Engineered human induced pluripotent stem cell models reveal altered podocytogenesis in congenital heart
Rohan Bhattacharya1,2,3, Tarsha Ward4, Titilola D Kalejaiye1,5
1Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, USA.
Insights
Genetic variants in SMAD2, linked to congenital heart disease, can directly impair kidney development and function. This research reveals how these SMAD2 mutations disrupt kidney cell formation and filtration, potentially leading to kidney disease.
Area of Science:
- Developmental Biology
- Genetics
- Nephrology
Background:
- Congenital heart disease (CHD) is associated with multi-organ impairments.
- Patients with CHD often exhibit kidney issues like glomerulosclerosis and albuminuria.
- The direct impact of SMAD2 variants on kidney development and function in CHD remains unclear.
Purpose of the Study:
- To investigate the role of pathogenic SMAD2 variants in kidney cell development and function.
- To understand how SMAD2 variants affect podocytogenesis, nephrogenic lineage specification, and glomerular filtration.
- To model the effects of SMAD2 mutations using advanced stem cell and organ-on-a-chip technologies.
Main Methods:
- CRISPR-based disease modeling to create SMAD2 variant models.
- Stem cell differentiation to study kidney cell lineage specification.
- Microfluidic glomerulus-on-a-chip systems to assess filtration barrier function.
Main Results:
- Abrogation of SMAD2 led to altered mesoderm and intermediate mesoderm patterning.
- Mutant podocytes showed impaired development, lacking arborizations and interdigitations.
- Glomerulus-on-a-chip models demonstrated significant albumin leakage, indicating barrier dysfunction.
Conclusions:
- Pathogenic SMAD2 mutations associated with CHD can directly cause kidney malformations.
- These findings highlight a link between SMAD2 variants, kidney development, and glomerular disease.
- This research may inform novel regenerative therapies for kidney complications in CHD patients.
Abstract:
Clinical 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.
