PT - JOURNAL ARTICLE AU - Bhattacharya, Rohan AU - Ward, Tarsha AU - Kalejaiye, Titilola D. AU - Mishra, Alekshyander AU - Leeman, Sophia AU - Arzaghi, Hamidreza AU - Seidman, Jonathan G. AU - Seidman, Christine E. AU - Musah, Samira TI - Engineered human iPS cell models reveal altered podocytogenesis and glomerular capillary wall in CHD-associated <em>SMAD2</em> mutations AID - 10.1101/2024.08.02.606108 DP - 2024 Jan 01 TA - bioRxiv PG - 2024.08.02.606108 4099 - http://biorxiv.org/content/early/2024/08/06/2024.08.02.606108.short 4100 - http://biorxiv.org/content/early/2024/08/06/2024.08.02.606108.full AB - Early developmental programming involves extensive cell lineage diversification through shared molecular signaling networks. Clinical observations of congenital heart disease (CHD) patients carrying SMAD2 genetic 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 whether SMAD2 variants 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 pathogenic SMAD2 variants in kidney podocytogenesis. Our results show that abrogation of SMAD2 causes 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-associated SMAD2 mutations in kidney tissue malformation and provides opportunities for therapeutic discovery in the future.Competing Interest StatementS.M. is an inventor on a patent regarding podocyte differentiation held by Harvard University, US20210338736A1. US Patent App 17/366,827, 2021. S.M. is also an inventor on a pending patent application regarding engineered microphysiological systems with in vivo-like tissue structure and function. The other authors declare no conflict of interest.