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Sci. Signal., 5 June 2012
Vol. 5, Issue 227, p. ra41
[DOI: 10.1126/scisignal.2003002]

RESEARCH ARTICLES

Matrix Rigidity Controls Endothelial Differentiation and Morphogenesis of Cardiac Precursors

Kshitiz1,2*, Maimon E. Hubbi2*, Eun Hyun Ahn3, John Downey1, Junaid Afzal4, Deok-Ho Kim1,5, Sergio Rey2, Connie Chang1, Arnab Kundu1,2, Gregg L. Semenza2,4,6,7, Roselle M. Abraham4, and Andre Levchenko1,2,8{dagger}

1 Department of Biomedical Engineering, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
2 Vascular Biology, Institute for Cell Engineering, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
3 Department of Pathology, School of Medicine, University of Washington, Seattle, WA 98195, USA.
4 Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
5 Department of Bioengineering, School of Medicine, University of Washington, Seattle, WA 98195, USA.
6 Departments of Pediatrics, Oncology, Radiation Oncology, and Biological Chemistry, The Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
7 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
8 Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21218, USA.

* These authors contributed equally to this work.

Abstract: Tissue development and regeneration involve tightly coordinated and integrated processes: selective proliferation of resident stem and precursor cells, differentiation into target somatic cell type, and spatial morphological organization. The role of the mechanical environment in the coordination of these processes is poorly understood. We show that multipotent cells derived from native cardiac tissue continually monitored cell substratum rigidity and showed enhanced proliferation, endothelial differentiation, and morphogenesis when the cell substratum rigidity closely matched that of myocardium. Mechanoregulation of these diverse processes required p190RhoGAP, a guanosine triphosphatase–activating protein for RhoA, acting through RhoA-dependent and -independent mechanisms. Natural or induced decreases in the abundance of p190RhoGAP triggered a series of developmental events by coupling cell-cell and cell-substratum interactions to genetic circuits controlling differentiation.

{dagger} To whom correspondence should be addressed. E-mail: alev{at}jhu.edu

Citation: Kshitiz, M. E. Hubbi, E. H. Ahn, J. Downey, J. Afzal, D.-H. Kim, S. Rey, C. Chang, A. Kundu, G. L. Semenza, R. M. Abraham, A. Levchenko, Matrix Rigidity Controls Endothelial Differentiation and Morphogenesis of Cardiac Precursors. Sci. Signal. 5, ra41 (2012).

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