Cetacean single-nucleus RNA-sequencing positions the cardioprotective gene FHL2 as a target for advancing pig-to-human heart xenotransplantation

Damage to the heart, an organ core to the circulation of oxygen and nutrients to the body, significantly reduces lifespan. A heart transplant from human donors (allografts) has been possible for the last four decades, but there is a severe shortage of donor hearts. While transplants from other species (xenografts) are now possible, post-transplant dysfunction limits their success. Herein, we employed a learn-from-nature approach to identify genes that underlie improved cardiac performance. We generated and compared cetacean (the rough-toothed dolphin, Steno bredanensis), bama pig, and human myocardial transcriptomes to identify cellular and molecular features underlying the exceptional resilience of the cetacean heart. The cetacean myocardium exhibits a distinct cell type gene expression signature, marked by a broad and elevated expression of FHL2 (four and a half LIM domains 2) by cardiomyocytes. Overexpression of FHL2 in a mouse model of cardiac failure alle viated pressure overload-induced cardiac dysfunction (hypertrophy). Our bioinspired study provides proof of principle for improved heart function through cardiomyocyte-targeted overexpression of a single gene as a promising candidate for gene editing to enhance pig-human xenotransplant success. Overall design: The snRNA-seq data from three human hearts, two pig hearts, and two technical replicates of the hearts of one whale heart were compared.