Development of a human cardiac organoid injury model reveals innate regenerative potential

Abstract

The adult human heart possesses a limited regenerative potential following an ischemic event, and undergoes a number of pathological changes in response to injury. While cardiac regeneration has been documented in zebrafish and neonatal mouse hearts, it is currently unknown whether the immature human heart is capable of undergoing complete regeneration. Combined progress in pluripotent stem cell differentiation and tissue engineering has facilitated the development of human cardiac organoids (hCO), which resemble fetal heart tissue and can be used to address this important knowledge gap. This study aimed to characterise the regenerative capacity of immature human heart tissue in response to injury. Following cryoinjury with a dry ice probe, hCO exhibited an endogenous regenerative response with full functional recovery by two weeks following acute injury. Cardiac functional recovery occurred in the absence of pathological fibrosis or cardiomyocyte hypertrophy. Consistent with regenerative organisms and neonatal human hearts, there was a high basal level of cardiomyocyte proliferation, which may be responsible for the regenerative capacity of the hCO. This study suggests that immature human heart tissue has an intrinsic capacity to regenerate.