PittsburghV1, Main, Exploration, bibRecord, 004473

ABCB5 is a limbal stem cell gene required for corneal development and repair

Identifieur interne : 004473 ( Main/Exploration ); précédent : 004472; suivant : 004474

ABCB5 is a limbal stem cell gene required for corneal development and repair

Auteurs : Bruce R. Ksander [États-Unis] ; Paraskevi E. Kolovou [États-Unis] ; Brian J. Wilson [États-Unis] ; Karim R. Saab [États-Unis] ; Qin Guo [États-Unis] ; Jie Ma [États-Unis] ; Sean P. Mcguire [États-Unis] ; Meredith S. Gregory [États-Unis] ; William J. B. Vincent [États-Unis] ; Victor L. Perez [États-Unis] ; Fernando Cruz-Guilloty [États-Unis] ; Winston W. Y. Kao [États-Unis] ; Mindy K. Call [États-Unis] ; Budd A. Tucker [États-Unis] ; Qian Zhan [États-Unis] ; George F. Murphy [États-Unis] ; Kira L. Lathrop [États-Unis] ; Clemens Alt [États-Unis] ; Luke J. Mortensen [États-Unis] ; Charles P. Lin [États-Unis] ; James D. Zieske [États-Unis] ; Markus H. Frank [États-Unis] ; Natasha Y. Frank [États-Unis]

Source :

Nature [ 0028-0836 ] ; 2014.

RBID : PMC:4246512

Descripteurs français

KwdFr :
- Animaux, Apoptose, Cellules souches (cytologie), Cellules souches (métabolisme), Cicatrisation de plaie, Différenciation cellulaire, Données de séquences moléculaires, Facteurs de transcription (métabolisme), Femelle, Glycoprotéine P (déficit), Glycoprotéine P (métabolisme), Humains, Limbe de la cornée (cytologie), Limbe de la cornée (physiologie), Marqueurs biologiques (métabolisme), Mâle, Prolifération cellulaire, Protéines suppresseurs de tumeurs (métabolisme), Régénération, Souris, Souris knockout, Transplantation de cellules souches, Transporteurs ABC (déficit), Transporteurs ABC (métabolisme).
MESH :
- cytologie : Cellules souches, Limbe de la cornée.
- déficit : Glycoprotéine P, Transporteurs ABC.
- métabolisme : Cellules souches, Facteurs de transcription, Glycoprotéine P, Marqueurs biologiques, Protéines suppresseurs de tumeurs, Transporteurs ABC.
- physiologie : Limbe de la cornée.
- Animaux, Apoptose, Cicatrisation de plaie, Différenciation cellulaire, Données de séquences moléculaires, Femelle, Humains, Mâle, Prolifération cellulaire, Régénération, Souris, Souris knockout, Transplantation de cellules souches.

English descriptors

KwdEn :
- ATP-Binding Cassette Transporters (deficiency), ATP-Binding Cassette Transporters (metabolism), Animals, Apoptosis, Biomarkers (metabolism), Cell Differentiation, Cell Proliferation, Female, Humans, Limbus Corneae (cytology), Limbus Corneae (physiology), Male, Mice, Mice, Knockout, Molecular Sequence Data, P-Glycoprotein (deficiency), P-Glycoprotein (metabolism), Regeneration, Stem Cell Transplantation, Stem Cells (cytology), Stem Cells (metabolism), Transcription Factors (metabolism), Tumor Suppressor Proteins (metabolism), Wound Healing.
MESH :
- chemical , deficiency : P-Glycoprotein.
- chemical , metabolism : Biomarkers, P-Glycoprotein, Transcription Factors, Tumor Suppressor Proteins.
- cytology : Limbus Corneae, Stem Cells.
- deficiency : ATP-Binding Cassette Transporters.
- metabolism : ATP-Binding Cassette Transporters, Stem Cells.
- physiology : Limbus Corneae.
- Animals, Apoptosis, Cell Differentiation, Cell Proliferation, Female, Humans, Male, Mice, Mice, Knockout, Molecular Sequence Data, Regeneration, Stem Cell Transplantation, Wound Healing.

Abstract

Corneal epithelial homeostasis and regeneration are sustained by limbal stem cells (LSCs)^1–3, and LSC deficiency is a major cause of blindness worldwide⁴. Transplantation is often the only therapeutic option available to patients with LSC deficiency. However, while transplant success depends foremost on LSC frequency within grafts⁵, a gene allowing for prospective LSC enrichment has not been identified so far⁵. Here we show that ATP-binding cassette, sub-family B, member 5 (ABCB5)^6,7 marks LSCs and is required for LSC maintenance, corneal development and repair. Furthermore, we demonstrate that prospectively isolated human or murine ABCB5-positive LSCs possess the exclusive capacity to fully restore the cornea upon grafting to LSC-deficient mice in xenogeneic or syngeneic transplantation models. ABCB5 is preferentially expressed on label-retaining LSCs² in mice and p63α-positive LSCs⁸ in humans. Consistent with these findings, ABCB5-positive LSC frequency is reduced in LSC-deficient patients. Abcb5 loss of function in Abcb5 knockout mice causes depletion of quiescent LSCs due to enhanced proliferation and apoptosis, and results in defective corneal differentiation and wound healing. Our results from gene knockout studies, LSC tracing and transplantation models, as well as phenotypic and functional analyses of human biopsy specimens, provide converging lines of evidence that ABCB5 identifies mammalian LSCs. Identification and prospective isolation of molecularly defined LSCs with essential functions in corneal development and repair has important implications for the treatment of corneal disease, particularly corneal blindness due to LSC deficiency.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4246512

DOI: 10.1038/nature13426
PubMed: 25030174
PubMed Central: 4246512

Affiliations:

Le document en format XML

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<author><name sortKey="Zieske, James D" sort="Zieske, James D" uniqKey="Zieske J" first="James D." last="Zieske">James D. Zieske</name>
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<author><name sortKey="Frank, Markus H" sort="Frank, Markus H" uniqKey="Frank M" first="Markus H." last="Frank">Markus H. Frank</name>
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<affiliation wicri:level="1"><nlm:aff id="A11">Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02138, USA</nlm:aff>
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<author><name sortKey="Frank, Natasha Y" sort="Frank, Natasha Y" uniqKey="Frank N" first="Natasha Y." last="Frank">Natasha Y. Frank</name>
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<affiliation wicri:level="1"><nlm:aff id="A4">Department of Medicine, VA Boston Healthcare System, Boston, Massachusetts 02130, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, VA Boston Healthcare System, Boston, Massachusetts 02130</wicri:regionArea>
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<affiliation wicri:level="1"><nlm:aff id="A11">Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02138, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
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<affiliation wicri:level="1"><nlm:aff id="A12">Division of Genetics, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Genetics, Brigham and Women’s Hospital, Boston, Massachusetts 02115</wicri:regionArea>
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<idno type="wicri:Area/Main/Merge">004704</idno>
<idno type="wicri:Area/Main/Curation">004473</idno>
<idno type="wicri:Area/Main/Exploration">004473</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main"><italic>ABCB5</italic>
 is a limbal stem cell gene required for corneal development and repair</title>
<author><name sortKey="Ksander, Bruce R" sort="Ksander, Bruce R" uniqKey="Ksander B" first="Bruce R." last="Ksander">Bruce R. Ksander</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary and Harvard Medical School, Boston, Massachusetts 02114, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary and Harvard Medical School, Boston, Massachusetts 02114</wicri:regionArea>
<wicri:noRegion>Massachusetts 02114</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Kolovou, Paraskevi E" sort="Kolovou, Paraskevi E" uniqKey="Kolovou P" first="Paraskevi E." last="Kolovou">Paraskevi E. Kolovou</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary and Harvard Medical School, Boston, Massachusetts 02114, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary and Harvard Medical School, Boston, Massachusetts 02114</wicri:regionArea>
<wicri:noRegion>Massachusetts 02114</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Wilson, Brian J" sort="Wilson, Brian J" uniqKey="Wilson B" first="Brian J." last="Wilson">Brian J. Wilson</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Transplant Research Program, Division of Nephrology, Boston Children’s Hospital, Boston, Massachusetts 02115, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Transplant Research Program, Division of Nephrology, Boston Children’s Hospital, Boston, Massachusetts 02115</wicri:regionArea>
<wicri:noRegion>Massachusetts 02115</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A3">Departmentof Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Departmentof Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts 02115</wicri:regionArea>
<wicri:noRegion>Massachusetts 02115</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A4">Department of Medicine, VA Boston Healthcare System, Boston, Massachusetts 02130, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, VA Boston Healthcare System, Boston, Massachusetts 02130</wicri:regionArea>
<wicri:noRegion>Massachusetts 02130</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Saab, Karim R" sort="Saab, Karim R" uniqKey="Saab K" first="Karim R." last="Saab">Karim R. Saab</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Transplant Research Program, Division of Nephrology, Boston Children’s Hospital, Boston, Massachusetts 02115, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Transplant Research Program, Division of Nephrology, Boston Children’s Hospital, Boston, Massachusetts 02115</wicri:regionArea>
<wicri:noRegion>Massachusetts 02115</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A3">Departmentof Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Departmentof Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts 02115</wicri:regionArea>
<wicri:noRegion>Massachusetts 02115</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Guo, Qin" sort="Guo, Qin" uniqKey="Guo Q" first="Qin" last="Guo">Qin Guo</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Transplant Research Program, Division of Nephrology, Boston Children’s Hospital, Boston, Massachusetts 02115, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Transplant Research Program, Division of Nephrology, Boston Children’s Hospital, Boston, Massachusetts 02115</wicri:regionArea>
<wicri:noRegion>Massachusetts 02115</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A3">Departmentof Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Departmentof Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts 02115</wicri:regionArea>
<wicri:noRegion>Massachusetts 02115</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A4">Department of Medicine, VA Boston Healthcare System, Boston, Massachusetts 02130, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, VA Boston Healthcare System, Boston, Massachusetts 02130</wicri:regionArea>
<wicri:noRegion>Massachusetts 02130</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Ma, Jie" sort="Ma, Jie" uniqKey="Ma J" first="Jie" last="Ma">Jie Ma</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Transplant Research Program, Division of Nephrology, Boston Children’s Hospital, Boston, Massachusetts 02115, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Transplant Research Program, Division of Nephrology, Boston Children’s Hospital, Boston, Massachusetts 02115</wicri:regionArea>
<wicri:noRegion>Massachusetts 02115</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A3">Departmentof Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Departmentof Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts 02115</wicri:regionArea>
<wicri:noRegion>Massachusetts 02115</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Mcguire, Sean P" sort="Mcguire, Sean P" uniqKey="Mcguire S" first="Sean P." last="Mcguire">Sean P. Mcguire</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary and Harvard Medical School, Boston, Massachusetts 02114, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary and Harvard Medical School, Boston, Massachusetts 02114</wicri:regionArea>
<wicri:noRegion>Massachusetts 02114</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Gregory, Meredith S" sort="Gregory, Meredith S" uniqKey="Gregory M" first="Meredith S." last="Gregory">Meredith S. Gregory</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary and Harvard Medical School, Boston, Massachusetts 02114, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary and Harvard Medical School, Boston, Massachusetts 02114</wicri:regionArea>
<wicri:noRegion>Massachusetts 02114</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Vincent, William J B" sort="Vincent, William J B" uniqKey="Vincent W" first="William J. B." last="Vincent">William J. B. Vincent</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary and Harvard Medical School, Boston, Massachusetts 02114, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary and Harvard Medical School, Boston, Massachusetts 02114</wicri:regionArea>
<wicri:noRegion>Massachusetts 02114</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Perez, Victor L" sort="Perez, Victor L" uniqKey="Perez V" first="Victor L." last="Perez">Victor L. Perez</name>
<affiliation wicri:level="1"><nlm:aff id="A5">Bascom Palmer Eye Institute and the Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Bascom Palmer Eye Institute and the Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida 33136</wicri:regionArea>
<wicri:noRegion>Florida 33136</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Cruz Guilloty, Fernando" sort="Cruz Guilloty, Fernando" uniqKey="Cruz Guilloty F" first="Fernando" last="Cruz-Guilloty">Fernando Cruz-Guilloty</name>
<affiliation wicri:level="1"><nlm:aff id="A5">Bascom Palmer Eye Institute and the Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Bascom Palmer Eye Institute and the Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida 33136</wicri:regionArea>
<wicri:noRegion>Florida 33136</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Kao, Winston W Y" sort="Kao, Winston W Y" uniqKey="Kao W" first="Winston W. Y." last="Kao">Winston W. Y. Kao</name>
<affiliation wicri:level="1"><nlm:aff id="A6">Department of Ophthalmology, University of Cincinnati Medical Center, Cincinnati, Ohio 45229, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Ophthalmology, University of Cincinnati Medical Center, Cincinnati, Ohio 45229</wicri:regionArea>
<wicri:noRegion>Ohio 45229</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Call, Mindy K" sort="Call, Mindy K" uniqKey="Call M" first="Mindy K." last="Call">Mindy K. Call</name>
<affiliation wicri:level="1"><nlm:aff id="A6">Department of Ophthalmology, University of Cincinnati Medical Center, Cincinnati, Ohio 45229, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Ophthalmology, University of Cincinnati Medical Center, Cincinnati, Ohio 45229</wicri:regionArea>
<wicri:noRegion>Ohio 45229</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Tucker, Budd A" sort="Tucker, Budd A" uniqKey="Tucker B" first="Budd A." last="Tucker">Budd A. Tucker</name>
<affiliation wicri:level="4"><nlm:aff id="A7">Stephen A Wynn Institute for Vision Research, Carver College of Medicine, Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa 52242, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Stephen A Wynn Institute for Vision Research, Carver College of Medicine, Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa 52242</wicri:regionArea>
<orgName type="university">Université de l'Iowa</orgName>
<placeName><settlement type="city">Iowa City</settlement>
<region type="state">Iowa</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Zhan, Qian" sort="Zhan, Qian" uniqKey="Zhan Q" first="Qian" last="Zhan">Qian Zhan</name>
<affiliation wicri:level="1"><nlm:aff id="A8">Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115</wicri:regionArea>
<wicri:noRegion>Massachusetts 02115</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Murphy, George F" sort="Murphy, George F" uniqKey="Murphy G" first="George F." last="Murphy">George F. Murphy</name>
<affiliation wicri:level="1"><nlm:aff id="A8">Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115</wicri:regionArea>
<wicri:noRegion>Massachusetts 02115</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Lathrop, Kira L" sort="Lathrop, Kira L" uniqKey="Lathrop K" first="Kira L." last="Lathrop">Kira L. Lathrop</name>
<affiliation wicri:level="1"><nlm:aff id="A9">Department of Ophthalmology, University of Pittsburgh School of Medicine & Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, Pennsylvania 15213, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Ophthalmology, University of Pittsburgh School of Medicine & Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, Pennsylvania 15213</wicri:regionArea>
<wicri:noRegion>Pennsylvania 15213</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Alt, Clemens" sort="Alt, Clemens" uniqKey="Alt C" first="Clemens" last="Alt">Clemens Alt</name>
<affiliation wicri:level="1"><nlm:aff id="A10">Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114</wicri:regionArea>
<wicri:noRegion>Massachusetts 02114</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Mortensen, Luke J" sort="Mortensen, Luke J" uniqKey="Mortensen L" first="Luke J." last="Mortensen">Luke J. Mortensen</name>
<affiliation wicri:level="1"><nlm:aff id="A10">Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114</wicri:regionArea>
<wicri:noRegion>Massachusetts 02114</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Lin, Charles P" sort="Lin, Charles P" uniqKey="Lin C" first="Charles P." last="Lin">Charles P. Lin</name>
<affiliation wicri:level="1"><nlm:aff id="A10">Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114</wicri:regionArea>
<wicri:noRegion>Massachusetts 02114</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Zieske, James D" sort="Zieske, James D" uniqKey="Zieske J" first="James D." last="Zieske">James D. Zieske</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary and Harvard Medical School, Boston, Massachusetts 02114, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary and Harvard Medical School, Boston, Massachusetts 02114</wicri:regionArea>
<wicri:noRegion>Massachusetts 02114</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Frank, Markus H" sort="Frank, Markus H" uniqKey="Frank M" first="Markus H." last="Frank">Markus H. Frank</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Transplant Research Program, Division of Nephrology, Boston Children’s Hospital, Boston, Massachusetts 02115, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Transplant Research Program, Division of Nephrology, Boston Children’s Hospital, Boston, Massachusetts 02115</wicri:regionArea>
<wicri:noRegion>Massachusetts 02115</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A3">Departmentof Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Departmentof Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts 02115</wicri:regionArea>
<wicri:noRegion>Massachusetts 02115</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A11">Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02138, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02138</wicri:regionArea>
<wicri:noRegion>Massachusetts 02138</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Frank, Natasha Y" sort="Frank, Natasha Y" uniqKey="Frank N" first="Natasha Y." last="Frank">Natasha Y. Frank</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Transplant Research Program, Division of Nephrology, Boston Children’s Hospital, Boston, Massachusetts 02115, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Transplant Research Program, Division of Nephrology, Boston Children’s Hospital, Boston, Massachusetts 02115</wicri:regionArea>
<wicri:noRegion>Massachusetts 02115</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A4">Department of Medicine, VA Boston Healthcare System, Boston, Massachusetts 02130, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, VA Boston Healthcare System, Boston, Massachusetts 02130</wicri:regionArea>
<wicri:noRegion>Massachusetts 02130</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A11">Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02138, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02138</wicri:regionArea>
<wicri:noRegion>Massachusetts 02138</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A12">Division of Genetics, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Genetics, Brigham and Women’s Hospital, Boston, Massachusetts 02115</wicri:regionArea>
<wicri:noRegion>Massachusetts 02115</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series><title level="j">Nature</title>
<idno type="ISSN">0028-0836</idno>
<idno type="eISSN">1476-4687</idno>
<imprint><date when="2014">2014</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>ATP-Binding Cassette Transporters (deficiency)</term>
<term>ATP-Binding Cassette Transporters (metabolism)</term>
<term>Animals</term>
<term>Apoptosis</term>
<term>Biomarkers (metabolism)</term>
<term>Cell Differentiation</term>
<term>Cell Proliferation</term>
<term>Female</term>
<term>Humans</term>
<term>Limbus Corneae (cytology)</term>
<term>Limbus Corneae (physiology)</term>
<term>Male</term>
<term>Mice</term>
<term>Mice, Knockout</term>
<term>Molecular Sequence Data</term>
<term>P-Glycoprotein (deficiency)</term>
<term>P-Glycoprotein (metabolism)</term>
<term>Regeneration</term>
<term>Stem Cell Transplantation</term>
<term>Stem Cells (cytology)</term>
<term>Stem Cells (metabolism)</term>
<term>Transcription Factors (metabolism)</term>
<term>Tumor Suppressor Proteins (metabolism)</term>
<term>Wound Healing</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term>
<term>Apoptose</term>
<term>Cellules souches (cytologie)</term>
<term>Cellules souches (métabolisme)</term>
<term>Cicatrisation de plaie</term>
<term>Différenciation cellulaire</term>
<term>Données de séquences moléculaires</term>
<term>Facteurs de transcription (métabolisme)</term>
<term>Femelle</term>
<term>Glycoprotéine P (déficit)</term>
<term>Glycoprotéine P (métabolisme)</term>
<term>Humains</term>
<term>Limbe de la cornée (cytologie)</term>
<term>Limbe de la cornée (physiologie)</term>
<term>Marqueurs biologiques (métabolisme)</term>
<term>Mâle</term>
<term>Prolifération cellulaire</term>
<term>Protéines suppresseurs de tumeurs (métabolisme)</term>
<term>Régénération</term>
<term>Souris</term>
<term>Souris knockout</term>
<term>Transplantation de cellules souches</term>
<term>Transporteurs ABC (déficit)</term>
<term>Transporteurs ABC (métabolisme)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="deficiency" xml:lang="en"><term>P-Glycoprotein</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Biomarkers</term>
<term>P-Glycoprotein</term>
<term>Transcription Factors</term>
<term>Tumor Suppressor Proteins</term>
</keywords>
<keywords scheme="MESH" qualifier="cytologie" xml:lang="fr"><term>Cellules souches</term>
<term>Limbe de la cornée</term>
</keywords>
<keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Limbus Corneae</term>
<term>Stem Cells</term>
</keywords>
<keywords scheme="MESH" qualifier="deficiency" xml:lang="en"><term>ATP-Binding Cassette Transporters</term>
</keywords>
<keywords scheme="MESH" qualifier="déficit" xml:lang="fr"><term>Glycoprotéine P</term>
<term>Transporteurs ABC</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>ATP-Binding Cassette Transporters</term>
<term>Stem Cells</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Cellules souches</term>
<term>Facteurs de transcription</term>
<term>Glycoprotéine P</term>
<term>Marqueurs biologiques</term>
<term>Protéines suppresseurs de tumeurs</term>
<term>Transporteurs ABC</term>
</keywords>
<keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Limbe de la cornée</term>
</keywords>
<keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Limbus Corneae</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Apoptosis</term>
<term>Cell Differentiation</term>
<term>Cell Proliferation</term>
<term>Female</term>
<term>Humans</term>
<term>Male</term>
<term>Mice</term>
<term>Mice, Knockout</term>
<term>Molecular Sequence Data</term>
<term>Regeneration</term>
<term>Stem Cell Transplantation</term>
<term>Wound Healing</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Apoptose</term>
<term>Cicatrisation de plaie</term>
<term>Différenciation cellulaire</term>
<term>Données de séquences moléculaires</term>
<term>Femelle</term>
<term>Humains</term>
<term>Mâle</term>
<term>Prolifération cellulaire</term>
<term>Régénération</term>
<term>Souris</term>
<term>Souris knockout</term>
<term>Transplantation de cellules souches</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p id="P1">Corneal epithelial homeostasis and regeneration are sustained by limbal stem cells (LSCs)<sup><xref rid="R1" ref-type="bibr">1</xref>
–<xref rid="R3" ref-type="bibr">3</xref>
</sup>
, and LSC deficiency is a major cause of blindness worldwide<sup><xref rid="R4" ref-type="bibr">4</xref>
</sup>
. Transplantation is often the only therapeutic option available to patients with LSC deficiency. However, while transplant success depends foremost on LSC frequency within grafts<sup><xref rid="R5" ref-type="bibr">5</xref>
</sup>
, a gene allowing for prospective LSC enrichment has not been identified so far<sup><xref rid="R5" ref-type="bibr">5</xref>
</sup>
. Here we show that ATP-binding cassette, sub-family B, member 5 (ABCB5)<sup><xref rid="R6" ref-type="bibr">6</xref>
,<xref rid="R7" ref-type="bibr">7</xref>
</sup>
 marks LSCs and is required for LSC maintenance, corneal development and repair. Furthermore, we demonstrate that prospectively isolated human or murine ABCB5-positive LSCs possess the exclusive capacity to fully restore the cornea upon grafting to LSC-deficient mice in xenogeneic or syngeneic transplantation models. ABCB5 is preferentially expressed on label-retaining LSCs<sup><xref rid="R2" ref-type="bibr">2</xref>
</sup>
 in mice and p63α-positive LSCs<sup><xref rid="R8" ref-type="bibr">8</xref>
</sup>
 in humans. Consistent with these findings, ABCB5-positive LSC frequency is reduced in LSC-deficient patients. Abcb5 loss of function in <italic>Abcb5</italic>
 knockout mice causes depletion of quiescent LSCs due to enhanced proliferation and apoptosis, and results in defective corneal differentiation and wound healing. Our results from gene knockout studies, LSC tracing and transplantation models, as well as phenotypic and functional analyses of human biopsy specimens, provide converging lines of evidence that ABCB5 identifies mammalian LSCs. Identification and prospective isolation of molecularly defined LSCs with essential functions in corneal development and repair has important implications for the treatment of corneal disease, particularly corneal blindness due to LSC deficiency.</p>
</div>
</front>
</TEI>
<affiliations><list><country><li>États-Unis</li>
</country>
<region><li>Iowa</li>
</region>
<settlement><li>Iowa City</li>
</settlement>
<orgName><li>Université de l'Iowa</li>
</orgName>
</list>
<tree><country name="États-Unis"><noRegion><name sortKey="Ksander, Bruce R" sort="Ksander, Bruce R" uniqKey="Ksander B" first="Bruce R." last="Ksander">Bruce R. Ksander</name>
</noRegion>
<name sortKey="Alt, Clemens" sort="Alt, Clemens" uniqKey="Alt C" first="Clemens" last="Alt">Clemens Alt</name>
<name sortKey="Call, Mindy K" sort="Call, Mindy K" uniqKey="Call M" first="Mindy K." last="Call">Mindy K. Call</name>
<name sortKey="Cruz Guilloty, Fernando" sort="Cruz Guilloty, Fernando" uniqKey="Cruz Guilloty F" first="Fernando" last="Cruz-Guilloty">Fernando Cruz-Guilloty</name>
<name sortKey="Frank, Markus H" sort="Frank, Markus H" uniqKey="Frank M" first="Markus H." last="Frank">Markus H. Frank</name>
<name sortKey="Frank, Markus H" sort="Frank, Markus H" uniqKey="Frank M" first="Markus H." last="Frank">Markus H. Frank</name>
<name sortKey="Frank, Markus H" sort="Frank, Markus H" uniqKey="Frank M" first="Markus H." last="Frank">Markus H. Frank</name>
<name sortKey="Frank, Natasha Y" sort="Frank, Natasha Y" uniqKey="Frank N" first="Natasha Y." last="Frank">Natasha Y. Frank</name>
<name sortKey="Frank, Natasha Y" sort="Frank, Natasha Y" uniqKey="Frank N" first="Natasha Y." last="Frank">Natasha Y. Frank</name>
<name sortKey="Frank, Natasha Y" sort="Frank, Natasha Y" uniqKey="Frank N" first="Natasha Y." last="Frank">Natasha Y. Frank</name>
<name sortKey="Frank, Natasha Y" sort="Frank, Natasha Y" uniqKey="Frank N" first="Natasha Y." last="Frank">Natasha Y. Frank</name>
<name sortKey="Gregory, Meredith S" sort="Gregory, Meredith S" uniqKey="Gregory M" first="Meredith S." last="Gregory">Meredith S. Gregory</name>
<name sortKey="Guo, Qin" sort="Guo, Qin" uniqKey="Guo Q" first="Qin" last="Guo">Qin Guo</name>
<name sortKey="Guo, Qin" sort="Guo, Qin" uniqKey="Guo Q" first="Qin" last="Guo">Qin Guo</name>
<name sortKey="Guo, Qin" sort="Guo, Qin" uniqKey="Guo Q" first="Qin" last="Guo">Qin Guo</name>
<name sortKey="Kao, Winston W Y" sort="Kao, Winston W Y" uniqKey="Kao W" first="Winston W. Y." last="Kao">Winston W. Y. Kao</name>
<name sortKey="Kolovou, Paraskevi E" sort="Kolovou, Paraskevi E" uniqKey="Kolovou P" first="Paraskevi E." last="Kolovou">Paraskevi E. Kolovou</name>
<name sortKey="Lathrop, Kira L" sort="Lathrop, Kira L" uniqKey="Lathrop K" first="Kira L." last="Lathrop">Kira L. Lathrop</name>
<name sortKey="Lin, Charles P" sort="Lin, Charles P" uniqKey="Lin C" first="Charles P." last="Lin">Charles P. Lin</name>
<name sortKey="Ma, Jie" sort="Ma, Jie" uniqKey="Ma J" first="Jie" last="Ma">Jie Ma</name>
<name sortKey="Ma, Jie" sort="Ma, Jie" uniqKey="Ma J" first="Jie" last="Ma">Jie Ma</name>
<name sortKey="Mcguire, Sean P" sort="Mcguire, Sean P" uniqKey="Mcguire S" first="Sean P." last="Mcguire">Sean P. Mcguire</name>
<name sortKey="Mortensen, Luke J" sort="Mortensen, Luke J" uniqKey="Mortensen L" first="Luke J." last="Mortensen">Luke J. Mortensen</name>
<name sortKey="Murphy, George F" sort="Murphy, George F" uniqKey="Murphy G" first="George F." last="Murphy">George F. Murphy</name>
<name sortKey="Perez, Victor L" sort="Perez, Victor L" uniqKey="Perez V" first="Victor L." last="Perez">Victor L. Perez</name>
<name sortKey="Saab, Karim R" sort="Saab, Karim R" uniqKey="Saab K" first="Karim R." last="Saab">Karim R. Saab</name>
<name sortKey="Saab, Karim R" sort="Saab, Karim R" uniqKey="Saab K" first="Karim R." last="Saab">Karim R. Saab</name>
<name sortKey="Tucker, Budd A" sort="Tucker, Budd A" uniqKey="Tucker B" first="Budd A." last="Tucker">Budd A. Tucker</name>
<name sortKey="Vincent, William J B" sort="Vincent, William J B" uniqKey="Vincent W" first="William J. B." last="Vincent">William J. B. Vincent</name>
<name sortKey="Wilson, Brian J" sort="Wilson, Brian J" uniqKey="Wilson B" first="Brian J." last="Wilson">Brian J. Wilson</name>
<name sortKey="Wilson, Brian J" sort="Wilson, Brian J" uniqKey="Wilson B" first="Brian J." last="Wilson">Brian J. Wilson</name>
<name sortKey="Wilson, Brian J" sort="Wilson, Brian J" uniqKey="Wilson B" first="Brian J." last="Wilson">Brian J. Wilson</name>
<name sortKey="Zhan, Qian" sort="Zhan, Qian" uniqKey="Zhan Q" first="Qian" last="Zhan">Qian Zhan</name>
<name sortKey="Zieske, James D" sort="Zieske, James D" uniqKey="Zieske J" first="James D." last="Zieske">James D. Zieske</name>
</country>
</tree>
</affiliations>
</record>

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ABCB5 is a limbal stem cell gene required for corneal development and repair

ABCB5 is a limbal stem cell gene required for corneal development and repair

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