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FOXM1 drives proximal tubule proliferation during repair from acute ischemic kidney injury
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 (Kim1-GCE) in order to perform genetic lineage tracing o...
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| Published in: | The Journal of clinical investigation 2019-12, Vol.129 (12), p.5501-5517 |
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| Main Authors: | , , , , , , , , , |
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| container_end_page | 5517 |
| container_issue | 12 |
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| container_title | The Journal of clinical investigation |
| container_volume | 129 |
| creator | Chang-Panesso, Monica Kadyrov, Farid F Lalli, Matthew Wu, Haojia Ikeda, Shiyo Kefaloyianni, Eirini Abdelmageed, Mai M Herrlich, Andreas Kobayashi, Akio Humphreys, Benjamin D |
| description | 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 (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. |
| doi_str_mv | 10.1172/JCI125519 |
| format | article |
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Here, we developed a Kim1-GFPCreERt2 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.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI125519</identifier><identifier>PMID: 31710314</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Acute Kidney Injury - pathology ; Adult ; Analysis ; Animals ; Cell Dedifferentiation ; Cell Lineage ; Cell Proliferation ; Criminal investigation ; Disease Models, Animal ; Epidermal growth factors ; ErbB Receptors - physiology ; Female ; Forkhead Box Protein M1 - physiology ; Humans ; Kidney - blood supply ; Kidney Tubules, Proximal - pathology ; Labels ; Male ; Mice ; Mice, Inbred C57BL ; Middle Aged ; Reperfusion Injury - pathology ; Scientific equipment industry</subject><ispartof>The Journal of clinical investigation, 2019-12, Vol.129 (12), p.5501-5517</ispartof><rights>COPYRIGHT 2019 American Society for Clinical Investigation</rights><rights>2019 American Society for Clinical Investigation 2019 American Society for Clinical Investigation</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c579t-9c783748f7799bec86d3e6abf4c6ec3d547c59f2ddbc5144ee78c5f282b6ae523</citedby><cites>FETCH-LOGICAL-c579t-9c783748f7799bec86d3e6abf4c6ec3d547c59f2ddbc5144ee78c5f282b6ae523</cites><orcidid>0000-0002-6420-8703 ; 0000-0002-7866-2544</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877314/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877314/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31710314$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chang-Panesso, Monica</creatorcontrib><creatorcontrib>Kadyrov, Farid F</creatorcontrib><creatorcontrib>Lalli, Matthew</creatorcontrib><creatorcontrib>Wu, Haojia</creatorcontrib><creatorcontrib>Ikeda, Shiyo</creatorcontrib><creatorcontrib>Kefaloyianni, Eirini</creatorcontrib><creatorcontrib>Abdelmageed, Mai M</creatorcontrib><creatorcontrib>Herrlich, Andreas</creatorcontrib><creatorcontrib>Kobayashi, Akio</creatorcontrib><creatorcontrib>Humphreys, Benjamin D</creatorcontrib><title>FOXM1 drives proximal tubule proliferation during repair from acute ischemic kidney injury</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>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 (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.</description><subject>Acute Kidney Injury - pathology</subject><subject>Adult</subject><subject>Analysis</subject><subject>Animals</subject><subject>Cell Dedifferentiation</subject><subject>Cell Lineage</subject><subject>Cell Proliferation</subject><subject>Criminal investigation</subject><subject>Disease Models, Animal</subject><subject>Epidermal growth factors</subject><subject>ErbB Receptors - physiology</subject><subject>Female</subject><subject>Forkhead Box Protein M1 - physiology</subject><subject>Humans</subject><subject>Kidney - blood supply</subject><subject>Kidney Tubules, Proximal - pathology</subject><subject>Labels</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Middle Aged</subject><subject>Reperfusion Injury - pathology</subject><subject>Scientific equipment industry</subject><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNqNkl1r2zAYhcXYWLNuF_sDQzAo7MKtZVuWfDMoYV0zWgL7YuxGyNIrR50sB8kuzb-vQtvQQC6GLoSk5z1wjg5C70l-Sggrzr7NF6SglDQv0IxQyjNelPwlmuV5QbKGlfwIvYnxJs9JVdHqNToqCSN5SaoZ-nux_HNNsA72FiJeh-HO9tLhcWonB9uzswaCHO3gsZ6C9R0OsJY2YBOGHks1jYBtVCvorcL_rPawwdbfTGHzFr0y0kV497gfo18XX37OL7Or5dfF_PwqU5Q1Y9YoxktWccNY07SgeK1LqGVrKlWDKjWtmKKNKbRuFU0GABhX1BS8aGsJtCiP0ecH3fXU9qAV-DFIJ9YhOQkbMUgr9l-8XYluuBU1ZyyFkAQ-Pgh00oGw3gwJU31yJc5rktcsJdskKjtAdeBTPG7wYGy63uNPD_Bp6W1UBwc-7Q0kZoS7sZNTjGLx4_v_s8vf--zJM3YF0o2rOLhp-6fxoKgKQ4wBzC5Dkott0cSuaIn98Dz0HfnUrPIehmTMCQ</recordid><startdate>20191201</startdate><enddate>20191201</enddate><creator>Chang-Panesso, Monica</creator><creator>Kadyrov, Farid F</creator><creator>Lalli, Matthew</creator><creator>Wu, Haojia</creator><creator>Ikeda, Shiyo</creator><creator>Kefaloyianni, Eirini</creator><creator>Abdelmageed, Mai M</creator><creator>Herrlich, Andreas</creator><creator>Kobayashi, Akio</creator><creator>Humphreys, Benjamin D</creator><general>American Society for Clinical Investigation</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-6420-8703</orcidid><orcidid>https://orcid.org/0000-0002-7866-2544</orcidid></search><sort><creationdate>20191201</creationdate><title>FOXM1 drives proximal tubule proliferation during repair from acute ischemic kidney injury</title><author>Chang-Panesso, Monica ; Kadyrov, Farid F ; Lalli, Matthew ; Wu, Haojia ; Ikeda, Shiyo ; Kefaloyianni, Eirini ; Abdelmageed, Mai M ; Herrlich, Andreas ; Kobayashi, Akio ; Humphreys, Benjamin D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c579t-9c783748f7799bec86d3e6abf4c6ec3d547c59f2ddbc5144ee78c5f282b6ae523</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Acute Kidney Injury - pathology</topic><topic>Adult</topic><topic>Analysis</topic><topic>Animals</topic><topic>Cell Dedifferentiation</topic><topic>Cell Lineage</topic><topic>Cell Proliferation</topic><topic>Criminal investigation</topic><topic>Disease Models, Animal</topic><topic>Epidermal growth factors</topic><topic>ErbB Receptors - physiology</topic><topic>Female</topic><topic>Forkhead Box Protein M1 - physiology</topic><topic>Humans</topic><topic>Kidney - blood supply</topic><topic>Kidney Tubules, Proximal - pathology</topic><topic>Labels</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Middle Aged</topic><topic>Reperfusion Injury - pathology</topic><topic>Scientific equipment industry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chang-Panesso, Monica</creatorcontrib><creatorcontrib>Kadyrov, Farid F</creatorcontrib><creatorcontrib>Lalli, Matthew</creatorcontrib><creatorcontrib>Wu, Haojia</creatorcontrib><creatorcontrib>Ikeda, Shiyo</creatorcontrib><creatorcontrib>Kefaloyianni, Eirini</creatorcontrib><creatorcontrib>Abdelmageed, Mai M</creatorcontrib><creatorcontrib>Herrlich, Andreas</creatorcontrib><creatorcontrib>Kobayashi, Akio</creatorcontrib><creatorcontrib>Humphreys, Benjamin D</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chang-Panesso, Monica</au><au>Kadyrov, Farid F</au><au>Lalli, Matthew</au><au>Wu, Haojia</au><au>Ikeda, Shiyo</au><au>Kefaloyianni, Eirini</au><au>Abdelmageed, Mai M</au><au>Herrlich, Andreas</au><au>Kobayashi, Akio</au><au>Humphreys, Benjamin D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>FOXM1 drives proximal tubule proliferation during repair from acute ischemic kidney injury</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2019-12-01</date><risdate>2019</risdate><volume>129</volume><issue>12</issue><spage>5501</spage><epage>5517</epage><pages>5501-5517</pages><issn>0021-9738</issn><eissn>1558-8238</eissn><abstract>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 (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.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>31710314</pmid><doi>10.1172/JCI125519</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0002-6420-8703</orcidid><orcidid>https://orcid.org/0000-0002-7866-2544</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of clinical investigation, 2019-12, Vol.129 (12), p.5501-5517 |
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| language | eng |
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| source | Open Access: PubMed Central; EZB Electronic Journals Library |
| subjects | Acute Kidney Injury - pathology Adult Analysis Animals Cell Dedifferentiation Cell Lineage Cell Proliferation Criminal investigation Disease Models, Animal Epidermal growth factors ErbB Receptors - physiology Female Forkhead Box Protein M1 - physiology Humans Kidney - blood supply Kidney Tubules, Proximal - pathology Labels Male Mice Mice, Inbred C57BL Middle Aged Reperfusion Injury - pathology Scientific equipment industry |
| title | FOXM1 drives proximal tubule proliferation during repair from acute ischemic kidney injury |
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