Our group was amongst the first to show how embryos can heal wounds without scarring. We speculated that this period of scar-free repair might be related to the observed failure of embryos to raise a robust inflammatory response until precisely the stage in embryonic development (about 2/3^rds through gestation in mouse and man) when scarring becomes an inevitable consequence of tissue healing.   Using a PU.1 knock-out mouse line that is deficient in all innate immune cells and thus incapable of raising an inflammatory response, we showed that neonatal repair without inflammation was as efficient as in wild type mice that do raise a wound inflammatory response, which demonstrated that inflammation per se is not essential for tissue repair beyond embryonic stages.  Even more strikingly, the PU.1 wounds healed without a scar showing that inflammation is causal of scarring.  We went onto search for inflammation-dependent, “scarring” genes and found the secreted, integrin binding protein, osteopontin to be such a gene/protein; when we knocked down osteopontin by delivery of antisense oligomers to the wound via a slow release Pluronic gel we observed dramatically reduced scarring, thus providing a lead towards potential anti-scarring therapeutics.

To understand the wound inflammatory response better we established novel in vivo models of inflammation in Drosophila and zebrafish that have, for example, enabled us to determine precisely how the actin and microtubule cytoskeletal machineries are regulated to drive the leukocyte wound migration response. We have gone on to use Drosophila genetics and imaging approaches, as well as mathematical modelling, to unravel elements of the signalling cascade activated by tissue damage including calcium signalling, and release of hydrogen peroxide which lead to inflammatory cell recruitment. 

Helen Weavers described how our collaboration with the Stumpf maths lab at Imperial allowed us to figure out key characteristics of the immune cell attractant released by wounds that had not previously been determined by biology alone.  These studies highlighted that the attractant diffuses much slower than the small molecules, like H₂O₂, that we and others had presumed were the sole damage signals.

Recently we showed that engulfment of apoptotic corpses is an essential initial priming trigger before macrophages can respond to these damage attractant cues, or to infection.

Helen Weavers and team talk through a “scribble video” explaining how genetic and cell biology studies in the fly embryo have revealed that before a macrophage is able to respond to the damage attractants that might attract it to a wound or to a site of infection, it must first be primed by engulfing/phagocytosing at least one apoptotic corpse.

Since the zebrafish larvae is translucent and each of the contributing cell lineages and collagen itself can be fluorescently tagged, we are currently using zebrafish to observe in real time how immune cells are recruited to various wounds (eg acute wound versus a chronic foreign body response), and precisely how these cells interact with wound stromal cells to lead fibroblasts to deposit collagen in a pathological fashion that results in a scar.

These studies in fish and flies are designed to offer useful insights for the clinic.  For example, a recent maths modelling study of wound inflammation in Drosophila pupae indicates that dynamic immune cell motility assays, rather than static gene/microbiome analyses of patient biopsy tissue, might provide a better prognostic tool to determine whether chronic wounds are likely to heal or not.

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Mori, R, Shaw, TJ & Martin, P 2008, 'Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring', Journal of Experimental Medicine, vol. 205 , no. 1, pp. 43 - 51. https://doi.org/10.1084/jem.20071412

Jones, RA, Feng, Y, Worth, AJ, Thrasher, AJ, Burns, SO & Martin, P 2013, 'Modelling of human Wiskott-Aldrich syndrome protein mutants in zebrafish larvae using in vivo live imaging', Journal of Cell Science, vol. 126, no. Pt 18, pp. 4077-84. https://doi.org/10.1242/jcs.128728

Weavers, H, Liepe, J, Sim, A, Wood, W, Martin, P & Stumpf, MPH 2016, 'Systems Analysis of the Dynamic Inflammatory Response to Tissue Damage Reveals Spatiotemporal Properties of the Wound Attractant Gradient', Current Biology, vol. 26, no. 15, pp. 1975-1989. https://doi.org/10.1016/j.cub.2016.06.012

Weavers, H, Evans, IR, Martin, P & Wood, W 2016, 'Corpse engulfment generates a molecular memory that primes the macrophage inflammatory response', Cell, vol. 165, no. 7, pp. 1658-1671. https://doi.org/10.1016/j.cell.2016.04.049

Gurevich, D, French, K, Collin, J, Cross, S & Martin, P 2019, 'Live imaging the Foreign Body Response reveals how dampening inflammation reduces fibrosis', Journal of Cell Science. https://doi.org/10.1242/jcs.236075

López-Cuevas, P, Cross, SJ, Martin, P 2021, 'Modulating the Inflammatory Response to Wounds and Cancer Through Infection', Frontiers in Cell and Developmental Biology. https://doi.org/10.3389/fcell.2021.676193