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Stem Cells. 2015 Jul;33(7):2148-57. doi: 10.1002/stem.2036. Epub 2015 May 11.

Mechanical Stress Promotes Maturation of Human Myocardium From Pluripotent Stem Cell-Derived Progenitors.

Ruan JL1,2,3, Tulloch NL2,3,4,5,6, Saiget M2,3,4, Paige SL2,3,4, Razumova MV1,2,3, Regnier M1,2,3, Tung KC7, Keller G7, Pabon L2,3,4, Reinecke H2,3,4, Murry CE1,2,3,4,8.

Author information

1
Department of Bioengineering, University of Washington, Seattle, Washington, USA.
2
Center for Cardiovascular Biology, University of Washington, Seattle, Washington, USA.
3
Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA.
4
Department of Pathology, University of Washington, Seattle, Washington, USA.
5
Molecular and Cellular Biology Program, University of Washington, Seattle, Washington, USA.
6
Medical Scientist Training Program, University of Washington, Seattle, Washington, USA.
7
McEwen Central for Regenerative Medicine, University Health Network, Toronto, Ontario, Canada.
8
Department of Medicine, Division of Cardiology, University of Washington, Seattle, Washington, USA.

Abstract

Recent advances in pluripotent stem cell biology and directed differentiation have identified a population of human cardiovascular progenitors that give rise to cardiomyocytes, smooth muscle, and endothelial cells. Because the heart develops from progenitors in 3D under constant mechanical load, we sought to test the effects of a 3D microenvironment and mechanical stress on differentiation and maturation of human cardiovascular progenitors into myocardial tissue. Progenitors were derived from embryonic stem cells, cast into collagen hydrogels, and left unstressed or subjected to static or cyclic mechanical stress. Compared to 2D culture, the unstressed 3D environment increased cardiomyocyte numbers and decreased smooth muscle numbers. Additionally, 3D culture suppressed smooth muscle α-actin content, suggesting diminished cell maturation. Cyclic stress-conditioning increased expression of several cardiac markers, including β-myosin heavy chain and cardiac troponin T, and the tissue showed enhanced calcium dynamics and force production. There was no effect of mechanical loading on cardiomyocyte or smooth muscle specification. Thus, 3D growth conditions favor cardiac differentiation from cardiovascular progenitors, whereas 2D conditions promote smooth muscle differentiation. Mechanical loading promotes cardiomyocyte structural and functional maturation. Culture in 3-D facilitates understanding how cues such as mechanical stress affect the differentiation and morphogenesis of distinct cardiovascular cell populations into organized, functional human cardiovascular tissue. Stem Cells 2015;33:2148-2157.

KEYWORDS:

Cardiac; Cardiovascular progenitor; Cardiovascular tissue engineering; Differentiation; Embryonic stem cells; Induced pluripotent stem cells; Progenitor cells; Vascular development

PMID:
25865043
PMCID:
PMC4478130
DOI:
10.1002/stem.2036
[Indexed for MEDLINE]
Free PMC Article

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