Abstract 9321: Selective Inhibition of Inositol Hexakisphosphate Kinases Enhances Mesenchymal Stem Cell Engraftment and Improves Therapeutic Efficacy for Myocardial Infarction

Abstract

Rationale: 5-diphosphoinositol pentakisphosphate (IP7), formed by a family of inositol hexakis phosphate kinases (IP6Ks), has been demonstrated to be a physiologic inhibitor of Akt. IP6K inhibition may increase Akt activation in mesenchymal stem cells (MSCs), resulting in enhanced cardiac protective effect after transplantation. Objective: To investigate the role of IP6Ks for improving MSCs’ functional survival and cardiac protective effect after transplantation into infarcted mice hearts. Methods and results: Bone marrow-derived mesenchymal stem cells (BMMSCs), isolated from dual-reporter firefly luciferase and enhanced green fluorescent protein positive (Fluc + -eGFP + ) transgenic mice, were preconditioned with IP6Ks inhibitor TNP (0.5μmol/L, 1μmol/L, 5μmol/L, and 10μmol/L) for 2 h followed by 6 hours of hypoxia and serum deprivation (H/SD) injury. TNP dose dependently significantly decreased IP7 production with increased Akt phosphorylation. Moreover,TNP at 10μmol/L significantly improved the viability and enhanced the paracrine effect of MSCs after H/SD. Furthermore, MSCs were transplanted into infarcted hearts with or without selective IP6Ks inhibition. Longitudinal in vivo bioluminescence imaging (BLI) and immunofluorescent staining revealed that TNP pretreatment enhanced the survival of engrafted MSCs, which promoted the anti-apoptotic and pro-angiogenic efficacy of MSCs in vivo . Furthermore, MSCs therapy with IP6Ks inhibition significantly decreased fibrosis and preserved heart function. Conclusion: Inhibition of IP6Ks promotes MSCs engraftment and paracrine effect in infarcted hearts at least in part by down-regulating IP7 production and enhancing Akt activation, which might contribute to the preservation of myocardial function after MI.