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Tissue repair: when macrophages lead the way



Through an international collaboration, researchers from the LRTS laboratory (IRCM/CEA-Jacob) have characterized the cellular and molecular events regulating the balance between fibrotic repair and tissue regeneration and have identified a key player in this balance : macrophages. This study, published in Science Advances, opens up a new therapeutic perspective for the treatment of pathological tissue lesions.

Published on 31 March 2020

The ability to repair tissue is essential for the survival of an organism. It involves the restoration of tissue architecture and tissue function after injury. Two processes can take place in the injured tissue: regeneration (to maintain function) or healing.

Tissue regeneration occurs through the proliferation of cells that retain the ability to divide, or replacement by tissue stem cells.

Wound healing occurs through the formation of connective (fibrous) tissue that provides architectural stability so that the altered tissue is able to function.

For example, the skin, which acts as a barrier essential to maintaining the body's integrity, is at the forefront of the response to environmental aggression. The initial scar response consists of the formation of tissue to compensate for the loss of substance and restore its barrier function. However, when the inflammation persists, a pathological scar response takes place, leading to the development of fibrous tissue: this is the process of fibrosis1.

Skin lesions mostly result in fibrotic scars, but may in some cases give rise to a beneficial regenerative repair response.

As part of an international collaboration, researchers from the LRTS laboratory (IRCM) have characterized the cellular and molecular events regulating the balance between fibrotic repair and tissue regeneration and have identified a key player in this balance: macrophages.

This study is based on the use of a mouse model mimicking the repair process following a skin injury. The researchers showed the importance of macrophages2 during the early stages of tissue repair and that their persistence over time in the skin wound was directly linked to a fibrotic process.

In addition, macrophages present late in the skin wound phagocyte and degrade an inhibitor (SFRP4) of a major metabolic pathway, the Wnt pathway. This leads to chronic activation of this pathway and consequently to skin fibrosis. The suppression of phagocytosis is sufficient to reverse the balance between fibrosis and skin regeneration. This mechanism would thus be a new pathway to target for the repair of skin fibrosis. In addition, this study showed that elements involved in the reconstruction of the damaged environment (such as fibronectin) could be key mediators in the mechanism of triggered phagocytosis.

This analysis has been deepened by studying the phenomenon in patients suffering from a chronic, recurrent and highly incapacitating skin pathology: suppurated hidradenitis. The lack of curative treatment and the recurrent nature of hidradenitis complicate its treatment.

The researchers observed in these patients that phagocytosis of the Wnt pathway inhibitor by macrophages was perfectly correlated with wound repair by a fibrotic process.

These results indicate that the mechanism identified is a major contributor to skin fibrosis and underline the importance of modulation of the Wnt pathway in tissue repair. Modulation of the regenerative activity of macrophages in this context opens up a new therapeutic perspective in the treatment of pathological or injury-induced tissue damage.


1: Fibrosis is characterized by an abnormal development of connective tissue, with proliferation and differentiation of fibroblasts in the dermis into myofibroblasts leading to significant development of extracellular matrix.
2: Macrophages are known to play a central role in the healing process and are involved in all stages of tissue repair. In the initial phase, they eliminate dead cells, protect the damaged tissue from microbial infection and regulate the inflammatory response. In the repair phase (scar tissue formation), they produce pro-angiogenic mediators and epithelial growth factors, which are necessary to repair the damaged tissue.


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