New paradigms in fibroblast-immune cells coordination in matrix homeostasis in health and disease

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Collagen is the most abundant protein in the human body (~25% by mass), and is formed into long fibrils that provide structure to organs with very different functions and mechanical properties (e.g. giant parallel bundles in tendons, smooth flat lattices in lungs). This suggests a fine control of the cells in producing and assembling these long fibrils, and dysregulation of this control underpins many pathologies, including fibrosis, heart disease, and many age-related conditions such as proneness to fractures, skin looseness, and osteoarthritis. Convention dictates that different cells have different functions - notably fibroblasts are the key arbiters to collagen matrix formation, and immune cells are the removers; however, recently it has been discovered that immune cells directly contribute to the production of collagen. This highlights how despite collagen's clear fundamental importance, we still do not fully understand the process of its assembly and maintenance, in particular how different types of cells communicate and cooperate with one another in this process. This forms the basis and goals of my research. My recent work has shown that the circadian rhythm controls collagen production and secretion, and I have also discovered that a specialised compartment of the cells (known as the endosome) holds the key to the fate of collagen within the cells, i.e. whether they will be made into fibrils, simply secreted out of the cells, or degraded. Using new mass spectrometry approaches that I have pioneered, I aim to determine how this control of fibril formation happens at the molecular level, as knowledge of how to direct collagen between the different fates will allow for new therapeutic strategies for fibrosis - a disease characterised by an abundance of collagen fibrils that currently has no effective cure. Using the same mass spectrometry technique, I will further determine the molecular networks in immune cells that control collagen uptake, which may provide further insights to targeting fibrosis from a different angle. This knowledge will also be fundamental to other conditions heavily involving the immune system and matrix, including wound healing and cancer metastasis. I have also found that immune cells induce fibroblast circadian rhythms, and that fibroblasts and immune cells make more collagen fibrils when they are mixed together. I will interrogate this relationship and determine the proportion of collagen produced by each cell type in the mixtures, using state-of-the-art genetic modification and high throughput biochemical assays, providing important insights into how fibroblasts and immune cells communicate and coordinate in collagen deposition. As such, my work has important and fundamental implications to further our mechanistic understanding of fibrotic responses, in its broadest sense.