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Heavy mice and lighter things: developing models of extracellular matrix in health and ageing

Professor of Biological and Biomedical Chemistry, University of Cambridge

The extracellular matrix (ECM) forms the bulk of our structural tissues and provides them with their particular mechanical properties. At the microscopic level, it provides the scaffold which supports cells but more intriguingly, at the molecular level, it provides the communication system between the cells in the tissue and the signals that drives the individual behaviour of cells. Ultimately, if we can understand how the extracellular matrix molecular structure and dynamics dictates the behaviour of cells, then we can develop ways to combat the effects of ageing, for instance, by doing chemistry in the extracellular matrix to drive the necessary change in cell behaviour. However, understanding the molecular level properties of the extracellular matrix has been hampered by the lack of methods to study tissues at the atomic scale. In this talk, I will describe the interdisciplinary approaches my group has taken over the last decade to tackle these complex questions, including in calcified tissues, both physiologically calcified bone and pathological vascular calcification.

Solid-state NMR spectroscopy underpins much of my work, offering a means to assess molecular structural changes in intact biological tissues. The first requirement for using solid-state NMR spectroscopy to study the molecular structures is native-like tissues in which we can introduce NMR -active stable nuclear isotopes,[1] 13C and 15N. Using multidimensional solid-state correlation NMR spectra (13C-13C, 13C-15N) as fingerprints of the underlying molecular structures in isotope-labelled native tissues has allowed us to develop laboratory-grown tissues that have demonstrably highly similar molecular structures to native tissues, and thus represent demonstrably good models of native tissue.[1-3] The refined laboratory-grown tissues can then be manipulated by growing them with isotope labels in specific components to allow detailed study of structure and function of the various extracellular matrix components.

We have now coupled this NMR approach with a variety of other methods to examine the chemistry of ageing in the extracellular matrix and of calcification in bone and vascular calcification (hardening of the arteries). We now have an intriguing insight into what may underlie the structural changes in the extracellular matrix with age.

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