Methods for Differentiating hiPSCs into Vascular Smooth Muscle Cells

Despite numerous efforts to generate vascular tissues that recapitulate the physiological characteristics of native vessels, vascular cell source remains one of the principal challenges in the construction of tissue-engineered vascular grafts (TEVGs). Human pluripotent stem cells, therefore, represent an indispensable source to supply a large production of vascular smooth muscle cells (VSMCs) for cell-based therapy. In particular, human induced pluripotent stem cells (hiPSCs) generated from the same individual have opened up new avenues of achieving patient specificity through the derivation of autologous and immunocompatible VSMCs. This book chapter will detail three representative methods of differentiating hiPSCs into VSMCs that are structurally and functionally mature for TEVG engineering. Luo et al. reported an embryoid body (EB)-based approach to generate a robust, large-scale production of mature, functional hiPSC-derived VSMCs as a cell replacement for vascular tissue engineering. EB formation has an advantage of resembling early embryonic development and allowing cellular interactions in three dimensions. Cheung et al. established a system to produce embryological origin-specific hiPSC-derived VSMCs from the neuroectoderm, lateral plate mesoderm, and paraxial mesoderm lineages in a chemically defined manner. This allows site-specific vascular disease modeling. Moreover, Eoh et al. followedWanjare et al.'s method to construct hiPSC-derived VSMCs using monolayer cultures of extracellular matrix proteins, with the addition of a pulsatile flow for the secretion of mature, organized elastic fibers. The generation of TEVGs, powered by the unlimited supply of hiPSC-derived VSMCs, has begun a new era in cellular therapy for vascular bypass and defective vessel segment replacement, aimed at addressing millions of cases of cardiovascular diseases across the globe.