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

Abstract

Our skin is continuously exposed to mechanical challenge, including shear, stretch, and compression. The extracellular matrix of the dermis is perfectly suited to resist these challenges and maintain integrity of normal skin even upon large strains. Fibroblasts are the key cells that interpret mechanical and chemical cues in their environment to turnover matrix and maintain homeostasis in the skin of healthy adults. Upon tissue injury, fibroblasts and an exclusive selection of other cells become activated into myofibroblasts with the task to restore skin integrity by forming structurally imperfect but mechanically stable scar tissue. Failure of myofibroblasts to terminate their actions after successful repair or upon chronic inflammation results in dysregulated myofibroblast activities which can lead to hypertrophic scarring and/or skin fibrosis. After providing an overview on the major fibrillar matrix components in normal skin, we will interrogate the various origins of fibroblasts and myofibroblasts in the skin. We then examine the role of the matrix as signaling hub and how fibroblasts respond to mechanical matrix cues to restore order in the confusing environment of a healing wound.

Pathophysiology of systemic sclerosis (scleroderma)

“…Myofibroblast transdifferentiation is also highly dependent on mechanical tension, which is significantly increased in the ECM of SSc tissues 84 . Mechanical tension is mediated to the fibroblasts via integrins and key components in focal adhesions 85,86 .…”

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

“…It is morphologically and functionally different from the native tissue as regards extracellular matrix (ECM) organization (in particular, collagen quality and assembly) and other features: for example, skin wounds heal with scars lacking hairs and glands ( Thulabandu et al, 2017 ). Therefore, the repair is considered successful when it ends with the formation of a limited amount of scar tissue that restores the integrity of the protective barrier and preserves organ function and tissue integrity ( Sawant et al, 2021 ). However, mammalian embryos (including human ones) can regenerate in the early stages of development, and oral mucosa wounds can heal nearly scarless also in adults ( Peake et al, 2014 ).…”

“…The fibroblast-myofibroblast transdifferentiation is mainly regulated by TFG-β1 and ECM stiffness. Myofibroblasts assume contractile properties by incorporating α-smooth muscle actin (α-SMA) into stress fibers ( Sawant et al, 2021 ). The contractile activity not only causes wound contraction but also increases ECM stiffness, which in turn induces myofibroblast differentiation and persistence ( Grinnell and Petroll, 2010 ).…”

Downregulation of senescence-associated secretory phenotype by knockdown of secreted frizzled-related protein 4 contributes to the prevention of skin aging

“…In particular, single-cell RNAseq revealed increased SFRP4 in different subgroups of fibroblasts isolated from systemic sclerosis interstitial lung disease (ILD) biosamples, which were hypothesized to be progenitor cells of myofibroblasts [34]. Even in normal skin, abnormal fibroblast activation and inadequate extracellular matrix deposition have been implicated in the aging skin phenotype [35], suggesting that SFRP4 expression in dermal fibroblasts may influence the skin phenotype associated with aging. However, the mechanisms by which SFRP4 is upregulated in dermal fibroblasts with aging are not fully understood, and should be investigated through comprehensive genetic and cascade analyses.…”