Background Despite the potential, bone marrow-derived mesenchymal stem cells (BMSCs) show limitations for beta (ß)-cell replacement therapy due to inefficient methods to deliver BMSCs into pancreatic lineage. In this study, we report TGF-ß family member protein, Activin-a potential to stimulate efficient pancreatic migration, enhanced homing and accelerated ß-cell differentiation. Methods Lineage tracing of permanent green fluorescent protein (GFP)- tagged donor murine BMSCs transplanted either alone or in combination with Activin-a in diabetic mice displayed potential ß-cell regeneration and reversed diabetes. Results Pancreatic histology of Activin-a treated recipient mice reflected high GFP + BMSC infiltration into damaged pancreas with normalized fasting blood glucose and elevated serum insulin. Whole pancreas FACS profiling of GFP + cells displayed significant homing of GFP + BMSC with Activin-a treatment (6%) compared to BMSCs alone transplanted controls (0.5%). Within islets, approximately 5% GFP+ cells attain ß-cell signature (GFP + Ins + ) with Activin-a treatment versus controls. Further, double immunostaining for mesenchymal stem cell markers CD44 + /GFP + in infiltrated GFP + BMSC deciphers substantial endocrine reprogramming and ß-cell differentiation (6.4% Ins + /GFP + ) within 15 days. Conclusion Our investigation thus presents a novel pharmacological approach for stimulating direct migration and homing of therapeutic BMSCs that re-validates BMSC potential for autologous stem cell transplantation therapy in diabetes.

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Pancreatic progenitors have been explored for their profound characteristics and unique commitment to generate new functional islets in regenerative medicine. Pancreatic resident endocrine progenitors (PREPs) with mesenchymal stem cell (MSC) phenotype were purified from BALB/c mice pancreas and characterized. PREPs were differentiated into mature islet clusters in vitro by activin‐A and swertisin and functionally characterized. A temporal gene and protein profiling was performed during differentiation. Furthermore, PREPs were labeled with green fluorescent protein (GFP) and transplanted intravenously into streptozotocin (STZ) diabetic mice while monitoring their homing and differentiation leading to amelioration in the diabetic condition. PREPs were positive for unique progenitor markers and transcription factors essential for endocrine pancreatic homeostasis along with having the multipotent MSC phenotype. These cells demonstrated high fidelity for islet neogenesis in minimum time (4 days) to generate mature functional islet clusters (shortest reported period for any isolated stem/progenitor). Furthermore, GFP‐labeled PREPs transplanted in STZ diabetic mice migrated and localized within the injured pancreas without trapping in any other major organ and differentiated rapidly into insulin‐producing cells without an external stimulus. A rapid decrease in fasting blood glucose levels toward normoglycemia along with significant increase in fasting serum insulin levels was observed, which ameliorated the diabetic condition. This study highlights the unique potential of PREPs to generate mature islets within the shortest period and their robust homing toward the damaged pancreas, which ameliorated the diabetic condition suggesting PREPs affinity toward their niche, which can be exploited and extended to other stem cell sources in diabetic therapeutics.

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