Stress-stiffening-mediated stem-cell commitment switch in soft responsive hydrogels

Das, Rajat K.; Gocheva, Veronika; Hammink, Roel; Zouani, Omar F.; Rowan, Alan E.

doi:10.1038/nmat4483

Cited by 345 publications

(391 citation statements)

References 55 publications

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“…22,44–48 These systems can be used to study how externally applied forces impact individual cells or multi-cellular tissue models. They also enable studies of how cell intrinsic forces regulate cell behaviour, often as a feedback from the resistance to these forces provided by the niche.…”

Section: Manipulating Mechanobiologymentioning

confidence: 99%

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Mechanical forces direct stem cell behaviour in development and regeneration

Vining

Mooney

2017

Nat Rev Mol Cell Biol

1,228

958

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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 differentiation and self-renewal. 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 examine how the mode and magnitude of mechanical cues, such as matrix stiffness or applied forces, direct stem cell differentiation and function. Fundamental insights on the mechanobiology of stem cells also inform the design of artificial niches to support stem cells for regenerative therapies.

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Section: Manipulating Mechanobiologymentioning

confidence: 99%

“…Additionally, substrate creep [G] and stress-stiffening [G] (Box 2) affect MSCs differentiation. 48,118 Unlike purely elastic systems, physical environments that exhibit viscoelastic behaviour allow cells to reversibly change their shape and volume in response to cues (FIG. 4B–C).…”

Section: Stem Cells Respond To Forcesmentioning

confidence: 99%

Mechanical forces direct stem cell behaviour in development and regeneration

Vining

Mooney

2017

Nat Rev Mol Cell Biol

1,228

958

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“…Although it has long been known that cells sense and respond to the elastic modulus of ECMs (11)(12)(13)(14), recent work has indicated an impact of nonlinear elasticity as well. Studies have found that the nonlinear elasticity of ECM regulates modes of cell motility (15) and differentiation of mesenchymal stem cells (16), alters how far cells are able to sense into the ECM (17), and enables long-range mechanical signaling between cells (18).…”

mentioning

confidence: 99%

Strain-enhanced stress relaxation impacts nonlinear elasticity in collagen gels

Nam

Butte

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

258

210

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The extracellular matrix (ECM) is a complex assembly of structural proteins that provides physical support and biochemical signaling to cells in tissues. The mechanical properties of the ECM have been found to play a key role in regulating cell behaviors such as differentiation and malignancy. Gels formed from ECM protein biopolymers such as collagen or fibrin are commonly used for 3D cell culture models of tissue. One of the most striking features of these gels is that they exhibit nonlinear elasticity, undergoing strain stiffening. However, these gels are also viscoelastic and exhibit stress relaxation, with the resistance of the gel to a deformation relaxing over time. Recent studies have suggested that cells sense and respond to both nonlinear elasticity and viscoelasticity of ECM, yet little is known about the connection between nonlinear elasticity and viscoelasticity. Here, we report that, as strain is increased, not only do biopolymer gels stiffen but they also exhibit faster stress relaxation, reducing the timescale over which elastic energy is dissipated. This effect is not universal to all biological gels and is mediated through weak cross-links. Mechanistically, computational modeling and atomic force microscopy (AFM) indicate that strain-enhanced stress relaxation of collagen gels arises from force-dependent unbinding of weak bonds between collagen fibers. The broader effect of strain-enhanced stress relaxation is to rapidly diminish strain stiffening over time. These results reveal the interplay between nonlinear elasticity and viscoelasticity in collagen gels, and highlight the complexity of the ECM mechanics that are likely sensed through cellular mechanotransduction.collagen mechanics | viscoelasticity | force-dependent unbinding | biopolymers | stress relaxation T he composition and architecture of ECM is heterogeneous and varies with tissue type and location. One particularly important ECM protein is type Ι collagen, which is the most abundant ECM component and primarily determines the mechanics of connective tissue (1). Type 1 collagen self-assembles into fibers, and these fibers can form networks in vitro. Studies investigating the mechanical properties of collagen networks have revealed that these networks are nonlinearly elastic and exhibit strain stiffening, or an increase in the elasticity as the strain on the network is enhanced (1-3). This nonlinear elasticity is also a characteristic feature of fibrin gels, which serve as the major component of blood clots, as well as in reconstituted networks of intermediate filaments and cytoskeletal actin networks (2, 4-7). These networks are all composed of semiflexible polymers or fibers, which are relatively rigid, so that the tangent to the contour of the polymer is correlated over long lengths, yet undergo substantial bending fluctuations due to thermal energy. Semiflexible polymers or fibers form networks at low volume fractions (8). Strain stiffening in these networks is thought to arise from either the entropic elasticity of single polymers...

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“…The critical strain of the PIC hydrogels was increased by increasing the PIC polymer chain length, while the adhesion‐ligand density and the stiffness of PIC bulk hydrogel were kept constant. When cells were cultured in 3D PIC hydrogels, hMSCs preferred to differentiate into osteoblasts when the critical strain was increased, a process apparently mediated by microtubule‐associated protein DCAMKL 29. Taken together, these results highlight the strain‐stiffening property as an important element in fabricating 3D microenvironments.…”

Section: The Stem Cell Micronichementioning

confidence: 74%

Recent Advances in Engineering the Stem Cell Microniche in 3D

Bao¹,

Xie²,

Huck³

2018

Advanced Science

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Conventional 2D cell culture techniques have provided fundamental insights into key biochemical and biophysical mechanisms responsible for various cellular behaviors, such as cell adhesion, spreading, division, proliferation, and differentiation. However, 2D culture in vitro does not fully capture the physical and chemical properties of the native microenvironment. There is a growing body of research that suggests that cells cultured on 2D substrates differ greatly from those grown in vivo. This article focuses on recent progress in using bioinspired 3D matrices that recapitulate as many aspects of the natural extracellular matrix as possible. A range of techniques for the engineering of 3D microenvironment with precisely controlled biophysical and chemical properties, and the impact of these environments on cellular behavior, is reviewed. Finally, an outlook on future challenges for engineering the 3D microenvironment and how such approaches would further our understanding of the influence of the microenvironment on cell function is provided.

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Stress-stiffening-mediated stem-cell commitment switch in soft responsive hydrogels

Cited by 345 publications

References 55 publications

Mechanical forces direct stem cell behaviour in development and regeneration

Mechanical forces direct stem cell behaviour in development and regeneration

Strain-enhanced stress relaxation impacts nonlinear elasticity in collagen gels

Recent Advances in Engineering the Stem Cell Microniche in 3D

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