Effect of Stem Cells and Gene Transfected Stem Cells Therapy on the Pancreas of Experimentally Induced Type 1 Diabetes (original) (raw)
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The Egyptian Journal of Biochemistry and Molecular Biology, 2017
Diabetes mellitus (D.M) is a disease with a high and increasing prevalence. Insulin-producing cells (IPCs) generated from mesenchymal stem cells (MSCs) have shown immense potential for therapy. This study aimed to compare the differentiation potential of 2 kinds of MSCs obtained from human bone marrow (BM), and umbilical cord blood (UCB) into IPCs. In addition, their therapeutic efficiency to control streptozotocin (STZ)-induced diabetic rats was investigated. MSCs were isolated from human BM and UCB, expanded and differentiated to IPCs. The Cells were evaluated by flow cytometry analysis for MSCs markers, RT-PCR for insulin gene expression and ELISA detection of C-peptide release. IPCS were transplanted into the liver of diabetic rats and then evaluated by weekly measurement of the fasting blood glucose (FBG) levels, and detection of in vivo release of C-peptide. This study demonstrated that FBG levels were reduced in diabetic rats transplanted with IPCs, but in rats transplanted with UCB-derived cells were significantly lower than in those transplanted with BM-derived cells. The amount of Cpeptide released from transplanted IPCs derived from BM-MSCs and UCB-MSCs was non-significantly different. The results indicate that UCB-MSCs and BM-MSCs are promising stem cell sources for IPCs that help in the development of a new strategy for treatment of D.M.
Egyptian Journal of Histology
Background: Diabetes Mellitus (D.M.) is a major health problem affecting more than 200 million worldwide. The ideal treatment for autoimmune type I diabetes is regeneration of endogenous β-cells which could be achieved by mesenchymal stem cells transplantation. Aim of the work: This work aimed to compare the effect of intravenous bone marrow derived mesenchymal stem cells (BMSCs) and adipose tissue derived mesenchymal stem cells (AMSCs) on Streptozotocin (STZ)-induced type I diabetes in albino rats. Material and Methods: Fifty albino male rats were divided into 4 groups; control, diabetic, BMSCs treated and AMSCs treated. Treated groups were intravenously given 1 ml PKH26 labeled allogenic BMSCs or AMSCs suspended in phosphate buffered saline, respectively. Animals of all groups were sacrificed 2 weeks after stem cells administration. Sections from control and treated groups were examined by fluorescence microscope. Sections from all groups were immunohistochemically stained to detect insulin and proliferating cell nuclear antigen (PCNA). Mean area percent of insulin and number of PCNA positive reactions were measured and statistically analyzed. Results: Diabetic rats showed cell death and congested blood vessels in both exocrine and endocrine pancreas. Treated groups revealed homing of stem cells in pancreas after their transplantation. Moreover, nearly normal histological features were seen in AMSCs treated group. Studying the treated groups immunohistochemically, revealed increase in insulin and PCNA positive reactions when compared to diabetic group with more increase in AMSCs treated group than BMSCs treated group. Conclusion: Intravenous AMSCs could be more effective than BMSCs in treatment of STZ-induced type I diabetes.
Journal of Physiology and Biochemistry, 2010
Cell therapy is thought to be a possible approach for treatment of diabetes. Cells with the ability to differentiate into insulin-producing cells (IPCs) would provide an unlimited source of islet cells for transplantation. In this study, the differentiation capacity of rat bone-marrow-derived mesenchymal stem cells (MSCs) to IPCs and the feasibility of using them for reversal of hyperglycemia were investigated.
Veterinary World, 2016
Aim: Various studies have shown that secreted factors alone in culture medium without stem cell are capable of repairing tissues by itself in various conditions involving damaged tissue/organ. Therefore, this study was aimed to investigate the role of human umbilical cord mesenchymal stem cell-derived conditioned medium (CM) on the recovery of pancreatic β-cells in Wistar rats (Rattus norvegicus) with type 1 diabetes mellitus. Materials and Methods: The 0.05 ml CM induction was applied to the diabetic group of rats in weeks 1, 2, 3, and 4. 1 week after each CM induction, insulin concentration was analyzed using ELISA. The pancreas was divided into 3 regions, processed by paraffin method, stained with hematoxylin-eosin, and immunohistochemical method for insulin. Results: This study indicated the decrease in the total number of islets and insulin concentration after the injection of single dose of alloxan. The exocrine acini were also damaged. Microscopic observation detected the presence of small islets in the diabetic group 1 week after the first 0.05 ml CM induction. The number and size of the islets increased in line with the CM doses and time of inductions. Immunohistochemically, the presence of low intensity of insulin-positive cells could be recognized at the splenic and duodenal regions of the pancreas, but not gastric region, 1 week after the first and second 0.05 ml CM induction. The intensity of staining and the number of insulin-positive cells increased dramatically in 1 week after the third and fourth 0.05 ml of CM induction in all regions of the pancreas. The data of insulin blood concentration showed clear differences between the second and the fourth induction of 0.05 ml CM induction. Conclusions: This study showed very strong evidence on the role of human umbilical cord mesenchymal stem cell-derived CM in recovering the pancreatic β-cells damage in Wistar rats (R. norvegicus) with type 1 diabetes mellitus, structurally and functionally.
STEM CELLS, 2012
Type 1 diabetes mellitus (T1DM) is a chronic metabolic disease that results from cell-mediated autoimmune destruction of insulin-producing cells. In T1DM animal models, it has been shown that the systemic administration of multipotent mesenchymal stromal cells, also referred as to mesenchymal stem cells (MSCs), results in the regeneration of pancreatic islets. Mechanisms underlying this effect are still poorly understood. Our aims were to assess whether donor MSCs (a) differentiate into pancreatic b-cells and (b) modify systemic and pancreatic pathophysiologic markers of T1DM. After the intravenous administration of 5 3 10 5 syngeneic MSCs, we observed that mice with T1DM reverted their hyperglycemia and presented no donor-derived insulin-producing cells. In contrast, 7 and 65 days post-transplantation, MSCs were engrafted into secondary lymphoid organs. This correlated with a systemic and local reduction in the abundance of autoaggressive T cells together with an increase in regulatory T cells. Additionally, in the pancreas of mice with T1DM treated with MSCs, we observed a cytokine profile shift from proinflammatory to antinflammatory. 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. Therefore, the antidiabetic effect of MSCs intravenously administered is unrelated to their transdifferentiation potential but to their capability to restore the balance between Th1 and Th2 immunological responses along with the modification of the pancreatic microenvironment. Our data should be taken into account when designing clinical trials aimed to evaluate MSC transplantation in patients with T1DM since the presence of endogenous precursors seems to be critical in order to restore glycemic control.
Medical Journal of Chinese People's Liberation Army, 2016
Objective To compare the effects on type 2 diabetes of mesenchymal stem cells (MSCs) derived from bone marrow and adipose tissue. Methods Thirty type 2 diabetic rat models were established by an eight weeks high-fat diet (HFD) with a low dose streptozotocin (STZ, 25mg/kg), and randomly assigned into three groups (10 each): diabetes group (T2DM), bone marrow MSCs transplantation group (BMSC) and adipose tissue MSCs transplantation group (ADSC). Ten normal rats were set as control. MSCs were isolated from bone marrow or inguinal adipose tissue of normal rats. One week after STZ injection, 3×10 6 MSCs suspended in 1ml PBS were infused into rats via tail vein. The blood glucose was measured every day after MSCs transplantation, the intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test (IPITT) were performed the 7th day after transplantation to evaluate the effects of MSCs on diabetic rats. Pancreatic tissues were collected for insulin/glucagon immun...
Advances in Life Science and Technology, 2018
Conditioned medium (CM) derived from human umbilical cord mesenchymal stem cell culture has been studied in Type 1 Diabetes Mellitus (T1DM) and showed a good prospect as an alternative treatment. However, effects of CM in Type 2 Diabetes Mellitus (T2DM) have not been studied. The purpose of this study was to investigate the ability of human umbilical cord mesenchymal stem cell-derived conditioned medium (CM) for the recovery of pancreatic β-cells in T2DM-induced Wistar Rats ( Rattus norvegicus ). The T2DM-induced rats were prepared by applying combination injection of nicotinamide (NA) and streptozotocin (STZ). The T2DM-induced rats were treated with 0.2 ml CM fourth times periodically, with a week interval. One week after each CM treatment, the pancreas glands were collect, fixed in Bouin’s solution, processed by paraffin method and carried out immunohistochemistry staining for insulin detection. The blood samples were collected for glucose concentration evaluation. Microscopic obs...
Mesenchymal Stem Cells in the Treatment of Type 1 Diabetes Mellitus
Endocrine Pathology, 2015
Diabetes mellitus type 1 is a form of diabetes mellitus that results from the autoimmune destruction of insulin-producing beta cells in the pancreas. The current gold standard therapy for pancreas transplantation has limitations because of the long list of waiting patients and the limited supply of donor pancreas. Mesenchymal stem cells (MSCs), a relatively new potential therapy in various fields, have already made their mark in the young field of regenerative med-icine. Recent studies have shown that the implantation of MSCs decreases glucose levels through paracrine influences rather than through direct transdifferentiation into insulinproducing cells. Therefore, these cells may use proangiogenic and immunomodulatory effects to control diabetes following the cotransplantation with pancreatic islets. In this review, we present and discuss new approaches of using MSCs in the treatment of diabetes mellitus type 1.
Cell Transplantation, 2013
Harvesting, expansion, and directed differentiation of human bone marrow-derived mesenchymal stem cells (BM-MSCs) could provide an autologous source of surrogate b-cells that would alleviate the limitations of availability and/or allogenic rejection following pancreatic or islet transplantation. Bone marrow cells were obtained from three adult type 2 diabetic volunteers and three nondiabetic donors. After 3 days in culture, adherent MSCs were expanded for two passages. At passage 3, differentiation was carried out in a three-staged procedure. Cells were cultured in a glucose-rich medium containing several activation and growth factors. Cells were evaluated in vitro by flow cytometry, immunolabeling, RT-PCR, and human insulin and c-peptide release in responses to increasing glucose concentrations. One thousand cell clusters were inserted under the renal capsule of diabetic nude mice followed by monitoring of their diabetic status. At the end of differentiation, ~5-10% of cells were immunofluorescent for insulin, c-peptide or glucagon; insulin, and c-peptide were coexpressed. Nanogold immunolabeling for electron microscopy demonstrated the presence of c-peptide in the rough endoplasmic reticulum. Insulin-producing cells (IPCs) expressed transcription factors and genes of pancreatic hormones similar to those expressed by pancreatic islets. There was a stepwise increase in human insulin and c-peptide release by IPCs in response to increasing glucose concentrations. Transplantation of IPCs into nude diabetic mice resulted in control of their diabetic status for 3 months. The sera of IPC-transplanted mice contained human insulin and c-peptide but negligible levels of mouse insulin. When the IPC-bearing kidneys were removed, rapid return of diabetic state was noted. BM-MSCs from diabetic and nondiabetic human subjects could be differentiated without genetic manipulation to form IPCs that, when transplanted, could maintain euglycemia in diabetic mice for 3 months. Optimization of the culture conditions are required to improve the yield of IPCs and their functional performance.
Biological & Pharmaceutical Bulletin, 2010
Cellular replacement therapy for diabetes mellitus has received much attention. In this study we investigated the effect of transplantation of bone marrow-derived mesenchymal stem cells (BM-MSCs) induced into endoderm and early hepatic cells in streptozotocin (STZ)-induced diabetic mice. Mouse BM-MSCs were cultured in the presence of hepatocyte growth factor (HGF) and fibroblast growth factor (FGF-4) for 2 weeks and transplanted into diabetic mice. Blood glucose levels, intraperitoneal glucose tolerance test, serum insulin, body weight and islets histology were analyzed. The results demonstrated that transplantation of syngeneic induced MSCs could reverse STZ-induced diabetes in mice. The treatment of mice with hyperglycemia and islet destruction resulted in the repair of pancreatic islets. Blood glucose levels, intraperitoneal glucose tolerance test, and serum insulin were significantly recovered in induced BM-MSCs (iBM-MSCs) group. In addition, in the iBM-MSCs group the body weight and the number of islets were significantly increased compared to other groups. The results demonstrate that BM-MSCs induced into endoderm and early hepatic cells are suitable candidates for cell-based therapy of diabetes mellitus.