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Y-27632 preconditioning enhances transplantation of human-induced pluripotent stem cell-derived cardiomyocytes in myocardial infarction mice.
- Source :
-
Cardiovascular research [Cardiovasc Res] 2019 Feb 01; Vol. 115 (2), pp. 343-356. - Publication Year :
- 2019
-
Abstract
- 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).<br />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.<br />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.
- Subjects :
- Animals
Apoptosis drug effects
Cell Adhesion drug effects
Cell Survival drug effects
Cells, Cultured
Disease Models, Animal
Graft Survival drug effects
Humans
Induced Pluripotent Stem Cells enzymology
Mice, Inbred NOD
Mice, SCID
Myocardial Contraction drug effects
Myocardial Infarction metabolism
Myocardial Infarction pathology
Myocardial Infarction physiopathology
Myocardium metabolism
Myocardium pathology
Myocytes, Cardiac enzymology
Phenotype
Recovery of Function
Time Factors
rho-Associated Kinases antagonists & inhibitors
rho-Associated Kinases metabolism
Amides pharmacology
Cell Differentiation
Induced Pluripotent Stem Cells drug effects
Induced Pluripotent Stem Cells transplantation
Myocardial Infarction surgery
Myocytes, Cardiac drug effects
Myocytes, Cardiac transplantation
Protein Kinase Inhibitors pharmacology
Pyridines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1755-3245
- Volume :
- 115
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cardiovascular research
- Publication Type :
- Academic Journal
- Accession number :
- 30107391
- Full Text :
- https://doi.org/10.1093/cvr/cvy207