Keratinocyte self-renewal and differentiation is dictated by extrinsic signals from dermal extracellular matrices

Fetal skin has an intrinsic regenerative capability to restore an injured site's architecture and functionality. This is preserved until the third trimester, when wound healing transitions to a scarring reparative response. This change coincides with the dynamic remodelling of dermal extracellular matrix (ECM). Here, we used primary human fetal or adult dermal fibroblast (fHDF and aHDF)-derived ECMs to demonstrate that different extrinsic signals from these ECMs dramatically altered gene expression in a primary human keratinocyte population grown on these matrices. Gene array data revealed keratinocytes grown on fHDF ECM markedly upregulated expression of cell-cycle genes, whereas on aHDF ECM expression of differentiation genes was favoured. Detailed proteomic analyses indicated compositionally distinct ECMs were deposited by aHDFs and fHDFs. Moreover, aHDFs and fHDFs contained subpopulation(s) that differentially expressed CD90, CD146 and CD26. On fHDFs the extracellular domain of CD26 was shed whereas on aHDFs full-length CD26 dominated. The proteomic and gene array data supported the fine-tuning of BMP/TGFβ/SMAD signalling pathways being a mechanism by which fetal matrices promote keratinocyte self-renewal. Collectively, these findings revealed that a fundamental aspect of skin development is dictated by the ECM of the dermis, specifically extrinsic signals from dermal fibroblast ECM direct keratinocyte self-renewal or differentiation.