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Genetically modified macrophages accelerate myelin repair
EMBO Molecular Medicine ( IF 11.1 ) Pub Date : 2022-07-13 , DOI: 10.15252/emmm.202114759
Marie-Stéphane Aigrot 1 , Clara Barthelemy 1 , Sarah Moyon 2 , Gaelle Dufayet-Chaffaud 1 , Leire Izagirre-Urizar 3, 4 , Beatrix Gillet-Legrand 1 , Satoru Tada 1 , Laura Bayón-Cordero 3, 4 , Juan-Carlos Chara 3, 4 , Carlos Matute 3, 4 , Nathalie Cartier 5 , Catherine Lubetzki 1, 6 , Vanja Tepavčević 3
Affiliation  

Preventing neurodegeneration-associated disability progression in patients with multiple sclerosis (MS) remains an unmet therapeutic need. As remyelination prevents axonal degeneration, promoting this process in patients might enhance neuroprotection. In demyelinating mouse lesions, local overexpression of semaphorin 3F (Sema3F), an oligodendrocyte progenitor cell (OPC) attractant, increases remyelination. However, molecular targeting to MS lesions is a challenge. A clinically relevant paradigm for delivering Sema3F to demyelinating lesions could be to use blood-derived macrophages as vehicles. Thus, we chose transplantation of genetically modified hematopoietic stem cells (HSCs) as means of obtaining chimeric mice with circulating Sema3F-overexpressing monocytes. We demonstrated that Sema3F-transduced HSCs stimulate OPC migration in a neuropilin 2 (Nrp2, Sema3F receptor)-dependent fashion, which was conserved in middle-aged OPCs. While demyelinating lesions induced in mice with Sema3F-expressing blood cells showed no changes in inflammation and OPC survival, OPC recruitment was enhanced which accelerated the onset of remyelination. Our results provide a proof of concept that blood cells, particularly monocytes/macrophages, can be used to deliver pro-remyelinating agents “at the right time and place,” suggesting novel means for remyelination-promoting strategies in MS.

中文翻译:

转基因巨噬细胞加速髓鞘修复

预防多发性硬化症 (MS) 患者与神经退行性变相关的残疾进展仍然是一项未满足的治疗需求。由于髓鞘再生可防止轴突变性,因此在患者中促进这一过程可能会增强神经保护作用。在脱髓鞘小鼠病变中,少突胶质祖细胞 (OPC) 引诱剂 semaphorin 3F (Sema3F) 的局部过表达增加了髓鞘再生。然而,针对 MS 病变的分子靶向是一个挑战。将 Sema3F 输送到脱髓鞘病变的临床相关范例可能是使用血液来源的巨噬细胞作为载体。因此,我们选择移植转基因造血干细胞 (HSC) 作为获得具有循环 Sema3F 过表达单核细胞的嵌合小鼠的手段。我们证明了 Sema3F 转导的 HSC 以依赖于神经纤维蛋白 2(Nrp2,Sema3F 受体)的方式刺激 OPC 迁移,这在中年 OPC 中是保守的。虽然用表达 Sema3F 的血细胞在小鼠中诱导的脱髓鞘病变显示炎症和 OPC 存活率没有变化,但 OPC 募集增强,加速了髓鞘再生的发生。我们的研究结果提供了一个概念证明,即血细胞,特别是单核细胞/巨噬细胞,可用于“在正确的时间和地点”递送促髓鞘再生剂,这为 MS 中促进髓鞘再生的策略提供了新的方法。OPC 招募得到加强,加速了髓鞘再生的发生。我们的研究结果提供了一个概念证明,即血细胞,特别是单核细胞/巨噬细胞,可用于“在正确的时间和地点”递送促髓鞘再生剂,这为 MS 中促进髓鞘再生的策略提供了新的方法。OPC 招募得到加强,加速了髓鞘再生的发生。我们的研究结果提供了一个概念证明,即血细胞,特别是单核细胞/巨噬细胞,可用于“在正确的时间和地点”递送促髓鞘再生剂,这为 MS 中促进髓鞘再生的策略提供了新的方法。
更新日期:2022-07-13
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