells” (MIAMIs)  
[35] and “very small embryonic-like stem cells” (VSELs) . However, even if the transdifferentiation capacities of  
these primitive cell types is of major interest, obtaining them requires highly specific culture conditions and, so  
far, it has not been possible to isolate these cells from fresh BM. Whether or not they represent a culture  
phenomenon remains an unanswered question [36].  
MSCs administration can prevent and treat diabetic nephropathy, which is a complication of DM and is  
defined as progressive kidney disease caused by angiopathy of the capillaries supplying the kidney glomeruli.  
MSCs have been used for the treatment of diabetic nephropathy in nonobese diabetic/severely compromised  
immunodeficient (NOD/SCID) and C57 black 6 (C57/BL6) mice, which succumb to DM after application of  
multiple low doses of STZ. About 3060 days after STZ injection, kidneys of treated mice showed the presence  
of abnormal glomeruli characterized by increased deposits of ECM protein in the mesangium, hyalinosis, and  
increased number of macrophages in the glomeruli [37].  
Induced pluripotent stem cells  
The use of iPSCs untangles regenerative therapy in diabetes from ethical constraints, but also poses its  
own unique challenges. The production of iPSCs from human fibroblasts was first demonstrated by Yamanaka  
and colleagues through retroviral transduction of four transcription factors (Oct-3/4, Sox-2, Klf-4, and c-Myc) in  
a process termed direct reprogramming. In lieu of the high tumorigenic potential of direct reprogramming  
resulting from genome integration and activation of oncogenic c-Myc, additional research proved iPSCs could  
be produced from somatic cells in the absence of c-Myc, but at the expense of efficiency [13]. Engraftment of  
mature insulin producing cells derived from induced pluripotent stem cells may represent the most promising  
treatment strategy for diabetic patients with impaired β-cell function [13].  
β cells from direct reprogramming  
One theme that has been explored extensively by researchers is to create new β cells from existing  
pancreatic cells. The rationale behind this approach is that because these cells are either β-cell precursors or  
developmentally related to β cells, the barrier to reprogramming them into functional β cells may be lower than  
in cells that are not as closely related developmentally.  
In normal healthy conditions β-cells have a long life-span with a low proliferation rate [38]. In response to  
increased metabolic demand or after injury, however, the adult pancreas maintains or acquires the ability to  
produce new cells, particularly β-cells. The precise identification of the mechanisms involved in the  
maintenance of β-cell mass under different conditions could offer new hints to help generating new β-cells as a  
cell replacement therapy for treating diabetes [39].  
Today, insulin-dependent patients rely on daily insulin injections. Transplantation of isolated islets from  
cadavers is problematic due to donor scarcity (about 6000 islets/kg of body weight are required [40], and is only  
applicable to certain forms of diabetes; in addition, transplantation has met with limited success due to  
restricted engraftment survival [41]. A promising approach relies on devising unlimited in vitro generation of  
insulin-producing cells derived from embryonic stem (ES) cells or, even more interestingly, from patient-  
derived induced pluripotent stem (iPS) cells [42]. Very recently, however, in view of new experimental evidence  
showing that adult differentiated pancreatic cells can reprogram and change their phenotype [43], exploration  
of the intrinsic spontaneous capacity of the adult pancreas to regenerate β-cells, in particular from heterologous  
origins, has acquired a new dimension as a route to the development of therapeutic treatments for diabetes [44].  
This review will focus on β-cell regeneration and its diverse mechanisms. In fact, exploiting the intrinsic  
capacity of the adult pancreas to produce new β-cells endogenously is probably the most promising way to  
develop cell replacement therapies to treat the forms of diabetes that result from massive β-cell loss.  
Nevertheless, a prerequisite for such an achievement will be to uncover the immunological basis of the  
pathogenesis of the disease. (Reference)  
Citation: Birhan M. 2019. Review on: regenerative medicine, tissue engineering and stem cell therapy in diabetes mellitus. J. Life Sci. Biomed. 9(4): 102-108;  
Antigen-presenting cells  
So far, at least 15 distinct peptides derived from β-cells and their corresponding CD4+ T cells have been  
identified [45]. The presentation of β-cell antigens is a complex issue as β-cells themselves do not express MHC  
class II molecules. It can be surmised that presentation of β-cell-specific antigens is mediated by Antigen-  
Presening Cells (APCs) within islets of Langerhans. These professional dendritic cells (DCs) are able to load the  
peptide groove of their MHC class II complexes with peptides derived from β-cell granules [46]. In this context,  
local lymph nodes draining the pancreas are crucial to the selection and activation of diabetogenic T cells [47].  
Here, the question arises, how the β-cell antigen presentation takes place. It is not clear yet, whether this occurs  
via migration of islet DCs to the lymph nodes or, instead, by drainage of β-cell products directly to the nodes  
and subsequent uptake by DCs in the draining lymph nodes. Based on our knowledge gathered from the NOD  
mouse, β-cell autoimmunity progresses in relatively well-defined checkpoints. A first checkpoint is marked by  
DC infiltration of islets in 2- to 3-week-old NOD mice. Early detection of DCs and macrophages is followed by  
CD8+ and CD4+ T cells, NK cells, and B cells. During islet cell infiltration these cells encounter β-cell  
autoantigens such as GAD65 and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP).  
The β-cell destruction resulting from inflammatory damage leads to release of cell contents including GAD65  
and other autoantigens. Subsequently, these can be taken up by activated endothelial cells able to process and  
present disease-related epitopes of the GAD65 autoantigen [48].  
Current and future cell-based therapies  
Recently, Andreas Lechner and colleagues failed to see transdifferentiation into pancreatic β cells after  
transplantation of bone-marrow cells into mice [49]. Last year, Jayaraj Rajagopal and colleagues failed to derive  
β cells from embryonic stem cells [50]. However, others have seen such effects [51].  
To date, no fully defined and clinically applicable stem cell, tissue engeenring and adult β-cell stem/progenitor  
has been isolated. Nevertheless, studies of the development and the physiology of the pancreas make the  
existence of pancreatic stem/progenitor cells highly likely. Additionally, several potential candidate cells are  
being studied, and although more rigid experimental criteria have yet to be met, the published results look  
highly promising. The utilization of adult stem/progenitor cells for the generation of insulin-producing β-cells  
in vitro and their use for the treatment of diabetes, therefore, seem to be feasible in the near future.  
Authors' contributions  
MB conceived the review, coordinated the overall activity, and reviewed the manuscript.  
Conflict of Interest  
The authors declare that they have no conflict of interest.  
The authors’ heartfelt thanks University of Gondar, Research and Community Service V/President Office,  
Collage Veterinary Medicine and Animal Sciences for the finance and resource supporting  
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Citation: Birhan M. 2019. Review on: regenerative medicine, tissue engineering and stem cell therapy in diabetes mellitus. J. Life Sci. Biomed. 9(4): 102-108;