Y-27632 preconditioning enhances transplantation of human-induced pluripotent stem cell-derived cardiomyocytes in myocardial infarction mice
| Autor: | Yasin Oduk, Anton V. Borovjagin, Lufang Zhou, Meng Zhao, Hanxi Zhu, Saidulu Mattapally, Chengming Fan, Jianyi Zhang, Patrick Ernst, Wuqiang Zhu, Yawen Tang |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Time Factors Physiology Cell Survival Pyridines Cellular differentiation Cell Induced Pluripotent Stem Cells Myocardial Infarction Apoptosis Mice SCID 030204 cardiovascular system & hematology Cell therapy 03 medical and health sciences 0302 clinical medicine Mice Inbred NOD Physiology (medical) medicine Cell Adhesion Myocyte Animals Humans Myocytes Cardiac Cell adhesion Induced pluripotent stem cell Protein Kinase Inhibitors Cells Cultured rho-Associated Kinases Chemistry Myocardium Graft Survival Cell Differentiation Recovery of Function Original Articles Amides Myocardial Contraction Cell biology Transplantation Disease Models Animal 030104 developmental biology medicine.anatomical_structure Phenotype Cardiology and Cardiovascular Medicine |
| Zdroj: | Cardiovascular research. 115(2) |
| ISSN: | 1755-3245 |
| Popis: | AIMS : The effectiveness of cell-based treatments for regenerative myocardial therapy is limited by low rates of cell engraftment. Y-27632 inhibits Rho-associated protein kinase (ROCK), which regulates the cytoskeletal changes associated with cell adhesion, and has been used to protect cultured cells during their passaging. Here, we investigated whether preconditioning of cardiomyocytes, derived from human-induced pluripotent stem cells (hiPSC-CM), with Y-27632 improves their survival and engraftment in a murine model of acute myocardial infarction (MI). METHODS AND RESULTS : After MI induction, mice were subjected to intramyocardial injections of phosphate-buffered saline, hiPSC-CM cultured under standard conditions (hiPSC-CM(–RI)), or Y-27632-preconditioned hiPSC-CM (hiPSC-CM(+RI)). The resulting engraftment rate calculated 4 weeks after implantation was significantly higher and the abundance of apoptotic transplanted cells was significantly lower in hiPSC-CM(+RI) recipients than in hiPSC-CM(–RI) animals. In cultured hiPSC-CM, Y-27632-preconditioning reversibly reduced contractile activity and the expression of troponin genes, while increasing their attachment to an underlying mouse cardiomyocyte (HL1) monolayer. Y-27632 preconditioning also increased the expression of N-cadherin and integrin ß1, the two cell junction proteins. hiPSC-CM(+RI) were also larger in cell area with greater cytoskeletal alignment and a more rod-like shape than hiPSC-CM(–RI), both after transplantation (in vivo) and in culture. The effects of Y-27632 preconditioning on contractile activity and morphology of hiPSC-CMs in culture, as well as on their engraftment rate and apoptotic death in MI mouse grafts, could be recapitulated by hiPSC-CM treatment with the L-type calcium-channel blocker verapamil. CONCLUSION : Preconditioning with the ROCK inhibitor Y-27632 increased the engraftment of transplanted hiPSC-CM in a murine MI model, while reversibly impairing hiPSC-CM contractility and promoting adhesion. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|