Comprehensive Physiology Wiley Online Library

Extracellular Matrix: A Solid‐State Regulator of Cell form, Function, and Tissue Development

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Abstract

The sections in this article are:

1 Extracellular Matrix: Composition and Structure
2 Extracellular Matrix and Tissue Architecture
3 Functions of the Extracellular Matrix
3.1 Physiological Cell Attachment Foundation
3.2 Spatial Organizer of Polarized Epithelium
3.3 Solid‐State Growth Regulator
3.4 Inducer of Differentiation
3.5 Tissue Boundary
3.6 Storage Site for Soluble Regulators
3.7 Scaffolding for Orderly Tissue Renewal and Repair
3.8 Target for Deregulation during Tumor Formation and Invasion
4 Transmembrane Signaling Across Matrix Receptors
4.1 Cell Surface Matrix Receptors
4.2 Chemical Signaling
4.3 Mechanical Signaling
4.4 Signal Integration
5 Conclusions
Figure 1. Figure 1.

Interstitial matrix versus basement membrane (BM). Phase contrast (A,C) and immunofluorescence (B,D) micrographs of frozen sections of normal rat exocrine pancreas stained with antibodies against interstitial type III collagen (A,B) or BM type IV collagen (C,D). Interstitial fibrillar collagen is distributed in an amorphous pattern filling the connective tissue space. Basement membrane collagen appears in a linear pattern (planar in three dimensions) and therefore forms a physical tissue boundary separating the epithelium and vascular endothelium from surrounding connective tissue.

Figure 2. Figure 2.

Extracellular matrix (ECM) and tissue development. Pattern formation during morphogenesis results from establishment of local differentials of cell growth, ECM turnover, the tissue expansion. Regions of tissue expansion correspond to areas in which basement membrane (BM) turnover and cell proliferation are the highest. Importantly, the rate of BM deposition must exceed its degradation in regions of rapid growth and turnover because net growth (lateral extension) of BM is observed during tissue development. Differences in tissue pattern (for example, glandular acini versus vascular tubes) result from differences in the number and distribution of the growth centers. Glandular morphogenesis involves complex epithelial‐mesenchymal interactions whereas angiogenesis (capillary morphogenesis) appears to be driven largely by the endothelial cell itself (see text for appropriate references).

Figure 3. Figure 3.

Extracellular matrix (ECM) and tissue remodeling. Changes in basement membrane (BM) turnover that accompany tissue growth and involution during capillary development are shown here. Regions of the growing vessel that undergo the most active remodeling exhibit high rates of ECM turnover. However, BM synthesis must exceed BM degradation to produce net BM extension in these regions. Formation of new stable tissue form correlates with a decrease in BM degradation and accumulation of an intact BM. Once fully formed, BM synthesis and degradation are maintained at very low and approximately equal levels throughout adult life. In contrast, growing tissues may be induced to regress by rapidly increasing ECM degradation or by inhibiting ECM deposition, such that total dissolution of BM results. Normal cells rapidly lose viability when they are freed from anchorage and thus progressive tissue involution ensues. During involution, cells at the leading edge that sit on the BM with the highest turnover rate are the first to lose their adhesions and retract. This proceeds backwards along the growing sprout in a progressive manner until the entire vessel involutes . In this sense, controlled tissue involution is essentially normal tissue development in reverse.

Figure 4. Figure 4.

Basement membranes (BM) supports cell attachment and spreading. Scanning electron micrograph showing that exogenous intact BM (isolated from human amnion) can promote cell attachment and spreading, even in the presence of the protein synthesis inhibitor cycloheximide (experimental details are described in ref. ).

Figure 5. Figure 5.

Basement membrane (BM) and epithelial polarity. Top: Cells consistently orient within polarized epithelium, nucleus and rough endoplasmic reticulum (ER) at the base, Golgi complex above, and secretory granules in the apex, as shown in this electron micrograph of rat exocrine pancreas. Bottom: A higher magnification image from the same view showing that the highly polarized epithelium sits atop a continuous BM that separates the cells from the surrounding connective tissue space. Tips of the small arrows abut on the epithelial BM; L, lumen of a small capillary.

Figure 6. Figure 6.

Diagram of the focal adhesion complex. The extracellular portion of integrin receptors recognize specific amino acid binding sites (for example, RGD) within extracellular matrix (ECM) molecules. The intracellular portion of these receptors physically interlinks with the actin cytoskeleton via binding interactions with actinassociated proteins, such as talin, α‐actinin, vinculin, and paxillin. This localized membrane/cytoskeletal microdomain also has been found to contain molecules that are thought to mediate chemical signaling by ECM (for example, the protein kinases, c‐src and FAK kinase). The precise location of these proteins within the complex is currently unknown.

Figure 7. Figure 7.

Extracellular matrix (ECM) mechanics and control of cell function. Cells exert tension on their ECM adhesions. Highly adhesive ECM substrata that are malleable (for example, native collagen gels, Matrigel, thin silicone rubber) can not resist cytoskeletal tension and thus they promote cell rounding. However, if the same substrata are made rigid (for example, due to chemical crosslinking or immobilizing the gel on a dish), they support cell extension. Similar changes in cell shape can be induced by varying the ability of a rigid substratum to resist cell tension. This can be done by changing the density of a single type of purified ECM molecule (for example, fibronectin, laminin, or different collagen types) that is preadsorbed on otherwise nonadhesive dishes. For many cell types, round cells tend to maintain high levels of tissue‐specific functions, whereas spread cells turn off differentiation and switch on growth, regardless of the method of cell shape control (see text for appropriate references).



Figure 1.

Interstitial matrix versus basement membrane (BM). Phase contrast (A,C) and immunofluorescence (B,D) micrographs of frozen sections of normal rat exocrine pancreas stained with antibodies against interstitial type III collagen (A,B) or BM type IV collagen (C,D). Interstitial fibrillar collagen is distributed in an amorphous pattern filling the connective tissue space. Basement membrane collagen appears in a linear pattern (planar in three dimensions) and therefore forms a physical tissue boundary separating the epithelium and vascular endothelium from surrounding connective tissue.



Figure 2.

Extracellular matrix (ECM) and tissue development. Pattern formation during morphogenesis results from establishment of local differentials of cell growth, ECM turnover, the tissue expansion. Regions of tissue expansion correspond to areas in which basement membrane (BM) turnover and cell proliferation are the highest. Importantly, the rate of BM deposition must exceed its degradation in regions of rapid growth and turnover because net growth (lateral extension) of BM is observed during tissue development. Differences in tissue pattern (for example, glandular acini versus vascular tubes) result from differences in the number and distribution of the growth centers. Glandular morphogenesis involves complex epithelial‐mesenchymal interactions whereas angiogenesis (capillary morphogenesis) appears to be driven largely by the endothelial cell itself (see text for appropriate references).



Figure 3.

Extracellular matrix (ECM) and tissue remodeling. Changes in basement membrane (BM) turnover that accompany tissue growth and involution during capillary development are shown here. Regions of the growing vessel that undergo the most active remodeling exhibit high rates of ECM turnover. However, BM synthesis must exceed BM degradation to produce net BM extension in these regions. Formation of new stable tissue form correlates with a decrease in BM degradation and accumulation of an intact BM. Once fully formed, BM synthesis and degradation are maintained at very low and approximately equal levels throughout adult life. In contrast, growing tissues may be induced to regress by rapidly increasing ECM degradation or by inhibiting ECM deposition, such that total dissolution of BM results. Normal cells rapidly lose viability when they are freed from anchorage and thus progressive tissue involution ensues. During involution, cells at the leading edge that sit on the BM with the highest turnover rate are the first to lose their adhesions and retract. This proceeds backwards along the growing sprout in a progressive manner until the entire vessel involutes . In this sense, controlled tissue involution is essentially normal tissue development in reverse.



Figure 4.

Basement membranes (BM) supports cell attachment and spreading. Scanning electron micrograph showing that exogenous intact BM (isolated from human amnion) can promote cell attachment and spreading, even in the presence of the protein synthesis inhibitor cycloheximide (experimental details are described in ref. ).



Figure 5.

Basement membrane (BM) and epithelial polarity. Top: Cells consistently orient within polarized epithelium, nucleus and rough endoplasmic reticulum (ER) at the base, Golgi complex above, and secretory granules in the apex, as shown in this electron micrograph of rat exocrine pancreas. Bottom: A higher magnification image from the same view showing that the highly polarized epithelium sits atop a continuous BM that separates the cells from the surrounding connective tissue space. Tips of the small arrows abut on the epithelial BM; L, lumen of a small capillary.



Figure 6.

Diagram of the focal adhesion complex. The extracellular portion of integrin receptors recognize specific amino acid binding sites (for example, RGD) within extracellular matrix (ECM) molecules. The intracellular portion of these receptors physically interlinks with the actin cytoskeleton via binding interactions with actinassociated proteins, such as talin, α‐actinin, vinculin, and paxillin. This localized membrane/cytoskeletal microdomain also has been found to contain molecules that are thought to mediate chemical signaling by ECM (for example, the protein kinases, c‐src and FAK kinase). The precise location of these proteins within the complex is currently unknown.



Figure 7.

Extracellular matrix (ECM) mechanics and control of cell function. Cells exert tension on their ECM adhesions. Highly adhesive ECM substrata that are malleable (for example, native collagen gels, Matrigel, thin silicone rubber) can not resist cytoskeletal tension and thus they promote cell rounding. However, if the same substrata are made rigid (for example, due to chemical crosslinking or immobilizing the gel on a dish), they support cell extension. Similar changes in cell shape can be induced by varying the ability of a rigid substratum to resist cell tension. This can be done by changing the density of a single type of purified ECM molecule (for example, fibronectin, laminin, or different collagen types) that is preadsorbed on otherwise nonadhesive dishes. For many cell types, round cells tend to maintain high levels of tissue‐specific functions, whereas spread cells turn off differentiation and switch on growth, regardless of the method of cell shape control (see text for appropriate references).

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Donald E. Ingber. Extracellular Matrix: A Solid‐State Regulator of Cell form, Function, and Tissue Development. Compr Physiol 2011, Supplement 31: Handbook of Physiology, Cell Physiology: 541-556. First published in print 1997. doi: 10.1002/cphy.cp140112