Regulation of epithelial differentiation and proliferation by the stroma – a role for the retinoblastoma protein

Signalling between the epithelium and stromal cells is crucial for growth, differentiation and repair of the epithelium. While the retinoblastoma protein is known to regulate the growth of keratinocytes, in a cell autonomous fashion, here we describe a function of Rb in the stromal compartment. We find that Rb depletion in fibroblasts leads to inhibition of differentiation and enhanced proliferation of the epithelium. Analysis of conditioned medium identified that keratinocyte growth factor (KGF) levels were elevated following Rb depletion. These findings were also observed with organotypic co cultures. Treatment of keratinocytes with KGF inhibited differentiation and enhanced keratinocyte proliferation, whilst reduction of KGF levels in Rb depleted fibroblasts was able to restore expression of differentiation markers. Our findings suggest a crucial role for dermal fibroblasts in regulating the differentiation and proliferation of keratinocytes, and we demonstrate a role for stromal Rb in this cross talk.