Mesenchymal Stromal Cells Are Required for Regeneration and Homeostatic Maintenance of Skeletal Muscle
Mesenchymal Stromal Cells Are Required for Regeneration and Homeostatic Maintenance of Skeletal Muscle
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DOI：
10.1016/j.celrep.2019.04.074
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发表时间：
2019-05-14
期刊：
影响因子：
8.8
通讯作者：
Rando, Thomas A.
中科院分区：
文献类型：
--
作者：
Wosczyna, Michael N.;Konishi, Colin T.;Rando, Thomas A.
间充质基质细胞称为成纤维脂肪前体细胞(FAPs)在骨骼肌再生和维持中的必要性仍未确定。我们报道了PDGFRα(Creer)敲打小鼠模型的产生，该模型提供了标记和靶向FAP的特定方法。依赖Cre的白喉毒素表达导致FAP耗尽，导致损伤后肌肉干细胞(MuSCs)和CD45+造血细胞的扩张丧失，并损害骨骼肌再生。此外，在稳态条件下，FAP耗尽的小鼠表现出肌肉萎缩和MUSCs的丢失，这表明FAP是维持骨骼肌和MUSC池所必需的。我们还报道，局部他莫昔芬代谢物输送到单个肌肉中的靶CRER活动，消除了远距离消融PDGFRα+细胞的潜在混杂全身效应，也会导致肌肉萎缩。这些数据确立了FAP在骨骼肌再生和维持中的关键作用。
The necessity of mesenchymal stromal cells, called fibroadipogenic progenitors (FAPs), in skeletal muscle regeneration and maintenance remains unestablished. We report the generation of a PDGFR alpha(creER) knockin mouse model that provides a specific means of labeling and targeting FAPs. Depletion of FAPs using Cre-dependent diphtheria toxin expression results in loss of expansion of muscle stem cells (MuSCs) and CD45+ hematopoietic cells after injury and impaired skeletal muscle regeneration. Further-more, FAP-depleted mice under homeostatic conditions exhibit muscle atrophy and loss of MuSCs, revealing that FAPs are required for the maintenance of both skeletal muscle and the MuSC pool. We also report that local tamoxifen metabolite delivery to target CreER activity in a single muscle, removing potentially confounding systemic effects of ablating PDGFR alpha+ cells distantly, also causes muscle atrophy. These data establish a critical role of FAPs in skeletal muscle regeneration and maintenance.