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Remodelling the extracellular matrix in development and disease

Nature Reviews Molecular Cell Biology volume 15, pages 786–801 (2014)Cite this article

Subjects

Key Points

  • The extracellular matrix (ECM) is a dynamic structure that is constantly remodelled to control tissue homeostasis.

  • The ECM in mammals is composed of around 300 proteins, known as the core matrisome.

  • Metalloproteinases are the main endopeptidases responsible for ECM degradation. These enzymes can also generate ECM fragments with different bioactive properties than their full-length proteins. These matrikines regulate many processes such as migration, adhesion and differentiation.

  • ECM remodelling is important during organogenesis and development of the intestine, mammary and salivary glands and lung.

  • Dysregulation of the ECM composition and structure and mutations in genes that affect ECM remodeling can lead to several severe human conditions, including fibrosis and cancer.

  • ECM components and the proteins that regulate ECM remodelling represent promising therapeutic targets. Additional preclinical and clinical studies are required to fully understand the role of the ECM in human disease.

Abstract

The extracellular matrix (ECM) is a highly dynamic structure that is present in all tissues and continuously undergoes controlled remodelling. This process involves quantitative and qualitative changes in the ECM, mediated by specific enzymes that are responsible for ECM degradation, such as metalloproteinases. The ECM interacts with cells to regulate diverse functions, including proliferation, migration and differentiation. ECM remodelling is crucial for regulating the morphogenesis of the intestine and lungs, as well as of the mammary and submandibular glands. Dysregulation of ECM composition, structure, stiffness and abundance contributes to several pathological conditions, such as fibrosis and invasive cancer. A better understanding of how the ECM regulates organ structure and function and of how ECM remodelling affects disease progression will contribute to the development of new therapeutics.

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Figure 1: Structure and targets substrates of metalloproteinases.
Figure 2: Extracellular matrix remodelling during intestinal development.
Figure 3: Extracellular matrix remodelling during branching morphogenesis.
Figure 4: Aberrant extracellular matrix remodelling leads to numerous human diseases.

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Acknowledgements

This study was supported by funds from the National Cancer Institute (grant numbers CA057621 and CA138818), a Department of Defense (DOD) Era of Hope Scholar Expansion grant (BC122990) and Institut National de la Santé et de la Recherche Médicale (INSERM).

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  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Anatomy, University of California, 513 Parnassus Avenue, San Francisco, 94143–0452, California, USA

    Caroline Bonnans, Jonathan Chou & Zena Werb

  2. Oncology Department, INSERM U661, Functional Genomic Institute, 141 rue de la Cardonille, Montpellier, 34094, France

    Caroline Bonnans

  3. Department of Medicine, University of California, 513 Parnassus Avenue, San Francisco, 94143–0452, California, USA

    Jonathan Chou

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  1. Caroline Bonnans
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Correspondence to Zena Werb.

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PowerPoint slides

Glossary

Basement membrane

The ECM layer that is located basolaterally to all epithelium and endothelium in the body. It provides structural support to the tissue and modulates epithelial and endothelial cell functions. It is mostly composed of collagen IV and laminins.

TGFβ

(Transforming growth factor-β). The TGFβ isoforms (TGFβ1–TGFβ3) are synthesized as latent precursors in complex with both latency-associated peptide (LAP) and latent TGFβ-binding proteins (LTBPs). Proteinases such as plasmin and MMPs catalyse the release of active TGFβ from the complex.

Zymogens

Proenzymes that are inactive enzyme precursors. Zymogens need to be biochemically modified to become active enzymes.

Integrins

Heterodimeric cell surface receptors that mediate cell–cell and cell–ECM interactions and orchestrate cell attachment, movement, growth, differentiation and survival.

von Willebrand factor

A blood glycoprotein that is involved in haemostasis and is defective in von Willebrand disease. This factor is also increased in the plasma of cardiovascular, neoplastic and connective tissue diseases and can contribute to an increased risk of thrombosis.

Villi

A finger-like projection that protrudes from the epithelium of the intestinal wall. Intestinal villi increase the epithelium surface area to promote the absorption of nutrients.

Intestinal crypts

(Also known as crypts of Lieberkühn). Proliferative compartments found in the small intestine and the colon; they contain intestinal stem cells and other specialized cells such as Paneth cells (only in the small intestine) and goblet cells.

Intestinal stem cells

Undifferentiated cells that can self-renew and differentiate into all of the specialized cell types of the tissue or organ. The main role of stem cells is to maintain and repair the tissue in which they reside.

RGD-dependent integrins

A group of integrins that specifically recognize the RGD motif, a sequence of three amino acids (Arg-Gly-Asp) found in many ECM molecules such as fibronectin and osteopontin. Collectively, these interactions are termed the RGD-dependent adhesion system.

Anoikis

A programmed cell death that is induced by lack of correct cell–ECM interactions. Invasive tumour cells may escape from anoikis to target different metastatic organs.

Organoids

Organ epithelial fragments that resemble the whole organ in structure and function during three-dimensional culture.

Stem cell niche

A specialized microenvironment that interacts with cells such as stem cells or tumour cells to regulate their fate.

E-cadherin

A calcium-dependent cell–cell adhesion molecule with pivotal roles in epithelial cell behaviour, tissue formation and suppression of cancer.

Matrikines

ECM fragments released from the ECM by proteolysis or by cryptic site exposure; they have biological activities that are different from those of the full-length protein.

Matrigel

A gelatinous protein mixture secreted by Engelbreth–Holm–Swarm (EHS) mouse sarcoma cells. It contains structural proteins such as laminin, entactin, collagen and HSPGs. Growth factors such as TGFβ and EGF are also present in Matrigel, although growth factor-reduced formulations are also available.

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Bonnans, C., Chou, J. & Werb, Z. Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol 15, 786–801 (2014). https://doi.org/10.1038/nrm3904

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