Human Vascular Tissue Models Formed from Human Induced Pluripotent Stem Cell Derived Endothelial Cells

Abstract

Here we describe a strategy to model blood vessel development using a well-defined iPSC-derived endothelial cell type (iPSC-EC) cultured within engineered platforms that mimic the 3D microenvironment. The iPSC-ECs used here were first characterized by expression of endothelial markers and functional properties that included VEGF responsiveness, TNF-α-induced upregulation of cell adhesion molecules (MCAM/CD146; ICAM1/CD54), thrombin-dependent barrier function, shear stress-induced alignment, and 2D and 3D capillary-like network formation in Matrigel. The iPSC-ECs also formed 3D vascular networks in a variety of engineering contexts, yielded perfusable, interconnected lumen when co-cultured with primary human fibroblasts, and aligned with flow in microfluidics devices. iPSC-EC function during tubule network formation, barrier formation, and sprouting was consistent with that of primary ECs, and the results suggest a VEGF-independent mechanism for sprouting, which is relevant to therapeutic anti-angiogenesis strategies. Our combined results demonstrate the feasibility of using a well-defined, stable source of iPSC-ECs to model blood vessel formation within a variety of contexts using standard in vitro formats.

Induced Pluripotent Stem Cell Model of Pulmonary Arterial Hypertension Reveals Novel Gene Expression and Patient Specificity

“…iPSC can be propagated indefinitely, differentiated into EC and smooth muscle cells (11), and used for vascular disease modeling (12) and drug screening (13), as shown with iPSCderived cardiomyocytes (14,15).…”

SIRT1 Overexpression Maintains Cell Phenotype and Function of Endothelial Cells Derived from Induced Pluripotent Stem Cells

“…There has been significant variability regarding the in vitro culture of iPSCECs as researchers have reported both satisfactory [7,20] and impaired [8,9] maintenance of EC phenotype. Herein, we report a simple and effective method to prolong EC phenotype, improve cell function, and improve cell proliferation in vitro by overexpressing SIRT1.…”

Generating induced pluripotent stem cell derived endothelial cells and induced endothelial cells for cardiovascular disease modelling and therapeutic angiogenesis

“…iPSC-ECs have been shown to possess all of these abilities to some extent, as well as expressing endothelial cell surface markers, such as CD31, CD144, VEGFR2 (KDR) and Von Willebrand factor [4][5][6]75]. Functional vascular endothelium has been derived from iPSCs and responds to shear stress, pro-inflammatory stimuli and multiple vascular permeability factors as well as displaying context-appropriate athero-protective or atheroprone behaviour in the same manner as primary endothelium [75,76].…”

“…iPSC-ECs have been shown to possess all of these abilities to some extent, as well as expressing endothelial cell surface markers, such as CD31, CD144, VEGFR2 (KDR) and Von Willebrand factor [4][5][6]75]. Functional vascular endothelium has been derived from iPSCs and responds to shear stress, pro-inflammatory stimuli and multiple vascular permeability factors as well as displaying context-appropriate athero-protective or atheroprone behaviour in the same manner as primary endothelium [75,76]. IPSC-ECs have also been generated in conjunction with iPSC-derived mesenchymal precursors and iPSC-derived pericytes and have been shown to form functionally competent networks of blood vessels with these supporting cells in vitro and incorporate into the vasculature of zebrafish embryos in vivo [65,77].…”