Fibroblast growth factor signaling induces a chondrocyte-like state of peripheral nerve fibroblast during aging

During aging, peripheral nerves undergo structural and cellular changes that trigger loss of function, impair quality of life, and increase disease risk. During peripheral nerve aging there are cellular and molecular changes, such as increased extracellular matrix deposition. The mechanisms behind these aging-induced alterations remain unclear. Here, we profile mouse sciatic nerves using single nucleus transcriptomics and unravel changes in macrophage subtypes during nerve aging. Phagocytic macrophage numbers increase at the onset of aging, followed by higher numbers of chronic inflammatory macrophages. Based on ligand-receptor analysis, we predict that increased fibroblast growth factor (FGF) signaling from adipocytes activates a chondrocyte-like neural fibroblast state during peripheral nerve aging. Finally, we show that FGF2 induces the co-expression of the chondrocyte markers SOX9 and FOXC2 in senescent human perineurial fibroblast, that can be blocked with FGF1. In conclusion, our findings reveal some of the molecular mechanisms of peripheral nerve aging by FGF-regulated induction of a chondrocyte-like fibroblast state.