Inactivating IL34 promotes regenerating muscle stem cell expansion and attenuates Duchenne muscular dystrophy in mouse models.
Inactivating IL34 promotes regenerating muscle stem cell expansion and attenuates Duchenne muscular dystrophy in mouse models.
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作者：
Su Y;Cao Y;Liu C;Xu Q;Li N;Lan M;Li L;Wang K;Zhang Z;Meng Q
背景：卫星细胞（SCs）分化和自我更新之间的平衡对于骨骼肌稳态和再生至关重要。我们对这个监管过程的了解是不完整的。方法：以全基因敲除小鼠和条件敲除小鼠为体内模型，以离体卫星细胞为体外系统，研究il - 34在骨骼肌再生过程中的体内和体外调控机制。结果：肌细胞和再生纤维是il - 34的主要来源。白细胞介素34 （IL34）的缺失通过牺牲SCs的分化来维持扩张，并导致显著的肌肉再生缺陷。我们进一步发现，sc中的IL34失活会导致NFKB1信号的过度激活；NFKB1易位到细胞核，结合Igfbp5的启动子区域，协同干扰蛋白激酶B （Akt）活性。值得注意的是，Igfbp5在SCs中的功能增强导致分化不足和Akt活性降低。此外，在体内和体外破坏Akt活性模拟IL34敲除的表型。最后，在mdx小鼠中，删除IL34或干扰Akt可改善营养不良的肌肉。结论：我们全面表征了再生肌纤维中表达的IL34在控制肌核结构域中起关键作用。结果还表明，通过促进SC维持来损害il - 34功能可以改善干细胞库受损的mdx小鼠的肌肉表现。
Background: The balance between the differentiation and self-renewal of satellite cells (SCs) is essential for skeletal muscle homeostasis and regeneration. Our knowledge of this regulatory process is incomplete. Methods: Using global and conditional knockout mice as in vivo models and isolated satellite cells as in vitro system, we investigated the regulatory mechanisms of IL34 in the process of skeletal muscle regeneration in vivo and in vitro. Results: Myocytes and regenerating fibers are major source of IL34. Deletion of interleukin 34 (IL34) sustains expansion by sacrificing the differentiation of SCs and leads to significant muscle regeneration defects. We further found that inactivating IL34 in SCs leads to hyperactivation of NFKB1 signaling; NFKB1 translocates to the nucleus and binds to the promoter region of Igfbp5 to synergistically disturb protein kinase B (Akt) activity. Notably, augmented Igfbp5 function in SCs led to deficient differentiation and Akt activity. Furthermore, disrupting Akt activity both in vivo and in vitro mimicked the phenotype of IL34 knockout. Finally, deleting IL34 or interfering Akt in mdx mice ameliorates dystrophic muscles. Conclusion: We comprehensively characterized regenerating myofibers-expressed IL34 plays a pivotal role in controlling myonuclear domain. The results also indicate that impairing IL34 function by promoting SC maintenance can lead to improved muscular performance in mdx mice in which the stem cell pool is compromised.
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影响因子：
5.2
作者：
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通讯作者：
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影响因子：
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影响因子：
82.9
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Rudnicki MA
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16.6
作者：
Sampath SC;Sampath SC;Ho ATV;Corbel SY;Millstone JD;Lamb J;Walker J;Kinzel B;Schmedt C;Blau HM
通讯作者：
Blau HM