Abstract
The vascular endothelium is present in all organs and blood vessels, facilitates the exchange of nutrients and waste throughout different organ systems in the body, and sets the tone for healthy vessel function. Mechanosensitive in nature, the endothelium responds to the magnitude and temporal waveform of shear stress in the vessels. Endothelial dysfunction can lead to atherosclerosis and other diseases. Modeling endothelial function and dysfunction in organ systems in vitro, such as the bloodâbrain barrier and tissue-engineered blood vessels, requires sourcing endothelial cells (ECs) for these biomedical engineering applications. It can be difficult to source primary, easily renewable ECs that possess the function or dysfunction in question. In contrast, human pluripotent stem cells (hPSCs) can be sourced from donors of interest and renewed almost indefinitely. In this review, we highlight how knowledge of vascular EC development in vivo is used to differentiate induced pluripotent stem cells (iPSC) into ECs. We then describe how iPSC-derived ECs are being used currently in in vitro models of organ function and disease and in vivo applications.
Highlights
Key functions of blood vessels are to transport oxygen, nutrients, hormones, and immune cells to various tissues of the body, and to move waste products from tissues to the kidneys, liver, and intestine for metabolism and removal
This review provides a summary of the development of human vascular endothelium in vivo relevant to differentiation of induced pluripotent stem cells (iPSC) to Endothelial cells (ECs)
ECs can be generated from iPSCs after lateral plate mesoderm development by first inducing the epiblast stage in iPSCs using a combination of Fibroblast growth factor 2 (FGF2), retinoic acid (RA), CHIR, and Bone morphogenic protein 4 (BMP4) [41]
Summary
Key functions of blood vessels are to transport oxygen, nutrients, hormones, and immune cells to various tissues of the body, and to move waste products from tissues to the kidneys, liver, and intestine for metabolism and removal. Stages of stem cell differentiation to ECs include lateral mesoderm induction, followed by vascular endothelial specification and selection (Figure 2). Orlova et al [39] developed a 10-day differentiation protocol for ECs and pericytes from human iPSCs. Treating iPSCs with BMP4, activin A, VEGF, and CHIR99021 (CHIR)âa GSK3 inhibitor that activates Wnt signalingâinduces mesoderm specification. Transcriptomic assays, barrier function, lipid uptake, cytokine response, and tube formation, show their similarity to primary ECs. ECs can be generated from iPSCs after lateral plate mesoderm development by first inducing the epiblast stage in iPSCs using a combination of FGF2, retinoic acid (RA), CHIR, and BMP4 [41].
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