Importantly, healthy keratinocytes were known to affect extracellular matrix (ECM) deposition and resorption by influencing fibroblasts, favoring resorption over deposition. This inter-relationship is modulated by a variety of other factors which participate to homeostatic crosstalk between keratinocytes and fibroblasts reviewed in. In turn, fibroblasts affect keratinocyte viability, proliferation, and differentiation mainly by producing KGF. Previous work, exploring physiological conditions, demonstrated that keratinocytes stimulate fibroblasts, mainly through the production of interleukin (IL)-1, inducing in fibroblasts the production of keratinocyte growth factor (KGF) also known as fibroblast growth factor 7. Recent work, however, has shown that the homeostatic relationships normally regulating the crosstalk between epidermal and dermal cell constituents is altered in scleroderma, thus reinforcing the concept that keratinocytes may take part to scleroderma pathogenesis. The potential contribution of the epidermis and in particular of keratinocytes to the pathogenesis of dermal fibrosis has been neglected for long time.
#PROTEIN SCAFFOLD INHIBITOR SKIN#
Improved methods for engineering epidermal and skin equivalents are helping to address the question whether keratinocyte alterations in SSc are primary and capable to dysregulate dermal homeostasis or secondary following dermal fibrotic changes. Overall, these data support keratinocyte-intrinsic SSc-related modifications. Further evidence indicated that the relative lack rather than the excess of interleukin-25 in keratinocytes may contribute to enhanced dermal fibrotic changes. SSc-EE supernatants more than HD-EE modified the inflammatory and extracellular matrix deposition/resorption program of dermal fibroblasts. Immunohistochemical studies demonstrated similarities between SSc-EE and SSc epidermis including altered keratinocyte differentiation, enhanced expression of activation markers, and reduced rate of basal keratinocytes proliferation. SSc-EE, among others, exhibited enhanced oxidative and metabolic response pathways. Recent findingsĮpidermal equivalents (EE) generated from primary SSc keratinocytes display a distinct gene expression program when compared to healthy donor (HD) EE. Adding to this complexity, novel evidence here reviewed suggests that keratinocytes may concur in the development of skin fibrosis. Currently, the altered function of endothelial cells and fibroblasts under the influence of an inappropriate immune response are considered central pathogenic events in SSc. The cellular pathogenesis of fibrotic disorders including systemic sclerosis (SSc) remains largely speculative.
0 kommentar(er)
