Abstract
Human induced pluripotent stem cells (iPSCs) can be differentiated into vascular endothelial (iEC) and smooth muscle (iSMC) cells. However, because iECs and iSMCs are not derived from an intact blood vessel, they represent an immature phenotype. Hemodynamics and heterotypic cell:cell communication play important roles in vascular cell phenotypic modulation. Here we tested the hypothesis that hemodynamic exposure of iECs in coculture with iSMCs induces an in vivo‐like phenotype. iECs and iSMCs were cocultured under vascular region‐specific blood flow hemodynamics, and compared to hemodynamic cocultures of blood vessel‐derived endothelial (pEC) and smooth muscle (pSMC) cells. Hemodynamic flow‐induced gene expression positively correlated between pECs and iECs as well as pSMCs and iSMCs. While endothelial nitric oxide synthase 3 protein was lower in iECs than pECs, iECs were functionally mature as seen by acetylated‐low‐density lipoprotein (LDL) uptake. SMC contractile protein markers were also positively correlated between pSMCs and iSMCs. Exposure of iECs and pECs to atheroprone hemodynamics with oxidized‐LDL induced an inflammatory response in both. Dysfunction of the transforming growth factor β (TGFβ) pathway is seen in several vascular diseases, and iECs and iSMCs exhibited a transcriptomic prolife similar to pECs and pSMCs, respectively, in their responses to LY2109761‐mediated transforming growth factor β receptor I/II (TGFβRI/II) inhibition. Although there are differences between ECs and SMCs derived from iPSCs versus blood vessels, hemodynamic coculture restores a high degree of similarity in their responses to pathological stimuli associated with vascular diseases. Thus, iPSC‐derived vascular cells exposed to hemodynamics may provide a viable system for modeling rare vascular diseases and testing new therapeutic approaches. Stem Cells Translational Medicine 2017;6:1673–1683
Highlights
Vascular diseases of genetic origin are often difficult to study in the human tissue given limitations in human sample availability and accurate modeling of the disease of interest
We tested the hypothesis that hemodynamic exposure of iPSCderived human vascular endothelial cells (iECs) in coculture with iPSC neural crest-derived human smooth muscle cells (iSMCs) induces an in vivo-like phenotype. iECs and iSMCs were cocultured under vascular region-specific blood flow hemodynamics, and compared to hemodynamic cocultures of blood vessel-derived endothelial and smooth muscle cells
We have previously demonstrated that this human vascular surrogate system utilizing cocultures of Primary endothelial cells (pECs):pSMC exposed to relevant hemodynamics mimics the in vivo endothelial and smooth muscle architecture, biology and physiology of the blood vessel wall, and is highly responsive to changes in hemodynamics, inflammatory milieu, and drug treatments [4,5,6]
Summary
Vascular diseases of genetic origin are often difficult to study in the human tissue given limitations in human sample availability and accurate modeling of the disease of interest. We sought to characterize the fidelity and functionality of iPSCs differentiated into vascular endothelial (iEC) and smooth muscle (iSMC) cells for vascular tissue modeling and disease characterization. We assessed human iECs and iSMCs cocultured under vascular region-specific blood flow hemodynamics to determine if they display similar transcriptomic and functional responses to cocultures of primary human endothelial (pEC) and smooth muscle (pSMC) cells exposed to the same hemodynamics. We have previously demonstrated that this human vascular surrogate system utilizing cocultures of pEC:pSMC exposed to relevant hemodynamics mimics the in vivo endothelial and smooth muscle architecture, biology and physiology of the blood vessel wall, and is highly responsive to changes in hemodynamics, inflammatory milieu, and drug treatments [4,5,6]. Our results indicate that iPSC-derived vascular cells exhibit an immature phenotype and that hemodynamic coculture of iEC:iSMC restores a high degree of similarity to that of pEC:pSMC. Application of the hemodynamic coculture model could provide a viable system for modeling rare vascular diseases using patient-derived iPSCs to develop and test new therapeutic approaches
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