Function of orthologous fibroblast growth factor 11 protein in angiogenesis and immunomodulatory after spinal cord injury.

Intracellular fibroblast growth factors (iFGFs) are emerging as promising therapeutic agents in tissue engineering and regenerative medicine. Although FGF11, a typical iFGF, plays crucial roles in cellular hypoxia adaptation, its roles in angiogenesis and immunomodulation post-spinal cord injury (SCI) remain poorly characterized. This study investigated four FGF11 orthologs: ZFgf11a/ZFgf11b from zebrafish (Danio rerio) and MFGF11a/MFGF11b from mouse (Mus musculus). In vitro, intracellularly delivered ZFgf11a and MFGF11b exhibited stronger pro-angiogenic effects compared to ZFgf11b or MFGF11a. In a contusive SCI model, treatment with ZFgf11a and MFGF11b loaded lipid nanoparticles enhanced angiogenesis and blood-spinal cord barrier integrity, accompanied by upregulation of VEGFA, CD31, and ZO-1. Additionally, ZFgf11a and MFGF11b revealed different immunomodulatory effects in vivo: ZFgf11a increased expression of GATA3 and Arg1 while decreasing TBX21 and iNOS in T cells and macrophages, whereas MFGF11b only suppressed expression of TBX21 and iNOS. Both orthologs conferred neuroprotection at 11 and 28 days post injury (dpi), but only ZFgf11a promoted obviously functional locomotor recovery. Mechanistic studies indicated that ZFgf11a and MFGF11b could modulate macrophage-driven immunity via STAT3/MYC/TBK1/NFκB signaling axis. These findings identify ZFgf11a as potent therapeutic candidates for SCI and other disorders involving vascular dysfunction and inflammatory responses.