Abstract
The vascular system is essential for the development and function of all organs and tissues in our body. The molecular signature and phenotype of endothelial cells (EC) are greatly affected by blood flow-induced shear stress, which is a vital component of vascular development and homeostasis. Recent advances in differentiation of ECs from human induced pluripotent stem cells (hiPSC) have enabled development of in vitro experimental models of the vasculature containing cells from healthy individuals or from patients harboring genetic variants or diseases of interest. Here we have used hiPSC-derived ECs and bulk- and single-cell RNA sequencing to study the effect of flow on the transcriptomic landscape of hiPSC-ECs and their heterogeneity. We demonstrate that hiPS-ECs are plastic and they adapt to flow by expressing known flow-induced genes. Single-cell RNA sequencing showed that flow induced a more homogenous and homeostatically more stable EC population compared to static cultures, as genes related to cell polarization, barrier formation and glucose and fatty acid transport were induced. The hiPS-ECs increased both arterial and venous markers when exposed to flow. Interestingly, while in general there was a greater increase in the venous markers, one cluster with more arterial-like hiPS-ECs was detected. Single-cell RNA sequencing revealed that not all hiPS-ECs are similar even after sorting, but exposing them to flow increases their homogeneity. Since hiPS-ECs resemble immature ECs and demonstrate high plasticity in response to flow, they provide an excellent model to study vascular development.
Highlights
Endothelial cells (ECs) are present in all tissues, and they regulate the development, growth and function of all organs
Patient derived Human induced pluripotent stem cell-derived endothelial cells (hiPS-EC) are increasingly used in disease modeling to study specific disease related phenotypes and genotype-phenotype correlations
HiPS-ECs do not gain full maturity and identity compared to ECs in vivo, human induced pluripotent stem cells (hiPSC)-Derived ECs in Flow where ECs are exposed to mechanical forces of blood flow such as shear stress and pulsatile pressure, and paracrine signals from neighboring parenchymal cells
Summary
Endothelial cells (ECs) are present in all tissues, and they regulate the development, growth and function of all organs. Laminar shear stress induced by blood flow is an essential regulator of blood vessel development (Campinho et al, 2020), and it promotes endothelial cell quiescence, which is required for vascular homeostasis (Baeyens et al, 2016). Multiple pathways classically known to be involved in embryonic development, such as BMP–TGFβ, WNT, NOTCH, HIF1α, TWIST1, and HOX family genes, are regulated by shear stress in adult arteries. Mechanical activation of these pathways likely evolved to orchestrate vascular development, but they can drive atherosclerosis upon disturbed flow and low shear stress
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