Generation of human vascular smooth muscle subtypes provides insight into embryological origin-dependent disease susceptibility

Heterogeneity of embryological origins is a hallmark of vascular smooth muscle cells (SMCs), which may influence vascular disease development. Differentiation of human pluripotent stem cells (hPSCs) into developmental origin-specific SMC subtypes remains elusive. In this study, we have established a chemically defined protocol where hPSCs were initially induced to form neuroectoderm, lateral plate mesoderm or paraxial mesoderm. These intermediate populations were further differentiated towards SMCs (>80% MYH11(+) and ACTA2(+)) which displayed contractile ability in response to vasoconstrictors and invested perivascular regions in vivo. Derived SMC subtypes recapitulated the unique proliferative and secretory responses to cytokines previously documented in studies using aortic SMCs of distinct origins. Importantly, this system predicted increased extracellular matrix degradation by SMCs derived from lateral plate mesoderm, which was confirmed using rat aortic SMCs from corresponding origins. Collectively, this work will have broad applications in modeling origin-dependent disease susceptibility and in bio-engineered vascular grafts for regenerative medicine.