Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA.
Mol Cell Biol. 2019 Apr 2;39(8). doi: 10.1128/MCB.00447-18. Print 2019 Apr 15.
Satellite cells (SCs) are skeletal muscle stem cells that proliferate in response to injury and provide myogenic precursors for growth and repair. Zfp423 is a transcriptional cofactor expressed in multiple immature cell populations, such as neuronal precursors, mesenchymal stem cells, and preadipocytes, where it regulates lineage allocation, proliferation, and differentiation. Here, we show that Zfp423 regulates myogenic progression during muscle regeneration. Zfp423 is undetectable in quiescent SCs but becomes expressed during SC activation. After expansion, Zfp423 is gradually downregulated as committed SCs terminally differentiate. Mice with satellite-cell-specific Zfp423 deletion exhibit severely impaired muscle regeneration following injury, with aberrant SC expansion, defective cell cycle exit, and failure to transition efficiently from the proliferative stage toward commitment. Consistent with a cell-autonomous role of Zfp423, shRNA-mediated knockdown of Zfp423 in myoblasts inhibits differentiation. Surprisingly, forced expression of Zfp423 in myoblasts induces differentiation into adipocytes and arrests myogenesis. Affinity purification of Zfp423 in myoblasts identified Satb2 as a nuclear partner of Zfp423 that cooperatively enhances Zfp423 transcriptional activity, which in turn affects myoblast differentiation. In conclusion, by controlling SC expansion and proliferation, Zfp423 is essential for muscle regeneration. Tight regulation of Zfp423 expression is essential for normal progression of muscle progenitors from proliferation to differentiation.
卫星细胞（SCs）是骨骼肌干细胞，它们在受到损伤时会增殖，并为生长和修复提供肌源性前体。Zfp423 是一种在多种未成熟细胞群体中表达的转录共因子，如神经元前体、间充质干细胞和前脂肪细胞，在这些细胞群体中，它调节谱系分配、增殖和分化。在这里，我们表明 Zfp423 调节肌肉再生过程中的成肌进展。Zfp423 在静止的 SC 中不可检测，但在 SC 激活时表达。在扩增后，随着定向 SC 终末分化，Zfp423 逐渐下调。卫星细胞特异性 Zfp423 缺失的小鼠在损伤后表现出严重的肌肉再生受损，表现为 SC 异常扩增、细胞周期退出缺陷以及从增殖阶段向定向分化的有效过渡失败。与 Zfp423 的细胞自主作用一致，用 shRNA 介导的 Zfp423 在成肌细胞中的敲低抑制了分化。令人惊讶的是，Zfp423 在成肌细胞中的强制表达诱导成脂肪细胞分化并阻止肌生成。在成肌细胞中 Zfp423 的亲和纯化鉴定出 Satb2 是 Zfp423 的核伴侣，它协同增强 Zfp423 的转录活性，进而影响成肌细胞分化。总之，通过控制 SC 的扩增和增殖，Zfp423 对肌肉再生是必不可少的。Zfp423 表达的紧密调控对于肌肉祖细胞从增殖到分化的正常进展是必不可少的。
