Read our full paper in @natbiomedeng.nature.com:
www.nature.com/articles/s41...

Because murine SMAD2 loss is embryonically lethal, we leveraged CRISPR-edited human iPS cells and organ-on-chip platforms to model human-specific developmental mechanisms.
These systems enabled functional and molecular dissection of SMAD2-dependent pathways in podocytogenesis.

These findings revealed how pathogenic SMAD2 mutations impair glomerular morphogenesis, disrupt podocyte–endothelial cross-talk, and ultimately affect organ-level filtration function.

We next integrated mutant and isogenic control podocytes with endothelial cells in a microengineered glomerulus-on-a-chip system.
Mutant chips displayed extensive cell delamination and increased albumin leakage, reflecting compromised glomerular barrier integrity.

Upon podocyte differentiation, SMAD2 mutant cells failed to form mature foot processes, exhibited reduced expression of lineage markers, and adopted a mesenchymal phenotype, indicating a loss of terminal differentiation potential.

We found that pathogenic SMAD2 mutations disrupt mesoderm commitment, leading to a skewed differentiation pathway toward the posterior mesoderm.
Mutant intermediate mesoderm (IM) cells show enhanced motility, mesenchymal features, upregulate EMT markers, and undergo necroptosis.

Variants in CHD-associated genes often lead to multisystem developmental abnormalities, including kidney malformations.
Given the strong association between SMAD2-mediated CHD and chronic kidney disease (CKD), we investigated how SMAD2 mutations affect podocytogenesis & function.

This has been an incredible collaboration with #TarshaWard, #ChristineSeidman, #JonathanSeidman from @harvardmed.bsky.social, and huge thanks to my Ph.D. advisor @stemcellengineer.bsky.social, the #MusahLab members #LolaKalejaiye, #AlekMishra, #SophiaLeeman, #Hamidreza for making this work possible.