The effects of mechanical force on fibroblast behavior in cutaneous injury

Abstract

Wound healing results in the formation of scar tissue which can be associated with functional impairment, psychological stress, and significant socioeconomic cost which exceeds 20 billion dollars annually in the United States alone. Pathologic scarring is often associated with exaggerated action of fibroblasts and subsequent excessive accumulation of extracellular matrix proteins which results in fibrotic thickening of the dermis. In skin wounds, fibroblasts transition to myofibroblasts which contract the wound and contribute to remodeling of the extracellular matrix. Mechanical stress on wounds has long been clinically observed to result in increased pathologic scar formation, and studies over the past decade have begun to uncover the cellular mechanisms that underly this phenomenon. In this article, we will review the investigations which have identified proteins involved in mechano-sensing, such as focal adhesion kinase, as well as other important pathway components that relay the transcriptional effects of mechanical forces, such as RhoA/ROCK, the hippo pathway, YAP/TAZ, and Piezo1. Additionally, we will discuss findings in animal models which show the inhibition of these pathways to promote wound healing, reduce contracture, mitigate scar formation, and restore normal extracellular matrix architecture. Recent advances in single cell RNA sequencing and spatial transcriptomics and the resulting ability to further characterize mechanoresponsive fibroblast subpopulations and the genes that define them will be summarized. Given the importance of mechanical signaling in scar formation, several clinical treatments focused on reducing tension on the wound have been developed and are described here. Finally, we will look toward future research which may reveal novel cellular pathways and deepen our understanding of the pathogenesis of pathologic scarring. The past decade of scientific inquiry has drawn many lines connecting these cellular mechanisms that may lead to a map for the development of transitional treatments for patients on the path to scarless healing.

Roles of Mechanosensitive Channel Piezo1 in Wound Healing and Scar Formation

“…While enhanced motility was noted in stretch-activated primary human fibroblasts [ 112 ], Piezo1 activation in mouse transformed 3T3B-SV40 fibroblasts inhibited cell migration [ 114 ]. However, experiments on the force-induced differentiation of fibroblasts to myofibroblasts have demonstrated more uniform results [ 112 , 115 , 116 , 117 , 118 ]. While the Transforming Growth Factor-β1(TGF-β1) is considered to be the principle soluble factor involved in myofibroblast differentiation, there is strong evidence that mechanical force plays a major role in fibroblast-to-myofibroblast differentiation.…”

“…Extensive experimental and clinical research has described mechanical loading as a significant and contributing factor in the development of hypertrophic scarring, with an increase in both cell density and volume [ 6 , 118 , 120 , 121 , 122 ]. In experiments conducted by He et al, a link between Piezo1 and excessive matrix production by dermal fibroblasts was accurately shown [ 112 , 119 ].…”

Natural Compounds and Biomimetic Engineering to Influence Fibroblast Behavior in Wound Healing

“…Sarıçiçek ( Achillea biebersteinii Afan ), a member of the Asteraceae family high in phenolic acids and flavonoids, widely utilized for wound healing in Mediterranean regions, inhibits scar formation by modulating the expression of TGF-β1 and basic fibroblast growth factor (bFGF) at both the gene and protein levels in murine embryonic fibroblasts [ 45 , 50 ]. These growth factors promote wound healing via fibroblast proliferation and granulation tissue formation [ 10 ]. Similarly, traditional Chinese herbs rich in saponins and flavonoids, such as Astragali Radix , Rehmanniae Radix , and Centella Asiatica , have been shown to modulate human skin fibroblast migration activities through the TGF-β1 pathway, ECM synthesis through the Suppressor of Mothers Against Decaptentaplegic (Smad) pathway, and cell motility through the Ras/MAPK (non-Smad) pathway [ 52 , 70 ].…”

“…During the proliferation phase, fibroblasts play a pivotal role in wound remodeling by secreting matrix metalloproteinases (MMPs) to break down the fibrin clot [ 9 ]. Fibroblast growth factor (FGF) and TGF-β induce fibroblast proliferation and granulation tissue formation, facilitating the production of ECM molecules for keratinocyte migration [ 10 ]. In the remodeling phase, fibroblasts remodel the ECM and differentiate into myofibroblasts, regulating mechanical wound contraction [ 11 ].…”