Semaphorin 3A (Sema3A) is a semaphorin involved in cell signaling with PlexinA1 and Neuropilin-1 (NRP1) receptors. It plays diverse roles in various biological processes, including axon guidance, and is also associated with the regulation of bone and lymphatic vessel development, as well as influencing tumor phenotypes [4].

In bone-related studies, Sema3A secreted by sensory nerves can induce bone formation under mechanical loads. It acts as a pain-sensitive analgesic and a positive regulator for bone formation, restoring suppressed alveolar bone formation and osteogenic differentiation of human periodontal ligament cells (hPDLCs) induced by mechanical overload [1]. In miR-196b-5p regulation of bone cells, Sema3A is directly targeted by miR-196b-5p, which inhibits osteoblast differentiation. Osteoblast-specific miR-196b transgenic mice with reduced SEMA3A levels show significant reduction of bone mass [2]. In distraction osteogenesis, local administration of Sema3A accelerates bone regeneration and improves angiogenesis in mice [5]. Osteoblast lineage cell-derived Sema3A is an osteoprotective factor regulating bone homeostasis independently of androgens [7]. In addition, Sema3A modified periodontal ligament stem cells (PDLSCs) exhibit enhanced osteogenic capabilities and stimulate the differentiation of pre-osteoblasts [6]. In pancreatic ductal adenocarcinoma (PDAC), SEMA3A promotes the aggressive phenotype of basal-like PDAC, acting through both cell-intrinsic and cell-extrinsic mechanisms [3]. In viral myocarditis, Sema3A alleviates the disease by modulating SIRT1 to regulate cardiomyocyte mitophagy [8].

In summary, Sema3A is crucial in multiple biological processes. Its role in bone homeostasis, tumor progression, and lymphatic vessel maturation has been revealed through various in vivo and functional studies, especially those using gene-targeted mouse models. Understanding Sema3A's functions provides insights into the mechanisms of these biological processes and disease conditions, which may potentially lead to new therapeutic strategies.