Mechanosensing in Monocytes and Macrophages Induces Scar Tissue Formation
Scar tissue is formed by excess deposition of extracellular matrix molecules such as collagen. It obstructs complete healing. In aged tissues, fibrosis is a form of inappropriate scarring and consequent loss of function produced by the disruption of normal tissue maintenance. Researchers here provide evidence for scarring following injury to be driven by a subpopulation of monocytes and macrophages, types of myeloid immune cell. The pro-fibrotic behavior of these cells is triggered by mechanical cues. Mechanosensing is a complex set of regulatory pathways by which cells react to the mechanical properties of the surrounding environment, such as degree of tissue stiffness or mechanical stresses placed upon the tissue. These regulatory pathways can be manipulated via drugs and genetic engineering, just like others, and this opens the door to a novel approach to reducing scar formation following injury.
In response to injury, a variety of different cells are recruited to sites of injury to facilitate healing. Recent studies have examined the importance of the heterogeneity of tissue resident fibroblasts and mechanical signalling pathways in healing and fibrosis. However, tissue repair and the inflammatory response also involves blood cells that are recruited from the circulation.
Here we identify mechanoresponsive myeloid subpopulations present in scar and unwounded skin. We then modulate these subpopulations by manipulating mechanical strain in vivo and in vitro and find that specifically targeting myeloid mechanical signalling is sufficient to reduce the pro-fibrotic myeloid subpopulations and restore the native, anti-inflammatory subpopulations.
In addition, myeloid-specific mechanotransduction ablation also downregulates downstream pro-fibrotic fibroblast transcriptional profiles, reducing scar formation. As inflammatory cells circulate and home to injury sites during the initial healing phases in all organs, focusing on mechanoresponsive myeloid subpopulations may generate additional directions for systemic immunomodulatory therapies to target fibrosis and other diseases across other internal organ systems.