ACS Biomaterials Science & Engineering· 2026Q1· Review
Cytoskeletal and Extracellular Factors Regulating Stem Cell Differentiation: Mechanisms, Tools, and Emerging Applications
- 0citations
- Q1SCImago
- 2026year
Short summary
Stem cell differentiation is regulated by both biochemical cues and the mechanical state of the cytoskeleton, which integrates external forces into cellular responses. This review highlights how matrix properties like viscoelasticity, beyond just stiffness, and mechanotransduction pathways (e.g., RhoA/ROCK, YAP/TAZ) direct stem cell fate, with potential applications in regenerative medicine.
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Key points
- Stem cell differentiation is influenced by cytoskeletal organization and mechanical forces from the extracellular environment.
- Matrix viscoelasticity and stress relaxation, in addition to stiffness, are key regulators of stem cell lineage commitment.
- Mechanotransduction pathways like RhoA/ROCK, Piezo1/2, and YAP/TAZ link cytoskeletal forces to gene regulation.
- Techniques such as traction force microscopy and molecular tension sensors can quantify cellular forces.
- Understanding these mechanisms can inform the design of biomaterials and biomanufacturing processes for regenerative medicine.
AI-generated from the title and abstract; the full text is not read.
Abstract
Abstract Stem cell lineage determination is governed not only by biochemical cues but also by the organization and force-generating state of the cytoskeleton, which integrates extracellular mechanical cues into transcriptional and epigenetic responses. Cytoskeletal organization and remodeling play essential roles in stem cell fate determination, as well as other relevant biological processes including development, tissue regeneration, and disease progression. In this review, we first outline the different types of cytoskeletal structures—actin filaments, microtubules, and intermediate filaments—and their coordinated roles in cell shape, polarity, and contractility. We then discuss how extracellular cues, including matrix stiffness, geometry, topography, shear, stretch, and compression remodel cytoskeletal distribution and adhesion dynamics to affect stem cell lineage commitment. We highlight matrix viscoelasticity and stress relaxation as time-dependent mechanical regulators that modulate traction transmission, focal adhesion, and cytoskeletal tension, thereby directing stem cell differentiation outcomes beyond stiffness alone. We next discuss mechanotransduction pathways, such as RhoA/ROCK-mediated contractility, Wnt/β-catenin, Piezo1/Piezo2, and YAP/TAZ nuclear shuttling, which couple cytoskeletal forces to gene regulation. We further summarize quantitative approaches to measure cell molecular forces, including traction force microscopy, molecular tension sensors, and advanced live-cell imaging platforms. Finally, we discuss the translational potential of cytoskeleton-informed design principles in regenerative medicine, where they can be leveraged to improve stem cell biomanufacturing, optimize tunable biomaterials, and develop more predictive mechanopathology models. Together, these developments will establish cytoskeletal organization as a controllable, engineerable lever for directing stem cell fate and enabling functional tissue formation.
The authors' abstract, as published at the source. ACS Biomaterials Science & Engineering, 2026 · DOI ↗
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Field: Cell Biology
Cell BiologyBiochemistry, Genetics and Molecular Biology