Ciliary Hedgehog Signaling Restricts Injury-Induced Adipogenesis.
Ciliary Hedgehog Signaling Restricts Injury-Induced Adipogenesis.
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DOI：
10.1016/j.cell.2017.06.035
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发表时间：
2017-07-13
期刊：
影响因子：
64.5
通讯作者：
Reiter JF
中科院分区：
文献类型：
--
作者：
Kopinke D;Roberson EC;Reiter JF
受伤的骨骼肌可以再生，但随着年龄的增长或肌肉萎缩症，肌肉被脂肪取代。损伤后，肌肉驻留的脂肪/脂肪生成祖细胞（FAP）增殖并产生脂肪细胞。这些FAP动态地产生初级纤毛，这种结构抑制细胞间的信号，如Hedgehog（Hh）信号。在损伤后和杜氏肌营养不良症小鼠模型中，从FAP中遗传性去除纤毛抑制肌内脂肪生成。在肌营养不良模型中，阻断FAP纤毛化也增强了损伤后的肌纤维再生，并减少了肌纤维尺寸的下降。通过FAP纤毛的Hh信号调节TIMP 3的表达，TIMP 3是一种分泌型金属蛋白酶抑制剂，其抑制MMP 14以阻断脂肪生成。TIMP 3的药理学模拟物阻断了FAP向脂肪细胞的转化，指出了对抗骨骼肌脂肪变性的策略。我们的结论是睫状Hh信号FAPs编排再生反应骨骼肌损伤。
Injured skeletal muscle regenerates, but with age or in muscular dystrophies, muscle is replaced by fat. Upon injury, muscle-resident fibro/adipogenic progenitors (FAPs) proliferated and gave rise to adipocytes. These FAPs dynamically produced primary cilia, structures that transduce intercellular cues such as Hedgehog (Hh) signals. Genetically removing cilia from FAPs inhibited intramuscular adipogenesis, both after injury and in a mouse model of Duchenne muscular dystrophy. Blocking FAP ciliation also enhanced myofiber regeneration after injury and reduced myofiber size decline in the muscular dystrophy model. Hh signaling through FAP cilia regulated the expression of TIMP3, a secreted metalloproteinase inhibitor, that inhibited MMP14 to block adipogenesis. A pharmacological mimetic of TIMP3 blocked the conversion of FAPs into adipocytes, pointing to a strategy to combat fatty degeneration of skeletal muscle. We conclude that ciliary Hh signaling by FAPs orchestrates the regenerative response to skeletal muscle injury.
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