Assessing the ability of human endothelial cells derived from induced‐pluripotent stem cells to form functional microvasculature in vivo

Abstract

Forming functional blood vessel networks is a major clinical challenge in the fields of tissue engineering and therapeutic angiogenesis. Cell‐based strategies to promote neovascularization have been widely explored, but cell sourcing remains a significant limitation. Induced‐pluripotent stem cell‐derived endothelial cells (iPSC‐ECs) are a promising, potentially autologous, alternative cell source. However, it is unclear whether iPSC‐ECs form the same robust microvasculature in vivo documented for other EC sources. In this study, we utilized a well‐established in vivo model, in which ECs (iPSC‐EC or human umbilical vein endothelial cells [HUVEC]) were coinjected with normal human lung fibroblasts (NHLFs) and a fibrin matrix into the dorsal flank of severe combined immunodeficiency mice to assess their ability to form functional microvasculature. Qualitatively, iPSC‐ECs were capable of vessel formation and perfusion and demonstrated similar vessel morphologies to HUVECs. However, quantitatively, iPSC‐ECs exhibited a two‐fold reduction in vessel density and a three‐fold reduction in the number of perfused vessels compared with HUVECs. Further analysis revealed the presence of collagen‐IV and α‐smooth muscle actin were significantly lower around iPSC‐EC/NHLF vasculature than in HUVEC/NHLF implants, suggesting reduced vessel maturity. Collectively, these results demonstrate the need for increased iPSC‐EC maturation for clinical translation to be realized.Forming functional blood vessel networks is a major clinical challenge in the fields of tissue engineering and therapeutic angiogenesis. Cell‐based strategies to promote neovascularization have been widely explored, but cell sourcing remains a significant limitation.