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A Human Pluripotent Stem Cell-Based Screen for Smooth Muscle Cell Differentiation and Maturation Identifies Inhibitors of Intimal Hyperplasia

Jue Zhang, Brian E McIntosh, Bowen Wang, Matthew E Brown, Mitchell D Probasco, Sarah Webster, Bret Duffin, Ying Zhou, Lian-Wang Guo, William J Burlingham, Craig Kent, Michael Ferris, James A Thomson

Stem Cell Reports. 2019 Jun 11;12(6):1269-1281.

PMID: 31080110

Abstract:

Contractile to synthetic phenotypic switching of smooth muscle cells (SMCs) contributes to stenosis in vascular disease and vascular transplants. To generate more contractile SMCs, we performed a high-throughput differentiation screen using a MYH11-NLuc-tdTomato human embryonic stem cell reporter cell line. We identified RepSox as a factor that promotes differentiation of MYH11-positive cells by promoting NOTCH signaling. RepSox induces SMCs to exhibit a more contractile phenotype than SMCs generated using PDGF-BB and TGF-β1, two factors previously used for SMC differentiation but which also cause intimal hyperplasia. In addition, RepSox inhibited intimal hyperplasia caused by contractile to synthetic phenotypic switching of SMCs in a rat balloon injury model. Thus, in addition to providing more contractile SMCs that could prove useful for constructing artificial blood vessels, this study suggests a strategy for identifying drugs for inhibiting intimal hyperplasia that act by driving contractile differentiation rather than inhibiting proliferation non-specifically.

Chemicals Related in the Paper:

Catalog Number Product Name Structure CAS Number Price
AP446859332 RepSox RepSox 446859-33-2 Price
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