Combined Treatment of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Endothelial Cells Regenerate the Infarcted Heart in Mice and Non-Human Primates.

Autor:	Cheng YC; Institute of Biomedical Sciences, Academia Sinica, Taiwan (Y.C.C., C.J.L., C.Y.H., C.Y.T., D.Z.H.C., M.W.N., P.J.L., H.C.C., P.C.H.H.)., Hsieh ML; Model Organisms Research Core, Department of Medicine (M.L.H., C.M.C.C., T.A.H.), University of Wisconsin-Madison., Lin CJ; Institute of Biomedical Sciences, Academia Sinica, Taiwan (Y.C.C., C.J.L., C.Y.H., C.Y.T., D.Z.H.C., M.W.N., P.J.L., H.C.C., P.C.H.H.)., Chang CMC; Model Organisms Research Core, Department of Medicine (M.L.H., C.M.C.C., T.A.H.), University of Wisconsin-Madison., Huang CY; Institute of Biomedical Sciences, Academia Sinica, Taiwan (Y.C.C., C.J.L., C.Y.H., C.Y.T., D.Z.H.C., M.W.N., P.J.L., H.C.C., P.C.H.H.)., Puntney R; Wisconsin National Primate Research Center (R.P., A.W.M., J.C., P.B., H.A.S.), University of Wisconsin-Madison., Wu Moy A; Wisconsin National Primate Research Center (R.P., A.W.M., J.C., P.B., H.A.S.), University of Wisconsin-Madison., Ting CY; Institute of Biomedical Sciences, Academia Sinica, Taiwan (Y.C.C., C.J.L., C.Y.H., C.Y.T., D.Z.H.C., M.W.N., P.J.L., H.C.C., P.C.H.H.)., Herr Chan DZ; Institute of Biomedical Sciences, Academia Sinica, Taiwan (Y.C.C., C.J.L., C.Y.H., C.Y.T., D.Z.H.C., M.W.N., P.J.L., H.C.C., P.C.H.H.)., Nicholson MW; Institute of Biomedical Sciences, Academia Sinica, Taiwan (Y.C.C., C.J.L., C.Y.H., C.Y.T., D.Z.H.C., M.W.N., P.J.L., H.C.C., P.C.H.H.)., Lin PJ; Institute of Biomedical Sciences, Academia Sinica, Taiwan (Y.C.C., C.J.L., C.Y.H., C.Y.T., D.Z.H.C., M.W.N., P.J.L., H.C.C., P.C.H.H.)., Chen HC; Institute of Biomedical Sciences, Academia Sinica, Taiwan (Y.C.C., C.J.L., C.Y.H., C.Y.T., D.Z.H.C., M.W.N., P.J.L., H.C.C., P.C.H.H.)., Kim GC; Department of Medicine and Stem Cell and Regenerative Medicine Center (G.C.K., J.Z., T.J.K., P.C.H.H.), University of Wisconsin-Madison., Zhang J; Department of Medicine and Stem Cell and Regenerative Medicine Center (G.C.K., J.Z., T.J.K., P.C.H.H.), University of Wisconsin-Madison., Coonen J; Wisconsin National Primate Research Center (R.P., A.W.M., J.C., P.B., H.A.S.), University of Wisconsin-Madison., Basu P; Wisconsin National Primate Research Center (R.P., A.W.M., J.C., P.B., H.A.S.), University of Wisconsin-Madison., Simmons HA; Wisconsin National Primate Research Center (R.P., A.W.M., J.C., P.B., H.A.S.), University of Wisconsin-Madison., Liu YW; Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan (Y.W.L.)., Hacker TA; Model Organisms Research Core, Department of Medicine (M.L.H., C.M.C.C., T.A.H.), University of Wisconsin-Madison., Kamp TJ; Department of Medicine and Stem Cell and Regenerative Medicine Center (G.C.K., J.Z., T.J.K., P.C.H.H.), University of Wisconsin-Madison., Hsieh PCH; Institute of Biomedical Sciences, Academia Sinica, Taiwan (Y.C.C., C.J.L., C.Y.H., C.Y.T., D.Z.H.C., M.W.N., P.J.L., H.C.C., P.C.H.H.).; Department of Medicine and Stem Cell and Regenerative Medicine Center (G.C.K., J.Z., T.J.K., P.C.H.H.), University of Wisconsin-Madison.; Institute of Medical Genomics and Proteomics and Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan (P.C.H.H.).
Jazyk:	angličtina
Zdroj:	Circulation [Circulation] 2023 Oct 31; Vol. 148 (18), pp. 1395-1409. Date of Electronic Publication: 2023 Sep 21.
DOI:	10.1161/CIRCULATIONAHA.122.061736
Abstrakt:	Background: Remuscularization of the mammalian heart can be achieved after cell transplantation of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs). However, several hurdles remain before implementation into clinical practice. Poor survival of the implanted cells is related to insufficient vascularization, and the potential for fatal arrhythmogenesis is associated with the fetal cell-like nature of immature CMs. Methods: We generated 3 lines of hiPSC-derived endothelial cells (ECs) and hiPSC-CMs from 3 independent donors and tested hiPSC-CM sarcomeric length, gap junction protein, and calcium-handling ability in coculture with ECs. Next, we examined the therapeutic effect of the cotransplantation of hiPSC-ECs and hiPSC-CMs in nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice undergoing myocardial infarction (n≥4). Cardiac function was assessed by echocardiography, whereas arrhythmic events were recorded using 3-lead ECGs. We further used healthy non-human primates (n=4) with cell injection to study the cell engraftment, maturation, and integration of transplanted hiPSC-CMs, alone or along with hiPSC-ECs, by histological analysis. Last, we tested the cell therapy in ischemic reperfusion injury in non-human primates (n=4, 3, and 4 for EC+CM, CM, and control, respectively). Cardiac function was evaluated by echocardiography and cardiac MRI, whereas arrhythmic events were monitored by telemetric ECG recorders. Cell engraftment, angiogenesis, and host-graft integration of human grafts were also investigated. Results: We demonstrated that human iPSC-ECs promote the maturity and function of hiPSC-CMs in vitro and in vivo. When cocultured with ECs, CMs showed more mature phenotypes in cellular structure and function. In the mouse model, cotransplantation augmented the EC-accompanied vascularization in the grafts, promoted the maturity of CMs at the infarct area, and improved cardiac function after myocardial infarction. Furthermore, in non-human primates, transplantation of ECs and CMs significantly enhanced graft size and vasculature and improved cardiac function after ischemic reperfusion. Conclusions: These results demonstrate the synergistic effect of combining iPSC-derived ECs and CMs for therapy in the postmyocardial infarction heart, enabling a promising strategy toward clinical translation. Competing Interests: Disclosures None.
Databáze:	MEDLINE
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