Diabets is a disease that deteriorates the body’s ability to utilize blood glucose, also called blood sugar. Diabetes is a group of metabolic disorders in which high blood sugar level persist for a long period of time, this may be a result of pancreas not producing enough insulin or cells of the body not responding properly to insulin produced. Symptoms of diabetes include frequent urination, increased thrust and increased hunger.
The untreated condition further produces complications some of which may be diabetic ketoacidosis, hyperosmolar hyperglycemic state or in some cases even death.Therefore, it developed the need for development of functional β-cells to treat type 1 and type 2 diabetes. Although, pancreas and islet transplantation presented a good option but major obstacle is shortage of organ donor.Hence,it shifted the focus towards developing insulin producing cells from stem cells.New strategies are developed to produce such cells that can reverse diabetes.Thus,stem cell therapy aided by cellular reprogramming and β-cell regeneration will offer new therapeutic opportunities for treatment of diabetes.
Types of Diabetes
- Type 1 Diabetes
- Type 2 Diabetes
- Gestational Diabetes
This is the result of the failure of the pancreas to produce insulin. This occurs due to loss of β cells. β cell mass is reduced to less than 20 % of the normal level. The initial stage of this type is insulin resistance that progresses to lack of insulin production due to loss of β cells. This form of diabetes develops during pregnancy.
Also known as “juvenile diabetes”, “insulin dependent diabetes” Also known as “non-insulin dependent diabetes” or “adult-onset diabetes” Pregnant women with no history diabetes show increased blood sugar levels.
Stem Cell Therapy For Diabetes
- Sources of Insulin-producing cells from stem cells: Stem cells are considered a promising source for insulin-producing cells (iPCSs) because of their potential to differentiate into multiple lineages of cells and self renewal properties. To date, researchers have tested the differentiation potential of various stem cells to establish the most optimum source of IPCs.
- The IPCS can be derived from different stem cells: Embryonic stem cell (ESCs), induced pluripotent stem cell (iPSCs) and adult stem cells like pancreatic stem cells, hepatic stem cell and mesenchymal stem cell (MSCs).
Embryonic Stem Cell as a Source of IPCS
ESCs are considered a potential source of IPCs because of their highest plasticity, ability to differentiate into all cell types of the body and unlimited capacity of self- renewal. Production of IPCs from ESCs requires the development of efficient protocols based on the mechanisms of pancreas development. Initial, in vitro studies reported the differentiation of ESCs to IPCs but with low efficiency but the produced IPCs showed all the 5 stages of pancreas development (definitive endoderm , foregut, hindgut, endoderm of pancreas and then to endocrine cell ) and also, the cell cluster was composed of glucagon-positive, somatostatin positive and insulin-positive cells and was able to secrete insulin in response to glucose . hence, signifying the potential of ESCs as IPCs also, when an in vivo study was performed on these pancreatic endocrine progenitor cells, these such further differentiated into IPCs and also responded to change in serum glucose concentration.
Recent research showed that some cells derived from ES cells contained insulin as a result of endogenous uptake by cell apoptosis ( rather than biosynthesis ). Therefore, to prove that insulin is synthesized C-peptide measurement is also needed. Kroonetal showed that stage of pancreatic progenitors can be determined in vitro but to obtain further differentiation to required islet cells, transplantation into mice was needed. In some studies, functional β – cells were produced but the efficiency was low and there was a failure to generate highly selective β cells. Hence, this presented the need to develop protocols that improve the effectiveness of ESC differentiation into pancreatic progenitor cells.
Pluripotent Ctem Cells (iPSCs) as The Source of IPCs
iPSCs are the somatic cells that are transformed into pluripotent stem cells under specific conditions and represent an autologous non-embryonic origin for IPCs . most commonly used technique for the generation of iPSCs is the integration of genetic material into the host genome using viral vectors but, this method presents a risk of tumor development by the reactivation of viral transgenes.
Therefore, many approaches are developed to overcome the use of viral vectors including the use of non- integrating and excisable vector system.
Melton et al. reported that functional human stem-cell derived β-cell (SC-β) can be produced from human pluripotent stem cells in vitro and these functioned similar to primary human cells both in vitro and in vivo posttransplantation. And when these, SC-β cells were exposed to different glucose concentration in vitro they secrete insulin comparable to adult β-cells. Also, transplantation of these cells in mice improves hyperglycemia in diabetic mice and in a glucose-regulated manner, secretes human insulin in the serum of mice shortly after transplantation. A recent study by this group showed that SC-β cells can also be generated hiPSCs derived from TI diabetes patients in vitro. Therefore, TID SC-β-cells can be used for the treatment of diabetes, drug screening, and a study of β-cell biology.
Today’s research mainly focuses on the development of protocol (based on the mechanism that regulates pancreatic development) that increase the efficient differentiation of pluripotent cells into functional islet cells.
The successful conversion of stem cell into mature IPCs is analyzed by various factors, most importantly by PDX1 and NKX6-1 (NK6 homeobox 1 ) (essential determinants of mature β- cell function). Another study showed that human iPSCs can be used to produce IPCs and these cells can be engrafted and also, secrete insulin in vivo. The major advantage of using iPSCs for production of IPCs is that safety and ethical issues can be addressed easily.
Adult Pancreatic Stem Cell as a Source of IPCs
Adult pancreatic stem cells can be used for generation of IPCs because of their characteristics of multipotency and clonogenic potential and also, these share an identical embryological origin with β- cells. The epithelial cells of pancreatic ducts are isolated and induced in vitro to become functional islets. The differentiated β – cells show glucose-dependent reactivity and also, secrete insulin. The major challenge is faced in the isolation, purification, and proliferation of various pancreatic progenitor cell populations and also induction of β-cell differentiation without genetic mutations.
Exocrine pancreatic cells, pancreatic ducts, and islets of Langerhans all can be considered as potential pancreatic stem cell sources. The adult stem cells of the pancreas have been successfully differentiated into islet-like cells. Initially, pancreatic duct cells were proliferated in vitro and differentiated into IPCs and when these cells were transplanted into mice they developed into mature ductal epithelial cells. Therefore, stem cells are present in the pancreas and can be used to generate new islet cells. But, this requires identification of specific markers for their efficient isolation.
Based on Thorel et al. study that upon loss of β-cells, genetically marked α-cells rapidly coexpress Nkx-6.1, insulin, and adult β-cells Pdx1, Nkx6.1 and Glut2 thereby forming β-cells, α-cells can also be considered as a storehouse of pre –β cells. Also, Nouha et al. showed that GABA by downregulation of Arx expression can cause conversion of α-cells to β-cells. Therefore, β-cells restoration can be considered a possible treatment for diabetes.
MSCs as a Source of IPCs
Mesenchymal stem cells can be isolated from various tissues such as bone marrow, umbilical cord, the placenta, and adipose tissue and these are able to proliferate in vitro and generate multiple cell lineages but their exact nature is still not clear.
MSCs(from bone marrow, umbilical cord blood, and adipose tissue) are considered as potential source of IPCs because of they express cell surface antigens similar to exocrine tissue of adult human pancreas also possess differentiation potential equal to endodermic and mesodermic cell lineages.
The use of MSCS for treatment of diabetes does not aim at direct differentiation of these cells into β-cells but utilizing their tropic and paracrine mechanisms for tissue repair and regeneration. The endocrine and paracrine mechanisms of bone marrow-derived MSCs are successfully used to aid existing cells in their proliferation and insulin secretion and effectively control blood glucose levels.
Xie et al. modified rat bone marrow-derived MSCs using rat injured pancreatic tissue. These differentiated cells secreted insulin but only one-tenth of natural islet cells when transplanted in vivo into rats but hold the ability to reverse hyperglycemia in diabetic rats.
The mechanism of action of bone marrow-derived stem cells are unclear but still, they can be used as a source of β-cells. Hence, IPCs derived from bone marrow stem cells can be effectively used as a treatment for diabetes.
Stem Cell As IPCs Sources
Highest plasticity Cellular differentiation may lead to change in secretome and phenotype that can induce immune response therefore, a need for immunosuppressive therapy.
- Tumourigenicity of ESCs.
- Ethical issues.
- iPSCs No ethical issues.
- Easily accessible stem cell source. Risk of tumor development due to the possibility of reactivation of viral transgenes.
- Autoimmune response can be generated.
- Frequently express non-selectively and display immature endocrine genes.
- Adult Pancreatic stem cells Common origin with islet cells.
- Clonogenic potential. Specific markers for isolation and identification are needed.
MSCs Minimum risk of tumorigenesis:
- Low risk of the autoimmune response. Temporary treatment requires regular administration and additional therapy.
- Hepatic stem cells Improved β-cell function using small molecules.
- Low efficiency
- Genetic manipulations needed.
- Nonselective effect.