The Contractile Phenotype of Dermal Fetal Fibroblasts in Scarless Wound Healing

Abstract

Purpose of Review Injured skin in the mammalian fetus can heal regeneratively due to the ability of fetal fibroblasts to effectively reorganize the extracellular matrix (ECM). This process occurs without fetal fibroblasts differentiating into highly contractile myofibroblasts which cause scarring and fibrosis in adult wounds. Here, we provide a brief review of fetal wound healing and the evidence supporting a unique contractile phenotype in fetal fibroblasts. Furthermore, we discuss the biomechanical role of the ECM in driving myofibroblast differentiation in wound healing and the implications for new clinical modalities based on the biophysical properties of fetal fibroblasts. Recent Findings We and others have found that fetal fibroblasts are refractory to the environmental stimuli necessary for myofibroblast differentiation in adult wound healing including mechanical stress. Summary Understanding the biomechanical mechanisms that regulate the contractile phenotype of fetal fibroblasts may unlock new avenues for anti-scarring therapies that target myofibroblast differentiation of adult fibroblasts.

The altered mechanical phenotype of fetal fibroblasts hinders myofibroblast differentiation

“…TGF‐β1 is a major regulator of myofibroblast differentiation and works synergistically with ECM rigidity to promote this phenotype . As the rigid PAAs fall within the mechanical range for inducing myofibroblast differentiation and led to differences in force production (Figure B and E), we treated adult and fetal fibroblasts with TGF‐β1 for 4 days and once again evaluated traction force generation and focal adhesion formation on rigid PAAs (same strains as Figures D–F and D–F).…”

“…As these forces increase and focal adhesions mature in response to increasing ECM stiffness or rigidity, a mechanical threshold is reached in which fibroblasts can incorporate α‐smooth muscle actin (α‐SMA) into stress fibers and increase collagen production which are hallmarks of myofibroblast differentiation . Myofibroblasts then utilize this contractile machinery rich in α‐SMA to generate large traction forces which excessively contract and remodel the newly deposited, collagenous ECM leading to scarring . In addition to mechanical stress, the cytokine transforming growth factor‐β1 (TGF‐β1) is also necessary to promote α‐SMA expression and collagen synthesis .…”

“…Myofibroblasts then utilize this contractile machinery rich in α‐SMA to generate large traction forces which excessively contract and remodel the newly deposited, collagenous ECM leading to scarring . In addition to mechanical stress, the cytokine transforming growth factor‐β1 (TGF‐β1) is also necessary to promote α‐SMA expression and collagen synthesis . Therefore, both biochemical and biomechanical factors work synergistically to regulate the transition to a myofibroblast phenotype and fibrotic healing.…”

“…However, we previously found that mechanical stress generated by contracting fibroblasts in anchored type I collagen gels promotes the formation of stress fibers containing α‐SMA in adult but not fetal fibroblasts . Despite the differences in the fetal wound environment, these results suggest that fetal fibroblasts exhibit distinct responses to mechanical factors that limit their ability to differentiate into myofibroblasts . Therefore, the goal of this study was to systematically test whether physiologic rigidities and TGF‐β1 regulate the contractile and adhesive properties necessary for myofibroblast differentiation of fetal fibroblasts using a polyacrylamide gel (PAA) system that spans the mechanical properties reported for different wound healing stages.…”

GMP-Compliant Human Fetal Skin Fibroblasts for Wound Healing

“…Fibroblasts, as wide spread cells of complex organisms contribute to wound healing of injured tissues with their ability to synthesize collagen resulting in wound edges closure (1)(2)(3)(4). Wound healing is an intricate process composed of a set of physiological events that recruits various cell types to fulfill their function in order to close the wound.…”