期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 129, 期 12, 页码 5501-5517出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI125519
关键词
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资金
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ReBuilding a Kidney consortium [DK107374]
- NIH/NIDDK [DK103740]
- Established Investigator Award of the American Heart Association [F32 DK103441]
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.
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