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Stem Cell Reports. 2019 Jun 11;12(6):1269-1281. doi: 10.1016/j.stemcr.2019.04.013. Epub 2019 May 9.

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

Author information

1
Regenerative Biology, Morgridge Institute for Research, 330 North Orchard Street, Madison, WI 53715, USA. Electronic address: juzhang@morgridge.org.
2
Regenerative Biology, Morgridge Institute for Research, 330 North Orchard Street, Madison, WI 53715, USA.
3
Department of Surgery, University of Wisconsin-Madison, Madison, WI 53792, USA; College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
4
Regenerative Biology, Morgridge Institute for Research, 330 North Orchard Street, Madison, WI 53715, USA; Department of Surgery, University of Wisconsin-Madison, Madison, WI 53792, USA.
5
Department of Surgery, University of Wisconsin-Madison, Madison, WI 53792, USA.
6
College of Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA; Computer Sciences, Industrial & Systems Engineering, Mathematics, Optimization, Wisconsin Institute for Discovery, Madison, WI 53715, USA.
7
Regenerative Biology, Morgridge Institute for Research, 330 North Orchard Street, Madison, WI 53715, USA; Department of Cell & Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Molecular, Cellular, & Developmental Biology, University of California, Santa Barbara, CA 93117, USA. Electronic address: jthomson@morgridge.org.

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.

KEYWORDS:

MYH11-NLuc-tdTomato reporter cell line; NOTCH; RepSox; contractile smooth muscle cells; differentiation; high-throughput screen; intima hyperplasia; maturation; pluripotent stem cells; restenosis

PMID:
31080110
DOI:
10.1016/j.stemcr.2019.04.013
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