CD34+ telocytes regulate Matrigel plug angiogenesis and wound healing via Sema3c

Telocytes (TCs), a newly identified population of interstitial cells, have been hypothesized to play important roles in angiogenesis and wound healing. However, direct evidence for whether and how TCs participate in angiogenesis remains limited, particularly regarding the specific signaling pathways involved. This study demonstrated that Matrigel plugs enriched a large population of TCs. Using single-cell RNA sequencing (scRNA-seq) and lentiviral-mediated knockdown, we found that TCs regulate endothelial cell (EC) migration and angiogenesis through semaphorin 3 C (Sema3c) signaling via the PlexinD1 receptor on ECs. Functional assays confirmed that inhibition of the Sema3c-PlexinD1 axis significantly impaired CD34 + TC-mediated angiogenic effects. Furthermore, in a murine full-thickness excisional wound model, CD34 + TCs delivered via gelatin methacryloyl (GelMA) hydrogels significantly enhanced wound healing and angiogenesis, as evidenced by improved wound closure rates and increased CD31 + vascular structures. Notably, knocking down Sema3c in TCs attenuated these pro-healing effects, underscoring the specificity of this pathway. Collectively, these findings highlight the central role of TC-derived paracrine Sema3c in angiogenesis and skin wound healing and support a cell-based therapeutic strategy for angiogenesis-related diseases.