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MSCs In diabetes treatments

Diabetes mellitus is characterized by hyperglycemia which results from defects in insulin secretion, insulin action, or both. Type 1 diabetes is often called juvenile-onset diabetes and is characterized by beta-cell destruction. This is typically by an autoimmune T cell-mediated mechanism and it leads to a deficiency of insulin in the body which is required for glucose metabolism. Type 2 diabetes or adult onset diabetes is characterized by the inability of insulin to properly metabolize glucose. Despite the different pathogenic mechanisms of Type 1 and Type 2 diabetes, they share common symptoms including glucose intolerance, hyperglycemia and hyperlipidemia. Diabetes mellitus is also implicated in other pathologies such as adult blindness, kidney failure, amputation of the legs and feet, pregnancy complications, and heart attack.

Current insulin therapy is neither capable of completely mimicking endogenously secreted insulin released nor is it safe as it often causes hypoglycemic coma. Taking all this into account, strategies to promote either the expansion of existing beta-cells within the body or the supply of stem cell derived insulin producing cells would provide future treatment options. MSCs are able to differentiate into several cell types making them a potentially important source for treating this debilitating human disease.

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In vitro differentiation of mesenchymal stem cells in insulin producing cells is well documented. The differentiation of bone marrow-derived MSCs is achieved by multi-step differentiation protocols. These protocols include a combination of nicotinamide, activin A, and β-cellulin in high glucose medium. At the end of the culture, differentiated cells show a similar morphology to that of pancreatic islet-like cells-high PDX-1, insulin and glucagon genes expression, and glucose dependent insulin production. Similar results were also reported when umbilical cord blood MSCs were used as a source of insulin producing cells. Obtained islet like clusters released insulin and C peptide in response to physiological glucose concentration in vitro. Generation of new islet from pancreatic epithelial cells in vitro is also reported. These in vitro islets contained alpha and delta cells, which responded well to in vitro glucose challenge and once implanted in non-obese diabetic mice reversed insulin-dependent diabetes. Combined transfection of the three transcriptional factors, PDX-1, NeuroD1 and MafA, causes differentiation of bone marrow MSCs into insulin-producing cells.

In another study, bone marrow derived mesenchymal stem cells were converted in vitro into insulin producing cells by suppressing two genes, repressor element-1 silencing transcription factor/neuronal restrictive silencing factor (Rest/Nrst) and sonic hedgehog (Shh) and by overexpressing Pdx1. The reprogrammed bone marrow derived MSCs expressed both genes and proteins specific for islet cells. Although it is very preliminary, the most promising results for cell based therapy for diabetes were reported when scientists showed the possibility to generate insulin producing cells from adipose derived MSCs.

The immunomodulatory capability of MSCs is considered equally important for diabetes treatment, especially in Type 1 diabetes. Pre-clinical studies suggested that the anti-diabetic effect of mesenchymal stem cells is unrelated to their transdifferentiation potential but to their capability to modulate immune response and modify the pancreatic micro-environment. They suggested that in the pancreas of mice with Type 1 diabetes treated with MSCs, a cytokine profile shift from pro-inflammatory to anti-inflammatory was observed. MSC transplantation did not reduce pancreatic cell apoptosis but recovered local expression and increased the circulating levels of epidermal growth factor, a pancreatic trophic factor. On the other hand, another study suggested the lasting therapeutic effect of MSCs was due to MSC engraftment and differentiation in insulin producing cells and also due to immunomodulation properties. Although the mechanism of action was not defined, in a phase I clinical trial Wharton's jelly derived MSCs show long-term beneficial effect on newly diagnosed Type 1 diabetes patients. There has been limited studies on MSCs and Type 2 diabetes, but initial pre-clinical and pilot clinical studies showed encouraging results. MSC inoculums improved metabolic control in experimental models of Type 2 diabetes. The use of MSCs was also implemented in several diabetes related complications like cardiomyopathy, nephropathy, polyneuropathy and diabetic wounds. Chronic hyperglycemia is responsible for myocardial remodeling and is a central feature in the progression of diabetic cardiomyopathy, which is characterized by hypertrophy and apoptosis of cardiomyocytes and alterations in the quality and composition of the extracellular matrix resulting in increased collagen deposition. Matrix Metalloproteinase (MMP) 2 and 9 activities play a central role in the pathology of cardiomyopathy; decreased MMP-2 activity leads to increased collagen accumulation and increased MMP-9 activity leads to increased apoptosis of endothelial cells, reduction of capillary density, and poor myocardial perfusion. In rat models of diabetic cardiomyopathy, intravenous administration of bone marrow derived MSCs improved myogenesis and angiogenesis.

In a mice model systematic administration of MSCs showed improvement of kidney function and regeneration of glomerular structure as mesenchymal stem cells are able to reconstitute necrotic segment of diabetic kidneys. As MSCs are not able to proliferate in the kidney, an alternative scenario for the improvement of kidney function could be the ability of MSCs to scavenge cytotoxic molecules or to promote neovascularization.

Diabetic polyneuropathy (DPN) is the most common complication of diabetes. This is characterized by damage to nerve fibers. The central features of DPN are neural cell degeneration and decreased nerve blood flow. One month after the intramuscular injection MSCs found to be producing bFGF and VEGF which led to the increase in the ration capillaries to muscle fibers followed by improvement of hyperalgesia and a corresponding functional improvement of neural fiber. Although studies suggested that MSCs have the capacity to differentiate into neural cells in vitro, this was not observed during in vivo studies on diabetic rat models. Studies on rats and mice showed that systematic and local administration of bone marrow derived mesenchymal stem cells improves healing of diabetic wounds. MSCs injections resulted in an increase in several growth factors important for successful wound healing. These factors stimulated cell adhesion at the site of injury and induced cells to secrete more chemokines resulting in neovascularization and the formation of inflammation infiltrate, containing predominantly mononuclear cells, without tissue necrosis.

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Promising preliminary and pre-clinical studies have led to Phase I and Phase II clinical trials and the results of these are eagerly awaited. The outcome of these studies will decide the future of cell-based therapy for the most devastating degenerative disease known to mankind.

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