FOXM1 drives proximal tubule proliferation during repair from acute ischemic kidney injury
FOXM1 drives proximal tubule proliferation during repair from acute ischemic kidney injury
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DOI：
10.1172/jci125519
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发表时间：
2019-12-02
影响因子：
15.9
通讯作者：
Humphreys, Benjamin D.
中科院分区：
文献类型：
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作者：
Chang-Panesso, Monica;Kadyrov, Farid F.;Humphreys, Benjamin D.
近端小管在急性损伤后具有显著的修复能力，但这种修复反应的细胞谱系和分子机制尚不完全清楚。在这里，我们开发了Kim 1-GFPCreER（t2）敲入小鼠系（Kim 1-GCE），以便在修复期间测量近端小管的细胞转录组的同时对去分化细胞进行遗传谱系追踪。急性损伤的基因标记克隆共表达KIM 1，波形蛋白，SOX 9和KI 67，表明去分化和增殖状态。克隆分析显示Kim 1（+）细胞的克隆扩增，表明急性损伤的去分化近端小管细胞，而不是固定的肾小管祖细胞，负责修复。损伤和修复期间的翻译分析揭示了成功和不成功的适应不良修复的特征。转录因子Foxm 1在损伤早期被诱导，是体外上皮细胞增殖所必需的，并且依赖于表皮生长因子受体（EGFR）刺激。总之，去分化的近端小管细胞影响近端小管修复，我们揭示了EGFR/FOXM 1依赖的信号通路，驱动损伤后的增殖修复。
The proximal tubule has a remarkable capacity for repair after acute injury, but the cellular lineage and molecular mechanisms underlying this repair response are incompletely understood. Here, we developed a Kim1-GFPCreER(t2) knockin mouse line (Kim1-GCE) in order to perform genetic lineage tracing of dedifferentiated cells while measuring the cellular transcriptome of proximal tubule during repair. Acutely injured genetically labeled clones coexpressed KIM1, VIMENTIN, SOX9, and KI67, indicating a dedifferentiated and proliferative state. Clonal analysis revealed clonal expansion of Kim1(+) cells, indicating that acutely injured, dedifferentiated proximal tubule cells, rather than fixed tubular progenitor cells, account for repair. Translational profiling during injury and repair revealed signatures of both successful and unsuccessful maladaptive repair. The transcription factor Foxm1 was induced early in injury, was required for epithelial proliferation in vitro, and was dependent on epidermal growth factor receptor (EGFR) stimulation. In conclusion, dedifferentiated proximal tubule cells effect proximal tubule repair, and we reveal an EGFR/FOXM1-dependent signaling pathway that drives proliferative repair after injury.