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Mechanisms of assembly and remodelling of the extracellular matrix

Nature Reviews Molecular Cell Biology (2024)Cite this article

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Abstract

The extracellular matrix (ECM) is the complex meshwork of proteins and glycans that forms the scaffold that surrounds and supports cells. It exerts key roles in all aspects of metazoan physiology, from conferring physical and mechanical properties on tissues and organs to modulating cellular processes such as proliferation, differentiation and migration. Understanding the mechanisms that orchestrate the assembly of the ECM scaffold is thus crucial to understand ECM functions in health and disease. This Review discusses novel insights into the compositional diversity of matrisome components and the mechanisms that lead to tissue-specific assemblies and architectures tailored to support specific functions. The Review then highlights recently discovered mechanisms, including post-translational modifications and metabolic pathways such as amino acid availability and the circadian clock, that modulate ECM secretion, assembly and remodelling in homeostasis and human diseases. Last, the Review explores the potential of ‘matritherapies’, that is, strategies to normalize ECM composition and architecture to achieve a therapeutic benefit.

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Fig. 1: Diversity of the core matrisome components.
Fig. 2: Diversity of the matrisome-associated components.
Fig. 3: Structural diversity of extracellular matrices.
Fig. 4: Synthesis, secretion and supramolecular assembly of collagens.
Fig. 5: Mechanism of fibronectin fibrillogenesis.
Fig. 6: Dynamic reciprocity and mechanisms of ECM remodelling.
Fig. 7: Modes of action of matritherapies.

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Acknowledgements

Research in the Naba laboratory is supported in part by grants from the NIH (HG012680, CA261642, GM148423). The author thanks her mentor R. O. Hynes for an introduction to the wonders of the extracellular matrix. The author thanks S. Ricard-Blum for her critical reading of the manuscript and excellent suggestions. The author also acknowledges D. Pally, postdoctoral fellow in the Naba laboratory, for proposing the term ‘matritherapy’. The author apologizes to colleagues whose work could not be cited owing to space limitation.

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  1. Department of Physiology and Biophysics, University of Illinois Chicago, Chicago, IL, USA

    Alexandra Naba

  2. University of Illinois Cancer Center, Chicago, IL, USA

    Alexandra Naba

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Correspondence to Alexandra Naba.

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Competing interests

The Naba laboratory holds a sponsored research agreement with Boehringer-Ingelheim for work not related to the content of this manuscript. A.N. holds a consulting agreement with XM Therapeutics, AbbVie, and RA Capital.

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Nature Reviews Molecular Cell Biology thanks Thomas Cox, Nikos Karamanos and Kenneth M. Yamada for their contribution to the peer review of this work.

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Related links

basement membraneBASE: https://bmbase.manchester.ac.uk/

MatrisomeDB: https://matrisomedb.org

MatrixDB: http://matrixdb.univ-lyon1.fr/

MEROPS peptidase database: https://www.ebi.ac.uk/merops/

Proteomics Standards Initiative: https://hupo.org/Proteomics-Standards-Initiative-(PSI)

SMART: http://smart.embl-heidelberg.de

The Matrixome Project (archived website): https://dbarchive.biosciencedbc.jp/archive/matrixome/bm/AboutProject/DesProject/description.html

The Matrisome Project website: https://matrisome.org

Glossary

Epidermolysis bullosa

Group of rare genetic skin disorders characterized clinically by skin and mucosal blistering and skin fragility.

Immune checkpoint inhibitors

Drugs that block proteins involved in immune checkpoints, the pathways that regulate activation of the immune system. In cancer imunotherapy, these drugs (for example, anti-CTLA4, anti-PD1) are used to activate antitumour immunity.

Intimal rupture

Rupture of the innermost — intimal — layer of a blood vessel wall. The tunica intima is composed of the endothelium and a subendothelial extracellular matrix including a basement membrane and elastic layer in arteries.

Liquid chromatography coupled to tandem mass spectrometry

(LC–MS/MS). Analytical proteomic method that combines peptide separation by LC and the subsequent analysis of these peptides by tandem MS.

Premature termination codon readthrough drugs

Drugs that allow the translation machinery to read through a premature stop codon and promote the synthesis of a full-length protein.

Proteoforms

Different molecular forms of a protein produced from a single gene. Can arise from single amino acid variant, alternative splicing or post-translational modification.

Schwann cells

Glial cells that form the myelin sheath of axons of the peripheral nervous system.

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Naba, A. Mechanisms of assembly and remodelling of the extracellular matrix. Nat Rev Mol Cell Biol (2024). https://doi.org/10.1038/s41580-024-00767-3

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