Leukemia inhibitory factor (LIF) can influence development by increasing cell proliferation and inhibiting differentiation. Because of its potency for expanding stem cell populations, delivery of exogenous LIF to diseased tissue could have therapeutic value. However, systemic elevations of LIF can have negative, off-target effects. We tested whether inflammatory cells expressing a LIF transgene under control of a leukocyte-specific, CD11b promoter provide a strategy to target LIF to sites of damage in the mdx mouse model of Duchenne muscular dystrophy, leading to increased numbers of muscle stem cells and improved muscle regeneration. However, transgene expression in inflammatory cells did not increase muscle growth or increase numbers of stem cells required for regeneration. Instead, transgene expression disrupted the normal dispersion of macrophages in dystrophic muscles, leading to transient increases in muscle damage in foci where macrophages were highly concentrated during early stages of pathology. The defect in inflammatory cell dispersion reflected impaired chemotaxis of macrophages to C-C motif chemokine ligand-2 and local increases of LIF production that produced large aggregations of cytolytic macrophages. Transgene expression also induced a shift in macrophage phenotype away from a CD206+, M2-biased phenotype that supports regeneration. However, at later stages of the disease when macrophage numbers declined, they dispersed in the muscle, leading to reductions in muscle fiber damage, compared to non-transgenic mdx mice. Together, the findings show that macrophage-mediated delivery of transgenic LIF exerts differential effects on macrophage dispersion and muscle damage depending on the stage of dystrophic pathology.

中文翻译：

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骨髓细胞介导的 LIF 靶向营养不良肌肉通过破坏肌肉中巨噬细胞的募集和分散导致肌纤维损伤的短暂增加

白血病抑制因子 (LIF) 可以通过增加细胞增殖和抑制分化来影响发育。由于其扩大干细胞群的效力，将外源性 LIF 递送至患病组织可能具有治疗价值。然而，LIF 的全身性升高可能会产生负面的脱靶效应。我们测试了在白细胞特异性 CD11b 启动子控制下表达 LIF 转基因的炎症细胞是否提供了一种将 LIF 靶向到杜氏肌营养不良 mdx 小鼠模型中的损伤部位的策略，从而导致肌肉干细胞数量增加和肌肉改善再生。然而，炎症细胞中的转基因表达并没有增加肌肉生长或增加再生所需的干细胞数量。反而，转基因表达破坏了营养不良肌肉中巨噬细胞的正常分散，导致在病理早期巨噬细胞高度集中的病灶中的肌肉损伤瞬时增加。炎症细胞分散的缺陷反映了巨噬细胞对 CC 基序趋化因子配体 2 的趋化性受损和 LIF 产生的局部增加，从而产生大量的溶细胞巨噬细胞聚集。转基因表达还诱导巨噬细胞表型从支持再生的 CD206+、M2 偏向表型转变。然而，在疾病的后期，当巨噬细胞数量下降时，它们分散在肌肉中，与非转基因 mdx 小鼠相比，导致肌纤维损伤减少。一起，