02249nas a2200301   4500000000100000000000100001008004100002260001500043653002700058653001600085653003000101653003000131653003000161100002300191700001600214700002600230700002400256700002100280700002200301700002400323700002500347700001700372245014400389856005500533300000900588520133600597022001401933       2025                            d  c2025-11-0310aBiomedical Engineering10aDevelopment10aPaediatric kidney disease10aStem-cell differentiation10aUrological manifestations1 aRohan Bhattacharya1 aTarsha Ward1 aTitilola D. Kalejaiye1 aAlekshyander Mishra1 aSophia M. Leeman1 aHamidreza Arzaghi1 aJonathan G. Seidman1 aChristine E. Seidman1 aSamira Musah00aEngineered human induced pluripotent stem cell models reveal altered podocytogenesis in congenital heart disease-associated SMAD2 mutations  uhttps://www.nature.com/articles/s41551-025-01543-0  a1-203 aClinical observations of patients with congenital heart disease carrying SMAD2 genetic variants revealed correlations with multi-organ impairments at the developmental and functional levels. Many patients with congenital heart disease present with glomerulosclerosis, periglomerular fibrosis and albuminuria. It remains largely unknown whether SMAD2 variants associated with congenital heart disease can directly alter kidney cell fate, tissue patterning and organ-level function. Here we investigate the role of pathogenic SMAD2 variants in podocytogenesis, nephrogenic cell lineage specification and glomerular filtration barrier function using a combination of CRISPR-based disease modelling, stem cell and microfluidic organ-on-a-chip technologies. We show that the abrogation of SMAD2 results in altered patterning of the mesoderm and intermediate mesoderm cell lineages, which give rise to nearly all kidney cell types. Following further differentiation of intermediate mesoderm cells, the mutant podocytes failed to develop arborizations and interdigitations. A reconstituted glomerulus-on-a-chip system showed substantial albumin leakage, as observed in glomerulopathies. This study implicates chronic heart disease-associated SMAD2 mutations in kidney tissue malformation that might inform targeted regenerative therapies.  a2157-846X