Allogeneic diabetic mesenchymal stem cells transplantation in streptozotocin-induced diabetic rat

Abstract

Background: Bone marrow-derived mesenchymal stem cells (BM-MSCs) are multipotent stroma cells which can provide a potential therapy for diabetes mellitus. But the mechanism is still controversial. Also, the status of BM-MSCs under hyperglycemia is not known. In the present study, we investigated the status of BM-MSCs in experimental-diabetic rat and demonstrated the rescue of experimental diabetes by diabetic MSCs transplantation. Methods: BM-MSCs were cultured and the potential of multiple-differentiation was identified through induction into osteoblasts. MSCs of passage 3 were used for the following experiment. The MSCs were labeled with 5-bromo-2?-deoxyuridine (BrdU). Diabetes in rats was induced by STZ injection. The rats were divided into three groups: normal control group (no DM, rats treated with saline through tail vein, n=10); DM control group (DM, no transplantation of MSCs, n=20); experimental group (DM and transplantation of MSCs, n=20). Body weight and blood glucose of the rats were monitored during the experiment after transplantation of MSCs. Paraffin sections of pancreas were obtained from rats of each group. Immuno-histochemistry analysis and double immunofluorescence were used to detect the BM-MSCs in the pancreatic tissue and their differentiating state. Results: MSCs were 89.5% labeled by BrdU and DAPI, which was green/blue double stained under fluorescent microscopy. Transplantation of diabetic MSCs resulted in a reduction of hyperglycemia on day 45 in experimental diabetic rats compared with control rats (17.7 mM ±3.9 vs 27.8 mM ± 2.1, P < 0.05), There was also a difference between MSC-treated experimental diabetic rats and control rats in body weight (232.7 g ±19.7 vs 133.3g ±13.1, P < 0.05). Histological and morphometric analysis of the pancreas of experimental diabetic rats showed the presence and differentiation of transplanted MSCs into insulin-producing cells which evidenced by double-staining of anti-BrdU and insulin. Also, there were many small islets throughout the sections. Their mean area and diameter analysis revealed that they were smaller thancontrol islets (1835.7 ± 175.8 µm2 vs 13257.2 ± 1457.6 µm2; 43.5 ± 3.7 µm vs 119.9 ± 5.8 µm, respectively, P < 0.05). Conclusion: Allogeneic MSCs transplantation can reduce blood glucose level in recipient rats. A relatively small quantity of transplanted diabetic MSCs survive and transdifferentiate into insulin-producing cells in the pancreas of recipient rats. Upon transplantation these cells initiate endogenous pancreatic regeneration by neogenesis of islet of recipient origin. The present study demonstrates that diabetic MSCs retains its stemness and potential to induce pancreatic regeneration on transplantation.

Bone Marrow-Derived Mesenchymal Stem cells Infusion Ameliorates Hyperglycemia, Dyslipidemia, Liver and Kidney Functions in Diabetic Rats

“…While hess et al [51] reported marked reduction of serum glucose occur as early as 4 days after transplantation of bone marrow derived cells into STZtreated mice due to stimulation of endogenous cells to proliferate and produce insulin. In accordance with our study, some evidences reported that single infusion of MSCs decrease blood glucose in STZ diabetic rats [52], [53]. Dong et al [52] reported that MSCs homed to pancreas of recipient rats and transdifferentiated into insulin-producing cells.…”

“…In accordance with our study, some evidences reported that single infusion of MSCs decrease blood glucose in STZ diabetic rats [52], [53]. Dong et al [52] reported that MSCs homed to pancreas of recipient rats and transdifferentiated into insulin-producing cells.…”

Preliminary evaluation of intravenous infusion and intrapancreatic injection of human umbilical cord blood-derived mesenchymal stem cells for the treatment of diabetic mice

“…MSCs have been shown to be capable of "homing" to the damaged area of the body and replacing injured cells (Vija et al, 2009). Xu et al reported that MSC transplantation could help in recovery of the pancreas that was injured by injection of STZ or attacked by T cells, through paracrine mechanisms (Xu et al, 2008). In fact, MSCs can secrete a variety of cytokines, growth factors, and stimulating factors that come in contact with the surrounding cells.…”

“…This positive paracrine effect on the damaged beta cells could help to protect these cells from apoptosis and to promote the proliferation of intrinsic pancreatic progenitor cells. This effect is also related to angiogenesis, cell protection, anti-inflammatory activities, promotion of mitosis, and apoptosis resistance (Bell et al, 2012;Gao et al, 2014;Xu et al, 2008). Furthermore, MSCs can trans-differentiate into insulin-producing cells (IPCs) in vivo in a suitable microenvironment (Chang et al, 2007).…”

“…Recent studies show that MSC transplantation may improve metabolism in animal models of diabetes mellitus (Pan et al, 2013;Tang et al, 2014;Xiao et al, 2013). Some researchers have suggested that MSCs should be transdifferentiated into insulin-producing cells (IPCs) before transplantation (Gabr et al, 2013;Wu et al, 2007), while others have used un-differentiated MSCs (Dong et al, 2008). MSCs could stimulate the production of cytokines and growth factors.…”