The G Protein-Coupled Receptor Latrophilin-2, A Marker for Heart Development, Induces Myocardial Repair After Infarction

Abstract

Abstract Discovering cell–surface markers based on a comprehensive understanding of development is utilized to isolate a particular cell type with high purity for therapeutic purposes. Given that latrophilin-2 (Lphn2) substantially contributes to cardiac differentiation, we examined whether Lphn2 regulates functional significance in heart development and repair. We performed whole-mount immunostaining followed by clearing technique of embryo, RNA sequencing related to Lphn2-knockout (KO) embryo, and in vivo functional analyses of Lphn2+ cells using echocardiography. After immunostaining the cleared embryo sample, Lphn2 was exclusively observed in cardiac cells expressing α-sarcomeric actinin at embryonic days E9.5 and E10.5. Homozygous Lphn2-KO mice were embryonically lethal and showed underdevelopment of the ventricular myocardium. However, Lphn2 was not required to develop vessels, including endothelial cells and smooth muscle cells. For the purpose of cardiac regeneration, we transplanted pluripotent stem cell (PSC)–derived Lphn2+ cells into the infarcted heart. PSC–derived Lphn2+ cells differentiated into cardiomyocytes and regenerated the myocardium when transplanted into the infarcted heart, unlike Lphn2− cells. Transplanted Lphn2+ cells improved left-ventricle systolic function and reduced infarct size. We demonstrated that Lphn2 exhibits potential as a cardiomyogenic marker to facilitate targeted stem cell therapy for heart repair in clinical practice.