Modulation of integrin and E-cadherin-mediated adhesions to spatially control heterogeneity in human pluripotent stem cell differentiation
Abstract
Heterogeneity in human pluripotent stem cell (PSC) fates is partially caused by mechanical asymmetry arising from spatial polarization of cell-cell and cell-matrix adhesions. Independent studies have shown that integrin and E-cadherin adhesions promote opposing differentiation and pluripotent fates respectively although their crosstalk mechanism in modulating cell fate heterogeneity remains unknown. Here, we demonstrated that spatial polarization of integrin and E-cadherin adhesions in a human PSC colony compete to recruit Rho-ROCK activated myosin II to different localities to pattern pluripotent-differentiation decisions, resulting in spatially heterogeneous colonies. Cell micropatterning was used to modulate the spatial polarization of cell adhesions, which enabled us to prospectively determine localization patterns of activated myosin II and mesoendoderm differentiation. Direct inhibition of Rho-ROCK-myosin II activation phenocopied E-cadherin rather than integrin inhibition to form uniformly differentiated colonies. This indicated that E-cadherin was the primary gatekeeper to differentiation progression. This insight allows for biomaterials to be tailored for human PSC maintenance or differentiation with minimal heterogeneity.
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Variants of ECM combinations, micropatterned 2D mono-culture or co-culture, cell sheets, stacked 3D structures, and micro-positioned ECM substrates allow formation of reproducible tissue structures and functions with high spatiotemporal control.
“Variants of ECM combinations, micropatterned 2D mono-culture or co-culture237,238, cell sheets239, stacked 3D structures26, and micro-positioned ECM substrates70,240 allow the formation of reproducible tissue structures and functions with a high degree of spatiotemporal control such as stretching241 and osmotic forces242 (FIG. 5).”
From Organoids (2022) · cites this paper as [238]
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- Authors
- Toh, Y.-C., Xing, J., & Yu, H.
- Affiliations
- Agency for Science, Technology and Research (SG)
- Corresponding author
- Toh, Yi-Chin
- Yu, Hanry
- Venue
- Biomaterials
- Publisher
- Elsevier BV
- Published
- 2015-05
- Volume
- 50
- Pages
- 87-97
- ISSN
- 0142-9612 (ISSN-L)
- OpenAlex
- W2051296058
- Cited by
- 53
- References
- 30
- Citations by year
- 2025: 4 · 2024: 5 · 2023: 5 · 2022: 4 · 2021: 6 · 2020: 1 · 2019: 3 · 2018: 10 · 2017: 5 · 2016: 6 · 2015: 3
- FWCI
- 4.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biomaterials (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Institute of Bioengineering and Nanotechnology, Biomedical Research Council, Agency for Science, Technology and Research (A*STAR) of Singapore
- Singapore-MIT Alliance for Research and Technology BioSyM and Mechanobiology Institute (MBI) (R714-006-008)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- human pluripotent stem cells, integrin-mediated adhesion, cell-cell adhesion, cell-matrix adhesion, Rho/ROCK signaling, myosin II, cell micropatterning
- MeSH terms
- Actomyosin, Cell Adhesion, Cell Differentiation, Collagen, Drug Combinations, Endoderm, Humans, Laminin, Mesoderm, Proteoglycans, Signal Transduction, Antigens, CD, Cadherins, Integrins, Cell Polarity, Cell Lineage, Myosin Type II, Pluripotent Stem Cells, Embryonic Stem Cells, rho-Associated Kinases
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