Cytokine Polarized Bone Marrow Neutrophils Drive Axon Regeneration

The adult central nervous system (CNS) has a limited capacity for self-repair. Severed CNS axons typically do not regrow. There is an unmet need for treatments specifically designed to enhance neuronal viability, facilitate CNS axon regeneration, and ultimately restore lost neurological functions to individuals with traumatic CNS injury, multiple sclerosis, and stroke, among other disorders. Here we demonstrate that both mouse and human bone marrow (BM) neutrophils upregulate markers of alternative activation, and acquire the ability to promote neurite outgrowth, following polarization with a combination of recombinant interleukin-4 (IL-4) and granulocyte-colony stimulating factor (G-CSF). Moreover, adoptively transferring IL-4/G-CSF polarized BM neutrophils into experimental models of CNS injury resulted in significant axon regeneration within the optic nerve and spinal cord. The findings reported in this paper hold significant implications for the future development of autologous myeloid cell-based therapies that may bring us closer to effective solutions for reversing CNS damage. Overall design: To investigate the effect of polarization on the generation of alternatively activated immune cells, mouse Ly6G+ bone marrow neutrophils and human CD34+ bone marrow cells were polarized with or without IL-4 and/or G-CSF.

成人中枢神经系统（CNS）的自我修复能力有限，离断的中枢神经轴突通常无法再生。目前针对创伤性中枢神经损伤、多发性硬化症及中风等疾病，仍存在未被满足的临床需求，亟需开发专为提升神经元存活率、促进中枢神经轴突再生、最终帮助患者恢复丧失神经功能的治疗方案。

本研究证实，在重组白细胞介素-4（IL-4）与粒细胞集落刺激因子（G-CSF）联合极化诱导后，小鼠与人类骨髓（BM）中性粒细胞均可上调替代性活化标志物，并获得促进神经突生长的能力。此外，将经IL-4/G-CSF极化的骨髓中性粒细胞过继转移至中枢神经损伤实验模型后，可显著促进视神经与脊髓内的轴突再生。本文所报道的研究结果对于未来基于自体髓系细胞的治疗方案开发具有重要意义，有望推动我们向逆转中枢神经损伤的有效治疗方案迈出关键一步。

整体实验设计：为探究极化诱导对替代性活化免疫细胞生成的影响，本研究分别对小鼠Ly6G+骨髓中性粒细胞与人类CD34+骨髓细胞施加或不施加IL-4及/或G-CSF进行极化处理。