title: Substratum-induced differentiation of human pluripotent stem cells reveals the coactivator YAP is a potent regulator of neuronal specification.
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.
authors.affiliation: Departments of Chemistry.
authors.forename: Samira
authors.initials: S
authors.lastname: Musah
authors.affiliation: Biochemistry.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Wrighton
authors.affiliation: Biochemistry.
authors.forename: Yefim
authors.initials: Y
authors.lastname: Zaltsman
authors.affiliation: Waisman Center, and.
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Zhong
authors.affiliation: Biomedical Engineering.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zorn
authors.affiliation: Biomedical Engineering.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Parlato
authors.affiliation: Chemical and Biological Engineering, and.
authors.forename: Cheston
authors.initials: C
authors.lastname: Hsiao
authors.affiliation: Chemical and Biological Engineering, and.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Palecek
authors.affiliation: Waisman Center, and Genetics Training Program, University of Wisconsin-Madison, Madison, WI 53706; and Medical Genetics and Neurology.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chang
authors.affiliation: Biomedical Engineering, Department of Orthopedics and Rehabilitation, University of Wisconsin, Wisconsin Institute for Medical Research, Madison, WI 53706.
authors.forename: William L
authors.initials: WL
authors.lastname: Murphy
authors.affiliation: Departments of Chemistry, Biochemistry, kiessling@chem.wisc.edu.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Kiessling
mesh_terms: D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D018929:Cell Culture Techniques / Q000379:methods*; D002454:Cell Differentiation; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000737:chemistry*; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human
keywords: YAP/TAZ; biomaterials; glycosaminoglycans; mechanotransduction; neuronal differentiation