Toward understanding scarless skin wound healing and pathological scarring

Abstract

The efficient healing of skin wounds is crucial for securing the vital barrier function of the skin, but pathological wound healing and scar formation are major medical problems causing both physiological and psychological challenges for patients. A number of tightly coordinated regenerative responses, including haemostasis, the migration of various cell types into the wound, inflammation, angiogenesis, and the formation of the extracellular matrix, are involved in the healing process. In this article, we summarise the central mechanisms and processes in excessive scarring and acute wound healing, which can lead to the formation of keloids or hypertrophic scars, the two types of fibrotic scars caused by burns or other traumas resulting in significant functional or aesthetic disadvantages. In addition, we discuss recent developments related to the functions of activated fibroblasts, the extracellular matrix and mechanical forces in the wound environment as well as the mechanisms of scarless wound healing. Understanding the different mechanisms of wound healing is pivotal for developing new therapies to prevent the fibrotic scarring of large skin wounds.

The Connexin 43 Carboxyl Terminal Mimetic Peptide αCT1 Prompts Differentiation of a Collagen Scar Matrix Resembling Unwounded Skin

“…Mathematical modeling, as well as experimental work, has strongly implicated directionality in the movement of collagensecreting cells as critical to the differentiation of scar ECM. [36][37][38][39][40] These studies includes our own computational simulations, which have elucidated the key role played by gradients of chemokines and mechanical strain in guiding fibroblast homing and the subsequent alignment of collagen bundles laid down by these cells. 41 The models in the present study indicate that the sensitivity of fibroblasts to αCT1 may be strongly influenced by mechanical strain.…”

“…The migratory behavior of fibroblasts, the main ECM-protein-expressing cell-type, canonically strongly influences scar organization. [36][37][38][39][40] To explore the possibility that the changes in scar structure we observed in response to αCT1 were influenced by alterations in cell motility, we undertook experiments on fibroblasts in vitro. As a first step, we surveyed whether fibroblast dynamics altered in response to αCT1 in a standard cell-cultured scratch-wound assay (Fig.…”

The role of the renin‐angiotensin system in skin physiology and pathophysiology

“…A major medical problem resulting from failed control of proliferative and fibrotic processes in wound healing is the formation of hypertrophic scars or keloids. [42] There is evidence that an overactivated cutaneous RAS is involved in this process, because Ang II via the AT 1 R is known to act pro-fibrotic [8,43] and because levels of Ang II and expression of AT 1 Rs and the enzymes catalysing Ang II formation, ACE and chymase, are increased in hypertrophic scars and keloids from rodents and humans. [44][45][46][47] As in other fibrotic conditions, pro-fibrotic signalling of the AT 1 R in hypertrophic scars or keloids involves activation of canonical and non-canonical TGFβ signalling thus leading to increased ECM production, myofibroblast transition and granulation tissue contraction.…”

Clinical Challenge and Call for Research on Keloid Disorder: Meeting Report from The 3rd International Keloid Research Foundation Symposium, Beijing 2019

“…Also, the individuals with Asian ancestral background have a high propensity for development of keloids (Lu et al, 2015). Thus, keloid disorder comprises a prevalent group of debilitating skin conditions with high degree of morbidity (Karppinen et al, 2019;Lyons et al, 2019). Besides aesthetic impact, the lesions are often pruritic and prone to infections, impairing the quality of life of the affected individuals, with no effective and specific treatment currently available.…”