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Nat Mater. 2014 Jun;13(6):599-604. doi: 10.1038/nmat3945. Epub 2014 Apr 13.

Hippo/YAP-mediated rigidity-dependent motor neuron differentiation of human pluripotent stem cells.

Author information

1
Department of Mechanical Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA.
2
1] Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
3
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.
4
Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA.
5
1] Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan 48109, USA [3] Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA.
6
1] Department of Mechanical Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA.

Abstract

Our understanding of the intrinsic mechanosensitive properties of human pluripotent stem cells (hPSCs), in particular the effects that the physical microenvironment has on their differentiation, remains elusive. Here, we show that neural induction and caudalization of hPSCs can be accelerated by using a synthetic microengineered substrate system consisting of poly(dimethylsiloxane) micropost arrays (PMAs) with tunable mechanical rigidities. The purity and yield of functional motor neurons derived from hPSCs within 23 days of culture using soft PMAs were improved more than fourfold and tenfold, respectively, compared with coverslips or rigid PMAs. Mechanistic studies revealed a multi-targeted mechanotransductive process involving Smad phosphorylation and nucleocytoplasmic shuttling, regulated by rigidity-dependent Hippo/YAP activities and actomyosin cytoskeleton integrity and contractility. Our findings suggest that substrate rigidity is an important biophysical cue influencing neural induction and subtype specification, and that microengineered substrates can thus serve as a promising platform for large-scale culture of hPSCs.

PMID:
24728461
PMCID:
PMC4051885
DOI:
10.1038/nmat3945
[Indexed for MEDLINE]
Free PMC Article

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