PMID- 30107391 OWN - NLM STAT- MEDLINE DCOM- 20200305 LR - 20200309 IS - 1755-3245 (Electronic) IS - 0008-6363 (Print) IS - 0008-6363 (Linking) VI - 115 IP - 2 DP - 2019 Feb 1 TI - Y-27632 preconditioning enhances transplantation of human-induced pluripotent stem cell-derived cardiomyocytes in myocardial infarction mice. PG - 343-356 LID - 10.1093/cvr/cvy207 [doi] AB - 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. FAU - Zhao, Meng AU - Zhao M AD - Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China. AD - Department of Biomedical Engineering, School of Medicine, School of Engineering, University of Alabama at Birmingham, 1670 University Blvd, VH G094E, Birmingham, AL, USA. FAU - Fan, Chengming AU - Fan C AD - Department of Biomedical Engineering, School of Medicine, School of Engineering, University of Alabama at Birmingham, 1670 University Blvd, VH G094E, Birmingham, AL, USA. AD - Department of Cardiovascular Surgery, the Second Xiangya Hospital, Central South University, Changsha, China; and. FAU - Ernst, Patrick J AU - Ernst PJ AD - Department of Biomedical Engineering, School of Medicine, School of Engineering, University of Alabama at Birmingham, 1670 University Blvd, VH G094E, Birmingham, AL, USA. AD - Division of Cardiovascular Diseases, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. FAU - Tang, Yawen AU - Tang Y AD - Department of Biomedical Engineering, School of Medicine, School of Engineering, University of Alabama at Birmingham, 1670 University Blvd, VH G094E, Birmingham, AL, USA. FAU - Zhu, Hanxi AU - Zhu H AD - Department of Biomedical Engineering, School of Medicine, School of Engineering, University of Alabama at Birmingham, 1670 University Blvd, VH G094E, Birmingham, AL, USA. FAU - Mattapally, Saidulu AU - Mattapally S AD - Department of Biomedical Engineering, School of Medicine, School of Engineering, University of Alabama at Birmingham, 1670 University Blvd, VH G094E, Birmingham, AL, USA. FAU - Oduk, Yasin AU - Oduk Y AD - Department of Biomedical Engineering, School of Medicine, School of Engineering, University of Alabama at Birmingham, 1670 University Blvd, VH G094E, Birmingham, AL, USA. FAU - Borovjagin, Anton V AU - Borovjagin AV AD - Department of Biomedical Engineering, School of Medicine, School of Engineering, University of Alabama at Birmingham, 1670 University Blvd, VH G094E, Birmingham, AL, USA. FAU - Zhou, Lufang AU - Zhou L AD - Department of Biomedical Engineering, School of Medicine, School of Engineering, University of Alabama at Birmingham, 1670 University Blvd, VH G094E, Birmingham, AL, USA. AD - Division of Cardiovascular Diseases, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. FAU - Zhang, Jianyi AU - Zhang J AD - Department of Biomedical Engineering, School of Medicine, School of Engineering, University of Alabama at Birmingham, 1670 University Blvd, VH G094E, Birmingham, AL, USA. FAU - Zhu, Wuqiang AU - Zhu W AD - Department of Biomedical Engineering, School of Medicine, School of Engineering, University of Alabama at Birmingham, 1670 University Blvd, VH G094E, Birmingham, AL, USA. LA - eng GR - R01 HL138023/HL/NHLBI NIH HHS/United States GR - R01 HL121206/HL/NHLBI NIH HHS/United States GR - R01 HL095077/HL/NHLBI NIH HHS/United States GR - R01 HL131017/HL/NHLBI NIH HHS/United States GR - R01 HL114120/HL/NHLBI NIH HHS/United States GR - R21 HL127599/HL/NHLBI NIH HHS/United States GR - U01 HL134764/HL/NHLBI NIH HHS/United States GR - R56 HL142627/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - England TA - Cardiovasc Res JT - Cardiovascular research JID - 0077427 RN - 0 (Amides) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyridines) RN - 138381-45-0 (Y 27632) RN - EC 2.7.11.1 (rho-Associated Kinases) SB - IM MH - Amides/*pharmacology MH - Animals MH - Apoptosis/drug effects MH - Cell Adhesion/drug effects MH - *Cell Differentiation MH - Cell Survival/drug effects MH - Cells, Cultured MH - Disease Models, Animal MH - Graft Survival/drug effects MH - Humans MH - Induced Pluripotent Stem Cells/*drug effects/enzymology/*transplantation MH - Mice, Inbred NOD MH - Mice, SCID MH - Myocardial Contraction/drug effects MH - Myocardial Infarction/metabolism/pathology/physiopathology/*surgery MH - Myocardium/metabolism/pathology MH - Myocytes, Cardiac/*drug effects/enzymology/*transplantation MH - Phenotype MH - Protein Kinase Inhibitors/*pharmacology MH - Pyridines/*pharmacology MH - Recovery of Function MH - Time Factors MH - rho-Associated Kinases/antagonists & inhibitors/metabolism PMC - PMC6341224 EDAT- 2018/08/15 06:00 MHDA- 2020/03/07 06:00 PMCR- 2020/02/01 CRDT- 2018/08/15 06:00 PHST- 2018/01/05 00:00 [received] PHST- 2018/08/10 00:00 [accepted] PHST- 2018/08/15 06:00 [pubmed] PHST- 2020/03/07 06:00 [medline] PHST- 2018/08/15 06:00 [entrez] PHST- 2020/02/01 00:00 [pmc-release] AID - 5073049 [pii] AID - cvy207 [pii] AID - 10.1093/cvr/cvy207 [doi] PST - ppublish SO - Cardiovasc Res. 2019 Feb 1;115(2):343-356. doi: 10.1093/cvr/cvy207.