Type 1 diabetes (T1D) is an autoimmune disease due to beta-cell destruction and leads to hyperglycemia and lifelong insulin dependency. Mesenchymal stem cell (MSC) infusion was reported to control hyperglycemia and preserve pancreatic beta-cell function. Most studies employed MSC through the systemic route (intravenous route) of transplantation in T1D animal models. However, the systemic route subjected MSC to the lungs, resulting in microvasculature entrapment and decreased therapeutic outcome. In this study, we investigated beta-cell regeneration after hTERT-MSC infusion in partially pancreatectomized mice and the antidiabetic effect of ADMSC through two different routes; intravenous (IVR) and intrapancreatic route (IPR) in streptozotocin-induced diabetic NMRI nude mice.Both hTERT-MSC and ADMSC were characterized by specific cell surface markers (CD90, CD44, CD105, CD73) using a flow cytometer. Further, possible tumor formation was ruled out by transplanting 0.5 x 106 ADMSC, hTERT-MSC and PANC1 into the flank of NMRI nude mice. No tumor was observed with ADMSC and hTERT-MSC.IPR-hTERT-MSC-administration increased the frequency of newly formed insulin producing beta-cells (labelled with BrdU) along with the number of islets per section and insulin content in the residual pancreas than IVR and control after partial pancreatectomy. However, IPR also exhibited greater retention of MSC after eight days of transplantation compared to IVR. In the presence of MSC, murine EGF was enhanced and inflammatory molecules such as IFN-gamma and TNF-alpha were decreased. MSC induced higher expression of FOXA2, PDX-1, P-AKT and downregulated FoxO1. Therefore, present work confirmed the superior effect of IPR over IVR in proliferating beta-cells through AKT/ PDX-1/ FOXA2/ FoxO1 signaling pathway in partially pancreatectomized mice.Further, IPR-ADMSC-administration in STZ-induced diabetic NMRI nude mice ameliorated hyperglycemia as compared to IVR, STZ and control groups. In the IPR group, replicating beta-cells, the number of islets per section and the islet area was enhanced. ADMSC rescued the diabetic pancreas by stimulating the secreting of growth factor (EGF) and maintaining Th1/ Th2 balance by downregulation of IL-1beta, TNF-alpha and upregulation of IL-10. Physical contact of MSC with the damaged MIN6 cells provided higher protection than the paracrine effect in in-vitro studies. In summary, this study reveals the higher antidiabetic effect of ADMSC through DLK1/ EGF/ ERK/ FoxO1 signaling cascade in the IPR group compared to the IVR group.
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