Studies on generation of cardiomyocytes and kidney organoids using induced pluripotent stem cells originated from Fabry disease patients

Abstract

Fabry disease (FD) is an X-linked recessive lysosomal storage disorder caused by a mutation of GLA gene. A deficiency of α-galactosidase (α-GAL) leads to the accumulation of globotriaosylceramide (Gb3) in lysosomes which induces severe symptoms such as cardiac hypertrophy and renal failure. The cardiac and renal defect is one of the most prevalent symptoms and major risk factors of FD. However, how Gb3 accumulation causes renal defects in FD remains to be elucidated. To study the cellular mechanism of those two symptoms, human induced pluripotent stem cells (FD-iPSCs) were generated from dermal fibroblasts of FD patients. Pluripotency markers were expressed in all FD-iPSC lines. Both wild-type (WT)-iPSCs (WT-iPSCs) and FD-iPSCs were efficiently differentiated into cardiomyocytes and kidney organoids. Cardiomyocytes derived from WT and FD-iPSCs (WT-CMs and FD-CMs) showed spontaneous beating and expression of sarcomere markers. Kidney organoids derived from WT and FD-iPSCs (WT-KOs and FD-KOs) showed nephron-like structure and physiological features. Glomerulus, tubules and collecting duct markers were expressed in those organoids. Gb3 accumulation was observed in FD-KOs, representing a typical phenotype of FD. FD-KOs also showed increased Thrombospondin1 (TSP1) suggesting relevance with an endothelial defect. Therefore, FD-CMs and FD-KOs would be useful tools for studying the relationship between Gb3 accumulation and renal defects in FD.