By Josephine Adams
The extracellular matrix (ECM) has fascinated me ever since I was a student, newly introduced to the concept that interactions between cells build and sustain multi-cellular tissues. Unlike the cells of plants or fungi, animal cells have no cell wall: molecules secreted by animal cells into the extracellular space can bind directly to plasma membrane receptors to influence gene expression and cell behaviour. This means that any dynamic change in the repertoire of ECM proteins secreted will feedback reciprocally to alter the functional state of cells in the surrounding tissue.
A second aspect of ECM proteins that intrigues me is their structure. Many ECM proteins are over 1000 amino acids long (the average length of proteins in different organisms is between 250-400 amino acids), and their polypeptide sequences are often built up of repeated copies of short amino acid motifs or small domains. After secretion, ECM proteins typically assemble in fibrils or networks (Fig.1) that provide structural and mechanical support in tissues, as well as holding cells in place by binding to cellular receptors. These properties pique the curiosity of cell biologists and biochemists: how are ECM molecules prevented from assembling with one another before they are secreted? After secretion, what processes drive the controlled assembly of different types of ECM structures?
Although research from around the world over the last 20-30 years has provided a framework of answers, many steps or details remain unclear. In devising the “Extracellular Matrix” issue of Essays in Biochemistry, I chose to focus on these uncertain areas, to invite articles that would bring together current knowledge and also point out unanswered questions and research directions for the future. It is not possible to include the whole vast field of ECM research in a volume of this type. So I selected several ECM proteins that are absolutely central to the assembly of ECM networks in vertebrate animals.
Readers will find articles on laminin and the collagens that form basement membranes, which are sheet-like ECM structures that provide structural support and form barriers beneath epithelial or endothelial cells (Fig.2).
Also vital for vertebrate animals are the elastic fibrils that give elastic recoil properties to blood vessel walls, skin, lungs and other tissues, so that they maintain shape and function after mechanical stretching. The article by Shin and Yanagisawa discusses the multi-step mechanisms for assembly of elastic fibrils. Fibril-forming collagens are the most abundant proteins in many tissues, yet many aspects of their synthesis, secretion and control of fibril turnover remain enigmatic. This important area is featured in five other articles from world-leading experts that discuss steps in the complex intracellular and extracellular mechanisms for assembly and function of the massive extracellular fibre bundles of collagens (Fig. 2).
Fig. 2. Scanning electron microscopy view of a basement membrane and underlying collagen fibres. The epithelial cell layer has been pushed back to show the ECM structures. Courtesy of R.L. Trelstad, reproduced from Alberts et al., Molecular Biology of the Cell
A second theme within the issue addresses the molecular complexity of ECM. The human genome encodes around 300 different ECM proteins, and proteomic analysis of ECM is enabling researchers to enumerate the diversity of ECM composition in different tissues (see article by Taha and Naba). I have a strong interest in applying an evolutionary framework to this complexity. By distinguishing which ECM proteins originated earliest in the evolution of animals, we can build models about which represent an ‘ancestral ECM’; this may help make predictions about the most suitable therapeutic targets. This evolutionary perspective is incorporated in the articles that discuss the ECM of modern representatives of some of the earliest animals to evolve: ctenophores and sponges (Draper et al.), and the cnidarians (Özbek and colleagues). Over the next decade, I expect biochemical knowledge of ECM biology to continue to expand, and this will drive better insights into potential drug targets.
About the author:
Josephine Adams is Professor of Cell Biology in the School of Biochemistry, University of Bristol. Her research focuses on signalling from the extracellular matrix to the actin cytoskeleton, with emphasis on thrombospondins and their roles in extracellular matrix organisation and cell-matrix adhesion under normal conditions, cancer progression, or fibrosis. She is also interested in the evolution of extracellular matrix.
Read the full issue of Essays in Biochemistry – The Extracellular Matrix here.
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