Granulation tissue myofibroblasts during normal and pathological skin healing: The interaction between their secretome and the microenvironment

Abstract

The first role that was proposed for the myofibroblasts located in skin granulation tissue was to contract the edges of the wound in order to reduce the surface to be repaired. This role, linked to the presence of alpha smooth muscle actin, was very quickly confirmed and is part of the definition of granulation tissue myofibroblasts.However, myofibroblasts are cells that also play a much more central role in wound healing. Indeed, it has been shown that these cells produce large quantities of matrix components, and that they stimulate angiogenesis and can recruit immune cells.These actions take place via the secretion of molecules into their environment or indirectly via the production of microvesicles containing pro-fibrotic and proangiogenic molecules. Pathologically, granulation tissue can develop into a hypertrophic scar that histologically looks like granulation tissue, but which can remain for months or even years. It has been hypothesized that the myofibroblasts in these tissues remained present instead of disappearing by apoptosis, causing the maintenance of granulation tissue rather than allowing its change into a mature scar. Understanding the roles of both pathological and healthy myofibroblasts in wound tissue is crucial in order to better intervene in the healing mechanism.

Role of fibroblasts in wound healing and tissue remodeling on Earth and in space

“…Proper timing for resolution of the inflammation is very important for successful healing progression: a persistent macrophage-fibroblast activation state, with excessive production of pro-inflammatory mediators by fibroblasts and further recruitment of immune cells, generates a feed-forward loop leading to altered repair processes from chronic wounds to fibrosis and scarring ( Wynn, 2008 ; Grinnell and Petroll, 2010 ; Wynn and Ramalingam, 2012 ). For example, the excessive fibroblast activity, often occurring in large burns and severe injuries, results in hypertrophic scarring and keloid formation (i.e., dysfunctional and disfiguring scar tissue) ( Hinz, 2016 ; Arif et al, 2021 ). The persistence of myofibroblast activity can also be caused by altered signaling pathways ( Leask, 2021 ), apoptosis failure ( Hinz and Lagares, 2020 ), and excessive mechanical stress, as in the case of high strains at the wound edges ( Wong et al, 2011a ) or ECM stiffness ( Sawant et al, 2021 ).…”

A story of fibers and stress: Matrix‐embedded signals for fibroblast activation in the skin

“…However, excessive dysregulated fibroblast activities, for instance in response to large area burns or trauma with or without underlying genetic predispositions, can result in severe hypertrophic scarring or keloid formation. [14][15][16][17] Fibrosis and scarring ensue when normal skin repair persists, for instance when myofibroblast fail to die 18,19 or when danger signals and inflammation become chronic like in systemic sclerosis. 20,21 Functional skin becomes then replaced by dysfunctional and disfiguring scar tissue.…”

Resina Draconis Particles Encapsulated in a Hyaluronic-Acid-Based Hydrogel to Treat Complex Burn Wounds

“…In the process of tissue injury, in order to replace the necrotic parenchyma, the surrounding immature connective tissue can proliferate to form a red granular soft tissue called granulation tissue [ 42 ]. The formation of granulation tissue is a key link in wound repair [ 43 ].…”