Aberrant tissue mechanics and mechanotransduction during heart development in down syndrome.

Abstract

Individuals with Down syndrome (DS) account for 70% of all cases of patients diagnosed with a septal heart defect. To investigate the mechanisms underlying aberrant septation in Down syndrome, we examined how altered extracellular-matrix composition and tissue stiffness in the Dp16 mouse model influence cardiomyocyte mechanotransduction using trisomy 21 iPSC-derived cardiomyocytes, revealing a potential biomechanical pathway contributing to congenital heart defects in the Down syndrome population. We hypothesized that in DS, upregulation of type VI collagen and hyaluronic acid in the endocardial cushion increases cushion stiffness, altering cellular mechanotransduction and ultimately leading to differences in cell proliferation and gene expression that perturb heart development. Results found that endocardial cushions of the Dp16 mouse model of DS showed a non-significant trend toward increased stiffness compared to WT. Furthermore, iPSC-CM with trisomy 21 exhibited decreased proliferation following culture on substrates of increasing stiffness, and following cyclic mechanical stretch, DS iPSC-CM developed stress fibers, disorganized sarcomeres and a decreased expression of mature cardiac markers. Yet cyclic mechanical stretch of control iPSC-CM induced sarcomere alignment and increased mature cardiac gene expression compared to static conditions. These data argue that tissue mechanics, driven by upregulation of ECM proteins, lead to increased endocardial cushion stiffness in the Dp16 mouse, and that iPSC-CM with trisomy 21 aberrantly respond to changes to stiffness and stretch, ultimately proposing a novel avenue to investigate congenital heart defects in the DS population.