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Mechanical forces direct stem cell behaviour in development and regeneration

Key Points

  • Stem cells are regulated by cell-intrinsic and cell-extrinsic forces in development, homeostasis and regeneration.

  • Mechanical tension regulates early embryogenesis ex vivo in embryoid self-organization, germ-band elongation, invagination and dorsal closure, and sorting of the germ layers.

  • During development, mechanical forces regulate the generation of organ systems by directing the specification and expansion of stem cells, as well as re-organizing the extracellular matrix that begins to accumulate in embryonic tissues.

  • Synthetic matrices enable the control of biophysical properties of the stem cell niche in order to test specific hypotheses on how mechanical cues regulate stem cells.

  • Synthetic matrices have been used to demonstrate how mechanical cues, such as stiffness and viscoelasticity, as well as externally applied mechanical loads, control stem cell self-renewal and proliferation, differentiation and organoid formation.

  • Externally applied mechanical forces can stimulate stem cells to promote tissue regeneration.

Abstract

Stem cells and their local microenvironment, or niche, communicate through mechanical cues to regulate cell fate and cell behaviour and to guide developmental processes. During embryonic development, mechanical forces are involved in patterning and organogenesis. The physical environment of pluripotent stem cells regulates their self-renewal and differentiation. Mechanical and physical cues are also important in adult tissues, where adult stem cells require physical interactions with the extracellular matrix to maintain their potency. In vitro, synthetic models of the stem cell niche can be used to precisely control and manipulate the biophysical and biochemical properties of the stem cell microenvironment and to examine how the mode and magnitude of mechanical cues, such as matrix stiffness or applied forces, direct stem cell differentiation and function. Fundamental insights into the mechanobiology of stem cells also inform the design of artificial niches to support stem cells for regenerative therapies.

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Figure 1: Stem cells exert forces and are subject to external forces, which regulate their intracellular signalling pathways.
Figure 2: Mechanobiology during early development.
Figure 3: Material systems to study stem cell mechanobiology.
Figure 4: Three-dimensional synthetic niches physically confine stem cells and present mechanical cues that impact cell behaviour and fate through forces.
Figure 5: Tissue regeneration can be improved by exploiting stem cell mechanobiology.

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Acknowledgements

The authors thank J. Li for assistance with revising this manuscript and D. Zhang for input on the figures. Funding was provided by the National Institute of Dental and Craniofacial Research of the US National Institutes of Health (NIH) under Award Numbers 5R01DE013033 (D.M.) and K08DE025292 (K.H.V.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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Authors and Affiliations

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Contributions

K.H.V. and D.J.M. researched data for the article, contributed to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to David J. Mooney.

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Supplementary information

Supplementary information S1 (table)

Mechanical cues guide development processes (PDF 104 kb)

Supplementary information S2 (box)

Techniques to apply and measure extrinsic forces on cells (PDF 97 kb)

Supplementary information S3 (table)

Stem cells respond diversely to forces in models of mechanobiology (PDF 128 kb)

PowerPoint slides

Glossary

Cadherin–catenin complexes

Complexes of cellular receptors termed cadherins, which bind to other cells, with β-catenin, an intracellular molecule, that connect to the actin cytoskeleton in epithelial tissues to convey forces between cells.

Dorsal closure

Closure of a dorsal epidermal opening that is initially formed naturally during embryonic development of Drosophila melanogaster; this process has similarities to wound healing in mammals.

Cortical tension

A type of cytoskeletal tension caused by actomyosin-generated forces; it contributes to cell shape and mechanical properties.

RHO-associated protein kinase

(ROCK). A serine/threonine kinase that can regulate actomyosin contractility and is downstream of RHOA and other pathways.

Stomodeum

A frontal opening in the developing embryo that forms a primordial mouth, separated from the pharynx by an oropharyngeal membrane.

Traction forces

Forces on extracellular matrix or other cells generated by receptor binding and actomyosin contractility.

Fractal patterns

Highly branched geometric patterns that are formed from repeated symmetrical branching, often across multiple length scales.

Submandibular salivary gland

One of the major salivary glands, it features a branched ductal structure that opens into the oral cavity, with secretory end pieces called acini that produce saliva by secretion of water, salts, proteins and other macromolecules.

Focal adhesions

Large and dynamic protein complexes of matrix receptors, actin cytoskeleton and other cytoskeletal and signalling molecules that link the cytoskeleton to the extracellular matrix.

Isometric muscle contraction

A type of force generated by muscle while maintaining constant muscle length and joint angle.

Convective flow

Fluid flow that transfers mass and/or heat down a fluid pressure gradient.

Microfluidics

The precise control of fluid shear forces and flow rates in micro-scale geometries, such as micro-channels.

Substrate creep

The deformation, or flow, of a material during a constant application of stress.

Stress stiffening

The mechanical stiffening of a polymer network with increasing strain.

Sarcomere

A fundamental active unit in skeletal muscle that generates force from overlapping striations of actin and myosin.

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Vining, K., Mooney, D. Mechanical forces direct stem cell behaviour in development and regeneration. Nat Rev Mol Cell Biol 18, 728–742 (2017). https://doi.org/10.1038/nrm.2017.108

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