Abstract 18849: Preconditioning of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes With Y-27632 Improves Their Ability for Myocardial Repair

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Abstract

Introduction: Cell-based therapy is promising for myocardial repair, but small engraftment rate due to low cell retention and high cell death in the ischemic environment remains a significant issue. The Rho kinases (ROCKs) were downstream targets of Rho, a small GTPase. It is well-known that ROCKs regulate cellular contraction, adhesion, and migration via regulating actin cytoskeleton. Pre-treatment with Y-27632, a well-known chemical that inhibit both ROCK1 and ROCK2, attenuates cardiac remodeling and improves cardiac function in myocardial infarction animal models. Here, we hypothesize that pretreatment of transplanted hiPSC-derived cardiomyocytes (hiPSC-CMs) with a single chemical Y-27632 (10 μM) can significantly enhance the survival of grafted cells and cardiac function recovery.

Methods and results: Immunodeficient mice were randomly assigned to four different groups: sham, myocardial infarction (MI), MI+Cells, and MI+Cells+RI (Rock inhibitor) preconditioning. hiPSC-CMs were injected into three different sites in the peri-infarcted area. HW/BW ratio is significantly reduced in mice in the MI+Cells+RI group comparing to mice in the MI+Cells group (P<0.05). Y-27632 treatment dramatically reduces infarction size by day 28 comparing to MI group (p<0.05) and to MI+Cells group (p<0.05). Luciferase activity was much higher in animals in the MI+Cells+RI group than those in MI+Cells group (p<0.05) at at day 3, 7 and 28 after cell transplantation. While most of the grafted cells without treatment are still round shape (a typical morphology for cells right after dissociation from the pertri dish), Y-27632 treated hiPSC-CMs showed uniformly rod-shape at 7 days after transplanted into infarcted mouse hearts. Furthermore, both N-cadherin (N-Cad) and Connexin 43 (Cx43), two junctional proteins were upregulated in Y-27632 treated cells. The cardiac troponin T and cardiac troponin I were decreased by Y-27632, which may promote cell extension.

Conclusion: Our data implicated that the cytoprotective effect of Y-27632 might result from upregulated cell junctional proteins such as N-Cad and Cx43 and downregulated cardiac troponin T and cardiac troponin I which might promote cell extension of the grafted cells, and hence enhancing cell survival.

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