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Proc Natl Acad Sci U S A. 2014 Sep 23;111(38):13805-10. doi: 10.1073/pnas.1415330111. Epub 2014 Sep 8.

Substratum-induced differentiation of human pluripotent stem cells reveals the coactivator YAP is a potent regulator of neuronal specification.

Author information

1
Departments of Chemistry.
2
Biochemistry.
3
Waisman Center, and.
4
Biomedical Engineering.
5
Chemical and Biological Engineering, and.
6
Waisman Center, and Genetics Training Program, University of Wisconsin-Madison, Madison, WI 53706; and Medical Genetics and Neurology.
7
Biomedical Engineering, Department of Orthopedics and Rehabilitation, University of Wisconsin, Wisconsin Institute for Medical Research, Madison, WI 53706.
8
Departments of Chemistry, Biochemistry, kiessling@chem.wisc.edu.

Abstract

Physical stimuli can act in either a synergistic or antagonistic manner to regulate cell fate decisions, but it is less clear whether insoluble signals alone can direct human pluripotent stem (hPS) cell differentiation into specialized cell types. We previously reported that stiff materials promote nuclear localization of the Yes-associated protein (YAP) transcriptional coactivator and support long-term self-renewal of hPS cells. Here, we show that even in the presence of soluble pluripotency factors, compliant substrata inhibit the nuclear localization of YAP and promote highly efficient differentiation of hPS cells into postmitotic neurons. In the absence of neurogenic factors, the effective substrata produce neurons rapidly (2 wk) and more efficiently (>75%) than conventional differentiation methods. The neurons derived from substrate induction express mature markers and possess action potentials. The hPS differentiation observed on compliant surfaces could be recapitulated on stiff surfaces by adding small-molecule inhibitors of F-actin polymerization or by depleting YAP. These studies reveal that the matrix alone can mediate differentiation of hPS cells into a mature cell type, independent of soluble inductive factors. That mechanical cues can override soluble signals suggests that their contributions to early tissue development and lineage commitment are profound.

KEYWORDS:

YAP/TAZ; biomaterials; glycosaminoglycans; mechanotransduction; neuronal differentiation

PMID:
25201954
PMCID:
PMC4183276
DOI:
10.1073/pnas.1415330111
[Indexed for MEDLINE]
Free PMC Article

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