November 10, 2025
Excited to share the newest publication from the Musah Lab, out in Nature Biomedical Engineering: "Engineered human induced pluripotent stem cell models reveal altered podocytogenesis in congenital heart disease-associated SMAD2 mutations." We hope our discovery informs clinicians, researchers, patients, and caregivers to catalyze earlier kidney monitoring and personalized care for all affected patients, especially children whose long-term health critically depends on timely intervention. Engineered human induced pluripotent stem cell models reveal altered podocytogenesis in congenital heart disease-associated SMAD2 mutations | Nature Biomedical Engineering
What we discovered:
- A genetic mutation that causes congenital heart disease (CHD) can independently disrupt kidney development and function. This helps explain why many children with CHD experience kidney complications early in life, which often persist through adulthood even when the heart defect is surgically repaired.
- Using human stem cell models, CRISPR genome engineering, organ-on-a-chip models, and clinical data, we show that loss-of-function SMAD2 variants disrupt early and intermediate mesoderm patterning, alter podocyte development, and impair the kidney's blood filtration barrier—consistent with the proteinuria observed in patients.
- These findings illuminate how multi-organ complications arise from a single genetic driver and point to opportunities for earlier detection and clinical intervention.
Why this matters:
- More than a quarter of children with CHD develop extracardiac complications; kidney problems are common by age four and strongly linked to mortality risk.
- Many genetic variants associated with kidney disease still lack clear evidence of pathogenicity or defined mechanisms. Our experimental approach provides a human-relevant framework to functionally test variants, map their developmental impact, and clarify clinical significance.
- Our results suggest that routine kidney screening, and testing at an earlier age, should be integrated into CHD care pathways to enable clinicians to identify risk sooner, tailor management, and improve long-term outcomes.
- Our research strategy can guide future efforts to assess the relevance of genetic variants to health and disease, accelerate biomarker discovery, and inform targeted regenerative or gene-based therapies to preserve organ function.
Huge congratulations to all co-authors! Special shout-out to our first author, Rohan Bhattacharya, for leading this project with tremendous effort, teamwork, and perseverance. Many thanks to our Harvard Medical School collaborators, Tarsha Ward and her postdoctoral advisors, Jonathan Seidman and Christine Seidman, for their contributions, generosity, and insights. We are grateful for the funding, in parts, from the Whitehead Foundation and the NIH.
Check out our related work at Publications & Patents | Musah Lab