Heo Keunjung, Ho Tammy Szu-Yu, Zeng Xiangsunze, Turnes Bruna Lenfers, Arab Maryam, Jayakar Selwyn, Chen Kuchuan, Kimourtzis Georgios, Condro Michael C, Fazzari Elisa, Song Xuan, Tabitha Hees J, Xu Zhuqiu, Chen Xirui, Barrett Lee B, Perrault Laura, Pandey Roshan, Zhang Kathleen, Bhaduri Aparna, He Zhigang, Kornblum Harley I, Hubbs Jed, Woolf Clifford J
F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.
Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
Nat Commun. 2025 Mar 26;16(1):2975. doi: 10.1038/s41467-025-58303-6.
Motor axon regeneration following peripheral nerve injury is critical for motor recovery but therapeutic interventions enhancing this are not available. We conduct a phenotypic screen on human motor neurons and identified blebbistatin, a non-muscle myosin II inhibitor, as the most effective neurite outgrowth promotor. Despite its efficacy in vitro, its poor bioavailability limits in vivo application. We, therefore, utilize a blebbistatin analog, NMIIi2, to explore its therapeutic potential for promoting axon regeneration. Local NMIIi2 application directly to injured axons enhances regeneration in human motor neurons. Furthermore, following a sciatic nerve crush injury in male mice, local NMIIi2 administration to the axonal injury site facilitates motor neuron regeneration, muscle reinnervation, and functional recovery. NMIIi2 also promotes axon regeneration in sensory, cortical, and retinal ganglion neurons. These findings highlight the therapeutic potential of topical NMII inhibition for treating axon damage.
周围神经损伤后运动轴突的再生对运动功能恢复至关重要，但目前尚无增强这一过程的治疗干预措施。我们对人类运动神经元进行了表型筛选，确定了非肌肉肌球蛋白II抑制剂blebbistatin是最有效的神经突生长促进剂。尽管它在体外有效，但其较差的生物利用度限制了其在体内的应用。因此，我们利用blebbistatin类似物NMIIi2来探索其促进轴突再生的治疗潜力。将NMIIi2直接局部应用于受损轴突可增强人类运动神经元的再生。此外，在雄性小鼠坐骨神经挤压损伤后，将NMIIi2局部给药至轴突损伤部位可促进运动神经元再生、肌肉再支配和功能恢复。NMIIi2还可促进感觉神经元、皮质神经元和视网膜神经节神经元的轴突再生。这些发现突出了局部抑制非肌肉肌球蛋白II治疗轴突损伤的治疗潜力。
