Various forms of fibrosis, including tissue thickening and scarring, make up 40% of deaths worldwide. Since the discovery of scarless functional healing in fetuses before a particular stage of development, scientists have tried to replicate scarless wound healing in adults with little success. Although studies have investigated the extracellular matrix (ECM), fibroblasts, and inflammatory mediators as separate branches of biology, it is crucial to consider them as parts of a complex and tightly regulated system that becomes dysregulated in fibrosis. With this new paradigm, understanding fetal scarless wound healing will provide a unique opportunity to understand how this highly regulated system operates mechanistically. 

A recent review navigated wound healing′s four stages (hemostasis, inflammation, repair, and remodeling) regarding adult versus fetal wound healing. Simultaneously it also explored the connection between the ECM, effector cells, and signaling molecules. It concluded by singling out recent findings that offer promising leads to alter the dynamics between the ECM, fibroblasts, and inflammation to promote scarless healing. One significant factor is fibroblast heterogeneity and the predisposition of specific fibroblast subpopulations to scarless healing. 

The interplay of the various factors contributing to fibrosis in fetal wound healing provides new research directions for understanding and addressing fibroproliferative diseases like idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis.

Moretti L, Stalfort J, Barker TH, Abebayehu D. The interplay of fibroblasts, the extracellular matrix, and inflammation in scar formation. J Biol Chem. 2022 Feb;298(2):101530. doi: 10.1016/j.jbc.2021.101530. Epub 2021 Dec 23. PMID: 34953859; PMCID: PMC8784641.