The Hippo pathway regulates density-dependent proliferation of iPSC-derived cardiac myocytes

Abstract Inducing cardiac myocytes to proliferate is considered a potential therapy to target heart disease, however, modulating cardiac myocyte proliferation has proven to be a technical challenge. The Hippo pathway is a kinase signaling cascade that regulates cell proliferation during the growth o...

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Autores principales:	Abigail C. Neininger, Xiaozhaun Dai, Qi Liu, Dylan T. Burnette
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f4155b51a5fa464eaa907c1d55a99b40
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spelling	oai:doaj.org-article:f4155b51a5fa464eaa907c1d55a99b402021-12-02T17:19:16ZThe Hippo pathway regulates density-dependent proliferation of iPSC-derived cardiac myocytes10.1038/s41598-021-97133-62045-2322https://doaj.org/article/f4155b51a5fa464eaa907c1d55a99b402021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97133-6https://doaj.org/toc/2045-2322Abstract Inducing cardiac myocytes to proliferate is considered a potential therapy to target heart disease, however, modulating cardiac myocyte proliferation has proven to be a technical challenge. The Hippo pathway is a kinase signaling cascade that regulates cell proliferation during the growth of the heart. Inhibition of the Hippo pathway increases the activation of the transcription factors YAP/TAZ, which translocate to the nucleus and upregulate transcription of pro-proliferative genes. The Hippo pathway regulates the proliferation of cancer cells, pluripotent stem cells, and epithelial cells through a cell–cell contact-dependent manner, however, it is unclear if cell density-dependent cell proliferation is a consistent feature in cardiac myocytes. Here, we used cultured human iPSC-derived cardiac myocytes (hiCMs) as a model system to investigate this concept. hiCMs have a comparable transcriptome to the immature cardiac myocytes that proliferate during heart development in vivo. Our data indicate that a dense syncytium of hiCMs can regain cell cycle activity and YAP expression and activity when plated sparsely or when density is reduced through wounding. We found that combining two small molecules, XMU-MP-1 and S1P, increased YAP activity and further enhanced proliferation of low-density hiCMs. Importantly, these compounds had no effect on hiCMs within a dense syncytium. These data add to a growing body of literature that link Hippo pathway regulation with cardiac myocyte proliferation and demonstrate that regulation is restricted to cells with reduced contact inhibition.Abigail C. NeiningerXiaozhaun DaiQi LiuDylan T. BurnetteNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Abigail C. Neininger Xiaozhaun Dai Qi Liu Dylan T. Burnette The Hippo pathway regulates density-dependent proliferation of iPSC-derived cardiac myocytes
description	Abstract Inducing cardiac myocytes to proliferate is considered a potential therapy to target heart disease, however, modulating cardiac myocyte proliferation has proven to be a technical challenge. The Hippo pathway is a kinase signaling cascade that regulates cell proliferation during the growth of the heart. Inhibition of the Hippo pathway increases the activation of the transcription factors YAP/TAZ, which translocate to the nucleus and upregulate transcription of pro-proliferative genes. The Hippo pathway regulates the proliferation of cancer cells, pluripotent stem cells, and epithelial cells through a cell–cell contact-dependent manner, however, it is unclear if cell density-dependent cell proliferation is a consistent feature in cardiac myocytes. Here, we used cultured human iPSC-derived cardiac myocytes (hiCMs) as a model system to investigate this concept. hiCMs have a comparable transcriptome to the immature cardiac myocytes that proliferate during heart development in vivo. Our data indicate that a dense syncytium of hiCMs can regain cell cycle activity and YAP expression and activity when plated sparsely or when density is reduced through wounding. We found that combining two small molecules, XMU-MP-1 and S1P, increased YAP activity and further enhanced proliferation of low-density hiCMs. Importantly, these compounds had no effect on hiCMs within a dense syncytium. These data add to a growing body of literature that link Hippo pathway regulation with cardiac myocyte proliferation and demonstrate that regulation is restricted to cells with reduced contact inhibition.
format	article
author	Abigail C. Neininger Xiaozhaun Dai Qi Liu Dylan T. Burnette
author_facet	Abigail C. Neininger Xiaozhaun Dai Qi Liu Dylan T. Burnette
author_sort	Abigail C. Neininger
title	The Hippo pathway regulates density-dependent proliferation of iPSC-derived cardiac myocytes
title_short	The Hippo pathway regulates density-dependent proliferation of iPSC-derived cardiac myocytes
title_full	The Hippo pathway regulates density-dependent proliferation of iPSC-derived cardiac myocytes
title_fullStr	The Hippo pathway regulates density-dependent proliferation of iPSC-derived cardiac myocytes
title_full_unstemmed	The Hippo pathway regulates density-dependent proliferation of iPSC-derived cardiac myocytes
title_sort	hippo pathway regulates density-dependent proliferation of ipsc-derived cardiac myocytes
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f4155b51a5fa464eaa907c1d55a99b40
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The Hippo pathway regulates density-dependent proliferation of iPSC-derived cardiac myocytes

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