Myotubes differentiate optimally on substrates with tissue-like stiffness

By A. Engler, Maureen A. Griffin, Shamik Sen, C. Bönnemann, H. Sweeney, Dennis E. Discher. Journal of Cell Biology, 2004

1,789 citations recorded by the source corpus.

Contractile myocytes provide a test of the hypothesis that cells sense their mechanical as well as molecular microenvironment, altering expression, organization, and/or morphology accordingly. Here, myoblasts were cultured on collagen strips attached to glass or polymer gels of varied elasticity. Subsequent fusion into myotubes occurs independent of substrate flexibility. However, myosin/actin striations emerge later only on gels with stiffness typical of normal muscle (passive Young's modulus, E ∼12 kPa). On glass and much softer or stiffer gels, including gels emulating stiff dystrophic muscle, cells do not striate. In addition, myotubes grown on top of a compliant bottom layer of glass-attached myotubes (but not softer fibroblasts) will striate, whereas the bottom cells will only assemble stress fibers and vinculin-rich adhesions. Unlike sarcomere formation, adhesion strength increases monotonically versus substrate stiffness with strongest adhesion on glass. These findings have major implications for in vivo introduction of stem cells into diseased or damaged striated muscle of altered mechanical composition.

Subfields: Biomedical Engineering, Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/86b7a525330c94d5e76fafdf987d5460bf9f5037

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Biomedical Engineering

In Cell Biology

In Molecular Biology

Citations in the corpus

Intrinsic extracellular matrix properties regulate stem cell differentiation. (2010, background): “2A (Engler et al., 2006; Rowlands et al., 2008)); they cannot fuse together as normal muscle cells do in culture (Collinsworth et al., 2002; Engler et al., 2004a).”
Matrices with compliance comparable to that of brain tissue select neuronal over glial growth in mixed cortical cultures. (2006, background): “The enhanced protrusion of neurites on soft gels together with the increase in branching probability (7) suggests that, despite the similarities between the neuronal growth cone and the lamellapodium of other cell types, the actin-dependent contraction of neurons may not be the motor that drives neu”
The Influence of Hydrogel Modulus on the Proliferation and Differentiation of Encapsulated Neural Stem Cells (2009, neutral): “…concentrated on the influence of biochemical cues on stem cell behavior, it has become increasingly clear that the mechanical properties of the microenvironment also influence the behavior of a wide variety of cells including stem cells [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16].”
Mechanical properties of biological specimens explored by atomic force microscopy (2013, background): “Moreover, recent results suggest that mechanical forces trigger numerous and important cellular physiological phenomena such as cell morphology, mobility and cellular differentiation [73–75].”
The effect of substrate stiffness on adult neural stem cell behavior. (2009, background): “Although the molecular pathways are yet to be characterized, it has been specifically shown that anchorage dependent cells are responsive to the mechanical properties of their matrix [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20].”
Mechanotransduction in development: a growing role for contractility (2009, background): “In direct contrast to traditional culture on plastic, many cell types maintain a more differentiated phenotype when cultured on less stiff substrates, as these are more reflective of the stiffness of their in vivo tissue environmen”
Control of stem cell fate by physical interactions with the extracellular matrix (2009, background): “While the fusion of myoblasts into myotubes was found to be independent of substrate stiffness, the development of actin/ myosin striations occurred only on gels that had properties similar to those of normal muscle (Engler et al., 2004).”
Satellite cells and the muscle stem cell niche. (2013, background): “Resting healthy skeletal muscles and cultured myotubes possess a similar elastic stiffness (elastic modulus 12 kPa) (106, 152), whereas aged (184, 444) and dystrophic (152) skeletal muscles are apparently stiffer (elastic modulus 418 kPa).”
Genetic and cell biological analysis of integrin outside-in signaling. (2009, background): “2006), and myotubes differentiate into striated muscle only on substrates approximating the stiffness of muscle (Engler et al. 2004).”