Direct Lineage Tracing Reveals Activin-a Potential for Improved Pancreatic Homing of Bone Marrow Mesenchymal Stem Cells and Efficient ß-cell Regeneration in Vivo
Overview
Affiliations
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 GFPBMSC infiltration into damaged pancreas with normalized fasting blood glucose and elevated serum insulin. Whole pancreas FACS profiling of GFP cells displayed significant homing of GFPBMSC 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 GFPBMSC 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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