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

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.