TY - JOUR
T1 - Y-27632 preconditioning enhances transplantation of human-induced pluripotent stem cell-derived cardiomyocytes in myocardial infarction mice
AU - Zhao, Meng
AU - Fan, Chengming
AU - Ernst, Patrick J.
AU - Tang, Yawen
AU - Zhu, Hanxi
AU - Mattapally, Saidulu
AU - Oduk, Yasin
AU - Borovjagin, Anton V.
AU - Zhou, Lufang
AU - Zhang, Jianyi
AU - Zhu, Wuqiang
N1 - Funding Information:
This study was supported by the National Institutes of Health (RO1 grants HL95077, HL114120, HL131017, HL138023, UO1 HL134764 to J.Z. and HL121206A1 to L.Z.), American Heart Association Scientist Development Grant (16SDG30410018 to W.Z.), and China Scholarship Council (to M.Z. and C.F.).
Publisher Copyright:
© 2018 Published on behalf of the European Society of Cardiology. All rights reserved.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - 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.
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.
KW - Cardiac
KW - Cell signalling
KW - Cellular therapy
KW - Induced pluripotent stem cells
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U2 - 10.1093/cvr/cvy207
DO - 10.1093/cvr/cvy207
M3 - Article
C2 - 30107391
AN - SCOPUS:85060390205
SN - 0008-6363
VL - 115
SP - 343
EP - 356
JO - Cardiovascular research
JF - Cardiovascular research
IS - 2
ER -