Abstract
BackgroundDespite 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.MethodsLineage 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.ResultsPancreatic 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.ConclusionOur 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.
Highlights
Stem cell-derived β-cells present a clear proof-of-concept for cell-based diabetes medication
To perform lineage tracing of Bone marrow-derived mesenchymal stem cells (BMSC), we created traceable BMSCs by permanent genomic integration of green fluorescent protein (GFP) using piggyback transposomal elements
Transfected BMSCs show a high frequency of GFP+ cells with flowcytometry (90.6%)
Summary
Stem cell-derived β-cells present a clear proof-of-concept for cell-based diabetes medication. An early study by Hess et al demonstrated the blood glucose-lowering effect within a week after intravenous infusion of GFP-tagged allogenic BMSCs into STZ-induced diabetic mice [4]. The authors reported as low as 0.5% frequency of donor GFP+BMSC to reach the pancreas while fewer differentiate into insulin-producing cells within the host islets. In another similar study, only 1% allogeneic chimerism of repopulated BMSCs were shown to reach recipient pancreas and reverse diabetes in NOD mice [12]. 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. We report TGF-ß family member protein, Activin-a potential to stimulate efficient pancreatic migration, enhanced homing and accelerated ß-cell differentiation
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