Engineered human iPS cell models reveal altered podocytogenesis and glomerular capillary wall in CHD-associatedSMAD2mutations

Abstract

AbstractEarly developmental programming involves extensive cell lineage diversification through shared molecular signaling networks. Clinical observations of congenital heart disease (CHD) patients carryingSMAD2genetic variants revealed correlations with multi-organ impairments at the developmental and functional levels. For example, many CHD patients present with glomerulosclerosis, periglomerular fibrosis, and albuminuria. Still, it remains largely unknown whetherSMAD2variants associated with CHD can directly alter kidney cell fate, tissue patterning, and organ-level function. To address this question, we engineered human iPS cells (iPSCs) and organ-on-a-chip systems to uncover the role of pathogenicSMAD2variants in kidney podocytogenesis. Our results show that abrogation ofSMAD2causes altered patterning of the mesoderm and intermediate mesoderm (IM) cell lineages, which give rise to nearly all kidney cell types. Upon further differentiation of IM cells, the mutant podocytes failed to develop arborizations and interdigitations. A reconstituted glomerulus-on-a-chip platform exhibited significant proteinuria as clinically observed in glomerulopathies. This study implicates CHD-associatedSMAD2mutations in kidney tissue malformation and provides opportunities for therapeutic discovery in the future.