Abstract 1799: Role of Elastogenesis in Cardiac Development: A Human Pluripotent Stem Cell Derived Model of Elastin Insufficiency
Elastin, extracellular matrix protein, is essential for arterial morphogenesis. Elastin insufficiency (Williams syndrome) causes smooth muscle cell (SMC) proliferation and vascular stenoses. We assessed elastogenesis during cardiovascular differentiation using human embryonic stem cell derived cardiac cells (HESC-C).
Methods: HESC-C (HES-2), day 20 of differentiation, were treated for 7 days with elastin binding protein ligand, EBPL-2, elastin binding inhibitor, lactose, +/− AG1024, inhibitor of insulin-like growth factor receptor (IGFR) which stimulates elastogenesis. Immunostaining was performed for elastin, α-smooth muscle actin, cardiac myosin heavy chain and Ki67. Cell proliferation was expressed as a % of Ki67 positive cells.
Results: Cardiomyocytes but not SMC stained positive for elastin. EBPL-2 increased elastin in cardiomyocytes with increased cardiomyocyte proliferation vs controls (38±1% vs 30±5%, p=.04) but reduced SMC proliferation (20±3% vs 28±3%, p=.04) (Figure⇓). Lactose reduced proliferation of cardiomyocytes (18±6% vs 30±5%, p=.004) and SMC (15±5% vs 28±3%, p=.02). This was likely related to increase in elastin production in SMCs via alternate pathways. IGFR inhibitor reversed the effect of lactose on cardiomyocyte and SMC proliferation.
Conclusion: This is the first study to show that elastin is expressed in cardiac cells during differentiation, that it induces cardiomyocyte proliferation but inhibits SMC proliferation, and that these effects occur via the IGFR. This highlights the importance of elastin in cardiovascular development and provides a cellular model to determine the effects of elastin insufficiency on cardiogenesis.