Stem Cell Differentiation is Regulated by Extracellular Matrix Mechanics - PubMed (original) (raw)

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Stem Cell Differentiation is Regulated by Extracellular Matrix Mechanics

Lucas R Smith et al. Physiology (Bethesda). 2018.

Abstract

Stem cells mechanosense the stiffness of their microenvironment, which impacts differentiation. Although tissue hydration anti-correlates with stiffness, extracellular matrix (ECM) stiffness is clearly transduced into gene expression via adhesion and cytoskeleton proteins that tune fates. Cytoskeletal reorganization of ECM can create heterogeneity and influence fates, with fibrosis being one extreme.

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Figures

FIGURE 1.

FIGURE 1.

Universal scale of micro-stiffness for tissues A: stem cells derive the tissues across that body that vary in stiffness of wide scales, from fluid like in the marrow at <1 kPa to rigid bone in the GPa range. The stiffness measured as microelasticity correlates with expression of collagen across the range of tissues but is generally much softer than the rigid plastic typically used in cell culture (21). B: hydration level of several human tissues after extraction of fat from a 46-yr-old male (26). Cartilage hydration state is age dependent and approximated for a 46-yr-old male (1). Bone matrix hydration is determined as a percentage of water and organic bone matrix (55, 56). The hydration state of tissues is inversely proportional to the tissue microelasticity (E) and collagen content. C: AFM is used to probe tissue or gel stiffness on the scale of the cell. The microelasticity is determined by measuring the restoring force relative to the indentation distance and depends on the probe tip (88). D: various cell types spread out when placed on a substrate with collagen coating of a stiff underlying gel. The spread-out cells contain a robust cytoskeleton with abundant actin stress fibers. E: collagen of the ECM provides adhesion sites for transmembrane integrins of the cell that form the basis of focal adhesions. Focal adhesions anchor the actin cytoskeleton at the membrane, whereas the LINC complex anchors the cytoskeleton at the nuclear membrane. LINC complexes also interact with the nuclear stiffness, determining lamins just inside the nuclear membrane, which provides a direct link to chromatin and DNA.

FIGURE 2.

FIGURE 2.

Stiffness-based differentiation of stem cells A: MSCs plated on collagen functionalized gels of the indicated stiffness differentiate over the course of a week into cells from tissues corresponding to the stiffness of the gel. Soft gels direct adipogenic differentiation, whereas the more stiff gels induce osteoblast differentiation. B: substrate stiffness drives the type of proliferation among MuSC, where substrates with tissue-like stiffness often maintain their stem-like properties (defined by expression of Pax7), stiff substrates deplete the stem cell pool by inducing differentiation of both daughter cells (defined by expression of MyoD). C: muscle progenitors eventually differentiate and fuse into multinucleated muscle fibers filled with contractile sarcomeres. The formation of sarcomeres is most prevalent on tissue-like stiffness, whereas stiffness above or below that level leads to impaired sarcomerogenesis. D: immature cardiomyocytes are derived along a series of steps from embryonic stem cells in the soft embryo. As the heart matures, it becomes more stiff, and the cardiomyocytes become more aligned and contractile. However, in a stiffer fibrotic heart, contraction of cardiomyocytes is impaired. Alternatively, iPSCs can be induced to form cardiomyocytes on plastic; however, they are not able to produce the contractile force of a healthy mature cardiomyocyte.

FIGURE 3.

FIGURE 3.

ECM malleability and heterogeneity A: MSCs placed in soft fibrous networks are able to pull the fibers and pack them near the cell, creating heterogeneity with high stiffness and ligand presentation local to the cell. However, in fibrous networks with stiff fibers, the cell is unable to deform the network and change the local stiffness. B: simple sandwich gels demonstrate that stiff regions dominate matrix mechanosensing. When a soft gel is placed on top of cells on either soft or stiff lower substrates, the cells maintain their rounded or spread morphology, respectively. However, when rounded cells are on a soft substrate or overlaid with a stiff gel, they actively spread to adopt the morphology expected from a stiff substrate. C: gels can also be made with heterogenous underlying collagen fibers that also introduce heterogenous stiffness within the 2D gel. Reminiscent of a fibrotic environment, these gels are termed “scar in a dish.” Although MSCs on a soft or stiff substrate adopt a rounded or spread morphology, respectively, the mechanical heterogeneity creates a near homogenous population of MSCs with a spread morphology. This spread morphology includes robust αSMA, which is a hallmark of fibrotic cells.

FIGURE 4.

FIGURE 4.

Schematic of stem-cell mechanosensing in fibrosis Fibrosis is the pathologic accumulation of ECM that is driven by myofibroblast in many tissues. A host of resident stem cells are known to differentiate into myofibroblast, which in many cases is known to be mechanosensitive. Myofibroblasts secrete matrix components that incorporate into the matrix to increase stiffness. Myofibroblasts are also highly contractile and stress the matrix, which leads to even higher levels of stiffness and also limits the ability of MMPs to degrade the matrix. Mechanical stress on the matrix has also been demonstrated to release active TGFB from the matrix, a critical soluble factor in the differentiation of myofibroblasts and other fibrotic programs. These processes demonstrate the critical nature of ECM mechanics in the positive feedback loop that results in progressive fibrosis.

References

    1. Amadò R, Werner G, Neukom H. Water content of human articular cartilage and its determination by gas chromatography. Biochem Med 16: 169–172, 1976. doi: 10.1016/0006-2944(76)90020-X. -DOI -PubMed
    1. Baker BM, Trappmann B, Wang WY, Sakar MS, Kim IL, Shenoy VB, Burdick JA, Chen CS. Cell-mediated fibre recruitment drives extracellular matrix mechanosensing in engineered fibrillar microenvironments. Nat Mater 14: 1262–1268, 2015. doi: 10.1038/nmat4444. -DOI -PMC -PubMed
    1. Balestrini JL, Chaudhry S, Sarrazy V, Koehler A, Hinz B. The mechanical memory of lung myofibroblasts. Integr Biol 4: 410–421, 2012. doi: 10.1039/c2ib00149g. -DOI -PubMed
    1. Bates JH, Davis GS, Majumdar A, Butnor KJ, Suki B. Linking parenchymal disease progression to changes in lung mechanical function by percolation. Am J Respir Crit Care Med 176: 617–623, 2007. doi: 10.1164/rccm.200611-1739OC. -DOI -PMC -PubMed
    1. Ben-Ze’ev A, Farmer SR, Penman S. Protein synthesis requires cell-surface contact while nuclear events respond to cell shape in anchorage-dependent fibroblasts. Cell 21: 365–372, 1980. doi: 10.1016/0092-8674(80)90473-0. -DOI -PubMed

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