Keratinocyte–Fibroblast Interactions in Wound Healing

Abstract

Cutaneous tissue repair aims at restoring the barrier function of the skin. To achieve this, defects need to be replaced by granulation tissue to form new connective tissue, and epithelial wound closure is required to restore the physical barrier. Different wound-healing phases are recognized, starting with an inflammation-dominated early phase giving way to granulation tissue build-up and scar remodeling after epithelial wound closure has been achieved. In the granulation tissue, mesenchymal cells are maximally activated, cells proliferate, and synthesize huge amounts of extracellular matrix. Epithelial cells also proliferate and migrate over the provisional matrix of the underlying granulation tissue, eventually closing the defect. This review focuses on the role of keratinocyte-fibroblast interactions in the wound-healing process. There is ample evidence that keratinocytes stimulate fibroblasts to synthesize growth factors, which in turn will stimulate keratinocyte proliferation in a double paracrine manner. Moreover, fibroblasts can acquire a myofibroblast phenotype under the control of keratinocytes. This depends on a finely tuned balance between a proinflammatory or a transforming growth factor (TGF)-beta-dominated environment. As the phenotype of fibroblasts from different tissues or body sites becomes better defined, we may understand their individual contribution in wound healing in more detail and possibly explain different clinical outcomes.

Aldara activates TLR7-independent immune defence

“…Stressed or dying keratinocytes commonly release IL-1a, a cytokine that stimulates production of keratinocyte mitogens by stromal cells 28,29 . To determine a possible role of such paracrineacting growth factors in the hyperproliferation induced by Aldara treatment, we demonstrated upregulation of IL-1a mRNA levels 24 h after one topical Aldara treatment (Fig.…”

“…We found that Aldara also activated the NLRP-1 inflammasome in (human) keratinocytes resulting in caspase-1-dependent production of biologically active IL-1b. In addition, Aldara induces expression of G-CSF production by fibroblasts and the induction of S100A8/A9 28,29 and IL-23 production by dermal myeloid cells, which in turn induces IL-17 secretion by dermal gd-T cells 8 . IL-17 and G-CSF have an impact on keratinocytes resulting in their proliferation, whereas S100A8/A9 and CXCL1 are strong chemoattractants for neutrophils.…”

The making of hemidesmosome structures in vivo

“…The hemidesmosomes in healing epithelia resemble C. elegans fibrous organelles in many ways. They are connected to the ECM underlying contracting myofibroblasts, and they undergo a dynamic reorganization process during epidermal cell migration and wound healing (Goldfinger et al, 1999;Werner et al, 2007). If the membrane receptor integrin level is aberrantly elevated, it will create unnecessary adhesion to the ECM and hamper cell migration.…”

An alginate hydrogel matrix for the localised delivery of a fibroblast/keratinocyte co‐culture

“…In addition, it is beneficial to have both the keratinocytes and fibroblasts present, as the paracrine interactions between these two cell types are also very important to F o r P e e r R e v i e w effective healing [13,14]. When co-cultures of these cells are used, however, it is important to mitotically inhibit the fibroblasts to prevent over-growth of the culture.…”