The Role of R-Spondin2 in Keratinocyte Proliferation and Epidermal Thickening in Keloid Scarring

Abstract

Keloids are found only in humans and the underlying biochemical mechanisms of their pathogenesis remain unknown. R-spondins (Rspos) are a relatively new group of secreted proteins known to be Wnt/β-catenin signaling agonists, but their role in keloids has yet to be elucidated. We investigated the expression levels of R-spondin2 (Rspo2) in cell lysates and conditioned media of monocultures and co-cultures of fibroblasts and keratinocytes derived from keloids and normal skin. In this study we found increased protein expression and secretion of Rspo2 in respective monocultures of keloid fibroblasts and keratinocytes when compared with their normal counterparts. Double-chamber co-culture experiments implicated the role of keloid keratinocytes (KKs) in the induction of Rspo2 secretion from fibroblasts because of epithelial-mesenchymal interactions. Addition of recombinant human Rspo2 in culture increased the proliferation of keratinocytes and it acted synergistically with Wnt3a through the canonical Wnt/β-catenin pathway. Overexpression of Rspo2 in normal fibroblasts brought about thicker epidermis when compared with control fibroblasts in a skin organotypic culture model. This observation coincides with the hyperproliferative phenotype of thickened epidermis seen in keloids. Taken together, the results suggest the possible double paracrine action of KKs in inducing higher expression of Rspo2 in fibroblasts that promotes keratinocyte proliferation and epidermal thickening.

A Rare Human Syndrome Provides Genetic Evidence that WNT Signaling Is Required for Reprogramming of Fibroblasts to Induced Pluripotent Stem Cells

“…WNT genes are required for blastema formation (Kawakami et al, 2006; Stoick-Cooper et al, 2007). In addition, several studies have linked WNT signaling to tissue repair and wound healing, including in skin and bone (Chen et al, 2007; Chua et al, 2011; Fathke et al, 2006; Lim et al, 2013; Whyte et al, 2013). It is tempting to speculate that the observed requirement for WNT signaling during the induction of the pluripotent state represents a cell culture equivalent to these in vivo regenerative processes.…”

Keloid fibroblasts are more sensitive to Wnt3a treatment in terms of elevated cellular growth and fibronectin expression

“…There is increasing evidence to show that the canonical Wnt/b-catenin signalling is involved in keloid pathogenesis [4]. Sato first reported that TGF-b induced the upregulation of Wnt/b-catenin signalling in hypertrophic scar and keloid fibroblasts (KFs) [5].…”

R-spondin1, WNT4, and the CTNNB1 signaling pathway: strict control over ovarian differentiation

“…Abnormal expression of RSPO2 or RSPO3 has been identified in 10% of colorectal cancer cases (Wu et al 2014). Moreover, RSPO2 can also induce proliferation of another epithelium, the epidermis during keloid scarring (Chua et al 2011). Rspo3 ablation in mice is lethal at 10 days post coitum (dpc).…”