Deciphering age‑related differences in wound healing: Insights from the interaction between endothelial cells and fibroblasts

Abstract

Aging impairs wound healing, primarily because of alterations in cell phenotypes and interactions, particularly between endothelial cells (ECs) and fibroblasts (Fibs). The present study investigated the dynamics of EC‑Fib interac‑ tions in aged wounds using a mouse model and single‑cell transcriptomics, supplemented by CellChat analysis and func‑ tional validation using in vitro co‑culture systems. Aged mice exhibited markedly reduced wound healing efficiency and impaired angiogenesis when compared with younger mice, as indicated by hematoxylin and eosin and immunohistochemical staining. Single‑cell transcriptomic analysis revealed that the regeneration of ECs and Fibs was delayed in aged wounds. Furthermore, key genes involved in angiogenesis and tissue repair were downregulated, whereas those related to inflam‑ mation and aging were upregulated. Integrating CellChat analysis with in vitro co‑culture validation, it was found that the bidirectional communication between ECs and Fibs, predominantly mediated via the transforming growth factor β pathway, was markedly reduced in aged wounds. These findings underscored the critical role of disrupted cell‑cell communication in age‑related impaired wound healing, providing mechanistic evidence for potential therapeutic strat‑ egies to enhance wound healing in the elderly.