Substrate elasticity regulates skeletal muscle stem cell self-renewal in culture

By P. Gilbert, K. Havenstrite, Klas E. G. Magnusson, A. Sacco, Nora Leonardi, P. Kraft, N. Nguyen, Sebastian Thrun, M. Lutolf, Helen M. Blau. Science, 2010

1,534 citations recorded by the source corpus.

Environment Matters Stem cells isolated from muscle can be used for muscle regeneration, but only if the stem cells are fresh. Under standard cell culture conditions in the laboratory, muscle stem cells fail to proliferate efficiently and lose their regenerative capacity. Gilbert et al. (p. 1078, published online 15 July; see the Perspective by Bhatia) built an in vitro–culture system that resembles the physical characteristics in which muscle stem cells normally reside: a squishy elastic bed (rather than the hard slab of a plastic culture flask). Laminin tethered to hydrogels was used to generate substrates of varying elasticity. When cultured on these substrates, muscle stem cells remained undifferentiated and were able to support muscle regeneration when transplanted back into mice. Muscle stem cells prefer a soft substrate. Stem cells that naturally reside in adult tissues, such as muscle stem cells (MuSCs), exhibit robust regenerative capacity in vivo that is rapidly lost in culture. Using a bioengineered substrate to recapitulate key biophysical and biochemical niche features in conjunction with a highly automated single-cell tracking algorithm, we show that substrate elasticity is a potent regulator of MuSC fate in culture. Unlike MuSCs on rigid plastic dishes (~106 kilopascals), MuSCs cultured on soft hydrogel substrates that mimic the elasticity of muscle (12 kilopascals) self-renew in vitro and contribute extensively to muscle regeneration when subsequently transplanted into mice and assayed histologically and quantitatively by noninvasive bioluminescence imaging. Our studies provide novel evidence that by recapitulating physiological tissue rigidity, propagation of adult muscle stem cells is possible, enabling future cell-based therapies for muscle-wasting diseases.

Subfields: Biomedical Engineering, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/995017fcc4f5a3b2f96cab093b1b9b203cc8bf33

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Citations in the corpus

Deconstructing the third dimension – how 3D culture microenvironments alter cellular cues (2012, background): “Recognizing the disparity between these artificial conditions and the markedly more-compliant microenvironment of most tissues, recent work using soft 2D gels has confirmed that ECM stiffness can influence adhesions, morphogenesis, and stem cell differentiation and maintenance (Engler et al., 2006; ”
Extracellular Matrix Degradation and Remodeling in Development and Disease (2011, background): “Likewise, muscle stem cells grown on soft hydrogels with elasticity mimicking that of real muscle differentiate into functional muscle (Gilbert et al. 2010), highlighting the great promise that tissue engineering may hold in regenerative medicine.”
Wound repair and regeneration: Mechanisms, signaling, and translation (2014, positive): “In this regard, biomaterials research could provide a better understanding of how the ECM and its mechanical forces affect cell invasion, growth, and differentiation (147-149).”
A batch algorithm using iterative application of the Viterbi algorithm to track cells and construct cell lineages (2012, methodology): “A precursor of the proposed algorithm was previously applied in a full scale biological study [6].”