A Human Pluripotent Stem Cell-Based Screen for Smooth Muscle Cell Differentiation and Maturation Identifies Inhibitors of Intimal Hyperplasia
Summary
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. Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
| Authors | Zhang J, McIntosh BE, Wang B, Brown ME, Probasco MD, Webster S, Duffin B, Zhou Y, Guo LW, Burlingham WJ, Kent C, Ferris M, Thomson JA |
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| Journal | Stem cell reports |
| Publication Date | 2019 Jun 11;12(6):1269-1281 |
| PubMed | 31080110 |
| PubMed Central | PMC6565755 |
| DOI | 10.1016/j.stemcr.2019.04.013 |