Non-muscle myosin II inhibition at the site of axon injury increases axon regeneration

Keunjung Heo, Tammy Szu-Yu Ho, Xiangsunze Zeng, Bruna Lenfers Turnes, Maryam Arab, Selwyn Jayakar, Kuchuan Chen, Georgios Kimourtzis, Michael C. Condro, Elisa Fazzari, Xuan Song, J. Tabitha Hees, Zhuqiu Xu, Xirui Chen, Lee B. Barrett, Laura Perrault, Roshan Pandey, Kathleen Zhang, Aparna Bhaduri, Zhigang He, Harley I. Kornblum, Jed Hubbs and Clifford J. Woolf ()
Additional contact information
Keunjung Heo: Boston Children’s Hospital
Tammy Szu-Yu Ho: Boston Children’s Hospital
Xiangsunze Zeng: Boston Children’s Hospital
Bruna Lenfers Turnes: Boston Children’s Hospital
Maryam Arab: Boston Children’s Hospital
Selwyn Jayakar: Boston Children’s Hospital
Kuchuan Chen: Boston Children’s Hospital
Georgios Kimourtzis: Boston Children’s Hospital
Michael C. Condro: University of California
Elisa Fazzari: University of California
Xuan Song: Boston Children’s Hospital
J. Tabitha Hees: Boston Children’s Hospital
Zhuqiu Xu: Boston Children’s Hospital
Xirui Chen: Boston Children’s Hospital
Lee B. Barrett: Boston Children’s Hospital
Laura Perrault: Boston Children’s Hospital
Roshan Pandey: Boston Children’s Hospital
Kathleen Zhang: Boston Children’s Hospital
Aparna Bhaduri: University of California
Zhigang He: Boston Children’s Hospital
Harley I. Kornblum: University of California
Jed Hubbs: Harvard Medical School
Clifford J. Woolf: Boston Children’s Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-58303-6

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