Associate professor University of Colorado Anschutz Medical Campus Aurora, Colorado, United States
Introduction: Approximately 50% of individuals diagnosed with Down syndrome (DS) or trisomy 21 present with congenital heart defects (CHD), predominantly involving septal malformations. Despite this prevalence, the precise mechanisms governing cardiac septation abnormalities in Down syndrome remain elusive. Septal development encompasses intricate processes, including cellular response to mechanical cues, migration within the developing septum, and the differentiation of endocardial cells via endothelial to mesenchymal transition (EMT). In our investigation, we posited several hypotheses. Firstly, we explored whether the cellular response to stretch and mechanical stiffness is altered in cells derived from individuals with DS. Additionally, we examined the impact of an elevated presence of collagen VI, located on chromosome 21, on cell migration in DS-derived cells. Lastly, we investigated the likelihood of endocardial cells from individuals with DS undergoing EMT.
Materials and
Methods: Utilizing a poly(ethylene glycol)-based culture platform with adjustable stiffness, we observed a noteworthy phenomenon: induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) with trisomy 21 displayed decreased proliferation as the substrate stiffened. Employing atomic force microscopy to assess the mechanical properties of cardiac cushions in DP16 mouse models of Down syndrome, we uncovered that the developing septum in DP16 mice exhibited increased stiffness compared to control mice. Furthermore, cyclic mechanical stretching of DS iPSC-CM resulted in distinctive sarcomere distribution patterns and reduced proliferation. Our investigation revealed that cardiomyocytes with trisomy 21 exhibited heightened expression of collagen VI and diminished migration on substrates with elevated collagen VI concentrations. Finally, through the differentiation of iPSCs from individuals with DS into endocardial cells, we observed impaired endothelial to mesenchymal transition in endocardial cells with trisomy 21.
Results, Conclusions, and Discussions: We postulate that these observed differences collectively render cardiac septation less resilient to variations in pressure and flow that may occur during development. Consequently, these alterations contribute to an increased susceptibility to septal defects in individuals with Down syndrome. Our findings shed light on the intricate interplay between genetic factors and mechanical cues in cardiac development, providing valuable insights for future research and potential therapeutic interventions.
