TY - JOUR
T1 - FOXM1 drives proximal tubule proliferation during repair from acute ischemic kidney injury
AU - Chang-Panesso, Monica
AU - Kadyrov, Farid F.
AU - Lalli, Matthew
AU - Wu, Haojia
AU - Ikeda, Shiyo
AU - Kefaloyianni, Eirini
AU - Abdelmageed, Mai M.
AU - Herrlich, Andreas
AU - Kobayashi, Akio
AU - Humphreys, Benjamin D.
N1 - Publisher Copyright:
Copyright: © 2019, American Society for Clinical Investigation.
PY - 2019/12/2
Y1 - 2019/12/2
N2 - 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-GFPCreERt2 knockin mouse line (Kim1GCE) 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.
AB - 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-GFPCreERt2 knockin mouse line (Kim1GCE) 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.
UR - http://www.scopus.com/inward/record.url?scp=85075468594&partnerID=8YFLogxK
U2 - 10.1172/JCI125519
DO - 10.1172/JCI125519
M3 - Article
C2 - 31710314
AN - SCOPUS:85075468594
SN - 0021-9738
VL - 129
SP - 5501
EP - 5517
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 12
ER -