The heterogeneity of dermal mesenchymal cells reproduced in skin equivalents regulate barrier function and elasticity

The heterogeneity of dermal mesenchymal cells, including perivascular mesenchymal cells and papillary and reticular fibroblasts, plays critical roles in skin homeostasis. Here, we present human skin equivalents (HSEs) in which pericytes, papillary fibroblasts, and reticular fibroblasts are spatially organized through autonomous three-cell interactions among epidermal keratinocytes, dermal fibroblasts, and vascular endothelial cells. The replication of dermal mesenchymal cell heterogeneity enhances skin functions, including epithelialization, epidermal barrier formation, and dermal elasticity, enabling the in vitro evaluation of drug efficacy using methodologies identical to those used in human clinical studies. Furthermore, we found that ascorbic acid-induced epidermal turnover and well-aligned extracellular matrix synthesis via perivascular niche cells play crucial roles in improving skin aging phenotypes. HSEs with heterogeneous dermal mesenchymal cells will improve our understanding of the mechanisms underlying skin homeostasis through cell-to-cell communication and serve as an alternative model to animal experiments for the development of precision medicine.