Investigating PKD2 deficiency-associated cardiomyopathies using hESC-cardiomyocytes and bioengineered 3D ventricular cardiac tissue strips.

Autosomal dominant polycystic kidney disease is a highly prevalent hereditary renal disorder caused by mutations in either polycystin-1 or polycystin-2. These patients also develop cardiomyopathies. However, the mechanism of how polycystin-2 defects could lead to cardiomyopathies is poorly understood. Moreover, previous studies using animal models cannot fully represent human cardiomyocyte pathophysiology. Human embryonic stem cells were differentiated into cardiomyocytes. These cardiomyocytes were transduced with viral-based polycystin-2-shRNAs, then mixed with an appropriate amount of human fetal fibroblasts, collagen, and Matrigel, and biofabricated into 3D bioengineered ventricular cardiac tissue strips (hvCTS). We used these 3D hvCTS and 2D human embryonic stem cells-derived cardiomyocytes to recapitulate polycystin-2 deficiency-associated cardiac contractile defects and to explore underlying mechanisms. Knockdown of polycystin-2 decreased the contractile force and slowed down the contraction and relaxation velocities in hvCTS, indicative of contractile malfunction. The underlying mechanisms involved an elevated endoplasmic reticulum stress and a decreased activity of sarcoplasmic reticulum Ca