Yes-Associated Protein Inhibits Transcription of Myocardin and Attenuates Differentiation of Vascular Smooth Muscle Cell from Cardiovascular Progenitor Cell Lineage

lunchang wang; Ping Qiu; Jiao Jiao; Hiroyuki Hirai; Wei Xiong; Jifeng Zhang; Tianqing Zhu; Peter X. Ma; Y. Eugene Chen; Bo Yang

doi:10.1002/stem.2484

Yes-Associated Protein Inhibits Transcription of Myocardin and Attenuates Differentiation of Vascular Smooth Muscle Cell from Cardiovascular Progenitor Cell Lineage

lunchang wang, Ping Qiu, Jiao Jiao, Hiroyuki Hirai, Wei Xiong, Jifeng Zhang, Tianqing Zhu, Peter X. Ma, Y. Eugene Chen, Bo Yang^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

Abstract

Vascular smooth muscle cells (VSMCs) derived from cardiovascular progenitor cell (CVPC) lineage populate the tunica media of the aortic root. Understanding differentiation of VSMCs from CVPC will further our understanding of the molecular mechanisms contributing to aortic root aneurysms, and thus, facilitate the development of novel therapeutic agents to prevent this devastating complication. It is established that the yes-associated protein (YAP) and Hippo pathway is important for VSMC proliferation and phenotype switch. To determine the role of YAP in differentiation of VSMCs from CVPCs, we utilized the in vitro monolayer lineage specific differentiation method by differentiating human embryonic stem cells into CVPCs, and then, into VSMCs. We found that expression of YAP decreased during differentiation of VSMC from CVPCs. Overexpression of YAP attenuated expression of VSMC contractile markers and impaired VSMC function. Knockdown of YAP increased expression of contractile proteins during CVPC-VSMCs differentiation. Importantly, expression of YAP decreased transcription of myocardin during this process. Overexpression of YAP in PAC1 SMC cell line inhibited luciferase activity of myocardin proximal promoter in a dose dependent and NKX2.5 dependent manners. YAP protein interacted with NKX2.5 protein and inhibited binding of NKX2.5 to the 5′-proximal promoter region of myocardin in CVPC-derived VSMCs. In conclusion, YAP negatively regulates differentiation of VSMCs from CVPCs by decreasing transcription of myocardin in a NKX2.5-dependent manner. Stem Cells 2017;35:351–361.

Original language	English (US)
Pages (from-to)	351-361
Number of pages	11
Journal	Stem Cells
Volume	35
Issue number	2
DOIs	https://doi.org/10.1002/stem.2484
State	Published - Feb 1 2017

Funding

This study was supported by AATS Graham foundation, Thoracic Surgery Foundation of Research and Education, and McKay Award, CVC Aiken's Award, Phil Jenkins Breakthrough Fund, University of Michigan and the National Institute of Health Grant (HL114038: PXM and YEC) and Grant R01HL068878 (YEC), and continuous financial support from Mr. Steven J. Szatmari and Mrs. Darlene Szatmari. We thank supports from University of Michigan Medical School (UMMS) and Central South University Xiangya School of Medicine (CSU-XYSM) Training Program. We appreciate the generosity of Dr. Shiyou Chen (The University of Georgia, Athens, GA) and Dr. Kunliang Guan (University of California, San Diego, CA) and Dr. William Hahn, (Dana Farber Cancer Institute, Boston, MA) Dr. Li Li (Wayne State University, Detroit, MI) in sharing the plasmids and cells. We appreciate Dr. Whitney Hornsby and Aroosa Malik for their contributions related to the drafting of this manuscript.

Keywords

Cardiovascular progenitor cell
Differentiation
Stem cells
Vascular smooth muscle cell
Yes-associated protein

ASJC Scopus subject areas

General Medicine

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10.1002/stem.2484

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title = "Yes-Associated Protein Inhibits Transcription of Myocardin and Attenuates Differentiation of Vascular Smooth Muscle Cell from Cardiovascular Progenitor Cell Lineage",

abstract = "Vascular smooth muscle cells (VSMCs) derived from cardiovascular progenitor cell (CVPC) lineage populate the tunica media of the aortic root. Understanding differentiation of VSMCs from CVPC will further our understanding of the molecular mechanisms contributing to aortic root aneurysms, and thus, facilitate the development of novel therapeutic agents to prevent this devastating complication. It is established that the yes-associated protein (YAP) and Hippo pathway is important for VSMC proliferation and phenotype switch. To determine the role of YAP in differentiation of VSMCs from CVPCs, we utilized the in vitro monolayer lineage specific differentiation method by differentiating human embryonic stem cells into CVPCs, and then, into VSMCs. We found that expression of YAP decreased during differentiation of VSMC from CVPCs. Overexpression of YAP attenuated expression of VSMC contractile markers and impaired VSMC function. Knockdown of YAP increased expression of contractile proteins during CVPC-VSMCs differentiation. Importantly, expression of YAP decreased transcription of myocardin during this process. Overexpression of YAP in PAC1 SMC cell line inhibited luciferase activity of myocardin proximal promoter in a dose dependent and NKX2.5 dependent manners. YAP protein interacted with NKX2.5 protein and inhibited binding of NKX2.5 to the 5′-proximal promoter region of myocardin in CVPC-derived VSMCs. In conclusion, YAP negatively regulates differentiation of VSMCs from CVPCs by decreasing transcription of myocardin in a NKX2.5-dependent manner. Stem Cells 2017;35:351–361.",

keywords = "Cardiovascular progenitor cell, Differentiation, Stem cells, Vascular smooth muscle cell, Yes-associated protein",

author = "lunchang wang and Ping Qiu and Jiao Jiao and Hiroyuki Hirai and Wei Xiong and Jifeng Zhang and Tianqing Zhu and Ma, {Peter X.} and Chen, {Y. Eugene} and Bo Yang",

note = "Publisher Copyright: {\textcopyright} 2016 AlphaMed Press",

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doi = "10.1002/stem.2484",

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AU - wang, lunchang

AU - Qiu, Ping

AU - Jiao, Jiao

AU - Hirai, Hiroyuki

AU - Xiong, Wei

AU - Zhang, Jifeng

AU - Zhu, Tianqing

AU - Ma, Peter X.

AU - Chen, Y. Eugene

AU - Yang, Bo

PY - 2017/2/1

Y1 - 2017/2/1

N2 - Vascular smooth muscle cells (VSMCs) derived from cardiovascular progenitor cell (CVPC) lineage populate the tunica media of the aortic root. Understanding differentiation of VSMCs from CVPC will further our understanding of the molecular mechanisms contributing to aortic root aneurysms, and thus, facilitate the development of novel therapeutic agents to prevent this devastating complication. It is established that the yes-associated protein (YAP) and Hippo pathway is important for VSMC proliferation and phenotype switch. To determine the role of YAP in differentiation of VSMCs from CVPCs, we utilized the in vitro monolayer lineage specific differentiation method by differentiating human embryonic stem cells into CVPCs, and then, into VSMCs. We found that expression of YAP decreased during differentiation of VSMC from CVPCs. Overexpression of YAP attenuated expression of VSMC contractile markers and impaired VSMC function. Knockdown of YAP increased expression of contractile proteins during CVPC-VSMCs differentiation. Importantly, expression of YAP decreased transcription of myocardin during this process. Overexpression of YAP in PAC1 SMC cell line inhibited luciferase activity of myocardin proximal promoter in a dose dependent and NKX2.5 dependent manners. YAP protein interacted with NKX2.5 protein and inhibited binding of NKX2.5 to the 5′-proximal promoter region of myocardin in CVPC-derived VSMCs. In conclusion, YAP negatively regulates differentiation of VSMCs from CVPCs by decreasing transcription of myocardin in a NKX2.5-dependent manner. Stem Cells 2017;35:351–361.

AB - Vascular smooth muscle cells (VSMCs) derived from cardiovascular progenitor cell (CVPC) lineage populate the tunica media of the aortic root. Understanding differentiation of VSMCs from CVPC will further our understanding of the molecular mechanisms contributing to aortic root aneurysms, and thus, facilitate the development of novel therapeutic agents to prevent this devastating complication. It is established that the yes-associated protein (YAP) and Hippo pathway is important for VSMC proliferation and phenotype switch. To determine the role of YAP in differentiation of VSMCs from CVPCs, we utilized the in vitro monolayer lineage specific differentiation method by differentiating human embryonic stem cells into CVPCs, and then, into VSMCs. We found that expression of YAP decreased during differentiation of VSMC from CVPCs. Overexpression of YAP attenuated expression of VSMC contractile markers and impaired VSMC function. Knockdown of YAP increased expression of contractile proteins during CVPC-VSMCs differentiation. Importantly, expression of YAP decreased transcription of myocardin during this process. Overexpression of YAP in PAC1 SMC cell line inhibited luciferase activity of myocardin proximal promoter in a dose dependent and NKX2.5 dependent manners. YAP protein interacted with NKX2.5 protein and inhibited binding of NKX2.5 to the 5′-proximal promoter region of myocardin in CVPC-derived VSMCs. In conclusion, YAP negatively regulates differentiation of VSMCs from CVPCs by decreasing transcription of myocardin in a NKX2.5-dependent manner. Stem Cells 2017;35:351–361.

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Yes-Associated Protein Inhibits Transcription of Myocardin and Attenuates Differentiation of Vascular Smooth Muscle Cell from Cardiovascular Progenitor Cell Lineage

Abstract

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Keywords

ASJC Scopus subject areas

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