Inhibition of Focal Adhesion Kinase Signaling by Integrin α6β1 Supports Human Pluripotent Stem Cell Self-Renewal
Open accessAbstract
Self-renewal of human embryonic stem cells and human induced pluripotent stem cells (hiPSCs)—known as pluripotent stem cells (PSC)—is influenced by culture conditions, including the substrate on which they are grown. However, details of the molecular mechanisms interconnecting the substrate and self-renewal of these cells remain unclear. We describe a signaling pathway in hPSCs linking self-renewal and expression of pluripotency transcription factors to integrin α6β1 and inactivation of focal adhesion kinase (FAK). Disruption of this pathway results in hPSC differentiation. In hPSCs, α6β1 is the dominant integrin and FAK is not phosphorylated at Y397, and thus, it is inactive. During differentiation, integrin α6 levels diminish and Y397 FAK is phosphorylated and activated. During reprogramming of fibroblasts into iPSCs, integrin α6 is upregulated and FAK is inactivated. Knockdown of integrin α6 and activation of β1 integrin lead to FAK phosphorylation and reduction of Nanog, Oct4, and Sox2, suggesting that integrin α6 functions in inactivation of integrin β1 and FAK signaling and prevention of hPSC differentiation. The N-terminal domain of FAK, where Y397 is localized, is in the nuclei of hPSCs interacting with Oct4 and Sox2, and this immunolocalization is regulated by Oct4. hPSCs remodel the extracellular microenvironment and deposit laminin α5, the primary ligand of integrin α6β1. Knockdown of laminin α5 resulted in reduction of integrin α6 expression, phosphorylation of FAK and decreased Oct4. In conclusion, hPSCs promote the expression of integrin α6β1, and nuclear localization and inactivation of FAK to supports stem cell self-renewal.
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Among the relevant integrins, only α6β1 has been reported to support pluripotency, whereas the others appear to promote differentiation in an ECM-specific way.
“only α6β1 has been reported to promote pluripotency37, while all others appear to promote differentiation in an ECM type-specific manner.”
From In situ expansion, differentiation, and electromechanical coupling of human cardiac muscle in a 3D bioprinted, chambered organoid (2020) · cites this paper as [37]
The Discussion (page unavailable) supports a role for α6β1 in maintaining human pluripotent stem-cell self-renewal. It does not support the claim that all other integrins promote ECM-specific differentiation: the Introduction says their roles remain incompletely understood, and the paper’s reference list identifies a study of self-renewal via αVβ5. (LLM, conf=0.88)
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- Authors
- Villa-Diaz, L. G., Kim, J. K., Laperle, A., Palecek, S. P., & Krebsbach, P. H.
- Affiliations
- University of Michigan (US)
- University of Wisconsin–Madison (US)
- Corresponding author
- Villa-Diaz, Luis G.
- Krebsbach, Paul H.
- Venue
- Stem Cells
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-03-27
- Volume
- 34
- Issue
- 7
- Pages
- 1753-1764
- ISSN
- 1066-5099 (ISSN-L)
- 1549-4918
- OpenAlex
- W2346942041
- Cited by
- 77
- References
- 51
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 4 · 2023: 7 · 2022: 2 · 2021: 10 · 2020: 6 · 2019: 15 · 2018: 9 · 2017: 7 · 2016: 5
- FWCI
- 6.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Stem Cells (publishedVersion)
- PubMed (publishedVersion)
- Deep Blue (University of Michigan) (submittedVersion)
- Funders
- National Institutes of Health (R01DE016530-08)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- focal adhesion kinase, alpha6beta1 integrin, beta1 integrin, human induced pluripotent stem cells, human embryonic stem cells, laminin alpha5, Oct4, Nanog, SOX2, pluripotency transcription factors, cell differentiation, reprogramming, extracellular matrix microenvironment
- MeSH terms
- Cell Self Renewal, Protein Domains, Cell Differentiation, Cell Nucleus, Humans, Laminin, Phosphorylation, Protein Binding, Transcription Factors, Signal Transduction, Protein Isoforms, Focal Adhesions, Integrin alpha6beta1, Pluripotent Stem Cells, Focal Adhesion Protein-Tyrosine Kinases, HEK293 Cells
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