Activation of MG53 Enhances Cell Survival and Engraftment of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Injured Hearts

BACKGROUND AND OBJECTIVE: Our previous studies demonstrated that MG53 protein can protect the myocardium, but its use as a therapeutic is challenging due to its short half-life in blood circulation. This study aimed to investigate the cardioprotective role of MG53 on human induced pluripotent stem cell-derived cardiomyocytes (HiPSC-CMs) in the context of myocardial ischemia/reperfusion (I/R). METHODS: In vitro: HiPSC-CMs were transfected with adenoviral MG53 (HiPSC-CMs(MG53)), in which the expression of MG53 can be controlled by doxycycline (Dox), and the cells were then exposed to H(2)O(2) to mimic ischemia/reperfusion injury. In vivo: HiPSC-CMs(MG53) were transplanted into the peri-infarct region in NSG™ mice after I/R. After surgery, mice were treated with Dox (+ Dox) to activate MG53 expression (sucrose as a control of -Dox) and then assessed by echocardiography and immunohistochemistry. RESULTS: MG53 can be expressed in HiPSC-CM(MG53) and released into the culture medium after adding Dox. The cell survival rate of HiPSC-CM(MG53) was improved by Dox under the H(2)O(2) condition. After 14 and 28 days of ischemia/reperfusion (I/R), transplanted HiPSC-CMs(MG53) + Dox significantly improved heart function, including ejection fraction (EF) and fractional shortening (FS) in mice, compared to HiPSC-CMs(MG53)-Dox, and reduced the size of the infarction. Additionally, HiPSC-CM(MG53) + Dox mice demonstrated significant engraftment in the myocardium as shown by staining human nuclei-positive cells. In addition, the cell survival-related AKT signaling was found to be more active in HiPSC-CM(MG53) + Dox transplanted mice’s myocardium compared to the HiPSC-CM(MG53)-Dox group. Notably, the Dox treatment did not cause harm to other organs. CONCLUSION: Inducible MG53 expression is a promising approach to enhance cell survival and engraftment of HiPSC-CMs for cardiac repair. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12015-023-10596-0.