Direct lineage tracing reveals Activin-A potential for improved pancreatic homing of bone marrow mesenchymal stem cells and efficient ß-cell regeneration in vivo

Abstract

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.