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

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

doi:10.1038/nature13426

Back

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

Journal article

Open access

Peer reviewed

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

Bruce R Ksander, Paraskevi E Kolovou, Brian J Wilson, Karim R Saab, Qin Guo, Jie Ma, Sean P McGuire, Meredith S Gregory, William J B Vincent, Victor L Perez, …

Nature (London), Vol.511(7509), pp.353-357

07/17/2014

DOI: 10.1038/nature13426

PMCID: PMC4246512

PMID: 25030174

Files and links (1)

url

http://doi.org/10.1038/nature13426View

Open Access

Abstract

Corneal epithelial homeostasis and regeneration are sustained by limbal stem cells (LSCs), and LSC deficiency is a major cause of blindness worldwide. Transplantation is often the only therapeutic option available to patients with LSC deficiency. However, while transplant success depends foremost on LSC frequency within grafts, a gene allowing for prospective LSC enrichment has not been identified so far. Here we show that ATP-binding cassette, sub-family B, member 5 (ABCB5) 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 in mice and p63α-positive LSCs 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.

Wound Healing

Cell Differentiation

Apoptosis

Biomarkers - metabolism

Tumor Suppressor Proteins - metabolism

Cell Proliferation

Humans

ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism

Molecular Sequence Data

Male

Stem Cells - cytology

Stem Cells - metabolism

Mice, Knockout

Stem Cell Transplantation

Transcription Factors - metabolism

ATP-Binding Cassette Transporters - deficiency

Regeneration

Animals

ATP-Binding Cassette Transporters - metabolism

ATP-Binding Cassette, Sub-Family B, Member 1 - deficiency

Female

Mice

Limbus Corneae - cytology

Limbus Corneae - physiology

Details

Title: Subtitle: ABCB5 is a limbal stem cell gene required for corneal development and repair
Creators: Bruce R Ksander - 1] Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary and Harvard Medical School, Boston, Massachusetts 02114, USA
Paraskevi E Kolovou - 1] Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary and Harvard Medical School, Boston, Massachusetts 02114, USA
Brian J Wilson - 1] Transplant Research Program, Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts 02115, USA Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA Department of Medicine, VA Boston Healthcare System, Boston, Massachusetts 02130, USA
Karim R Saab - 1] Transplant Research Program, Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts 02115, USA Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA
Qin Guo - 1] Department of Medicine, VA Boston Healthcare System, Boston, Massachusetts 02130, USA Transplant Research Program, Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts 02115, USA Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA
Jie Ma - 1] Transplant Research Program, Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts 02115, USA Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA
Sean P McGuire - Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary and Harvard Medical School, Boston, Massachusetts 02114, USA
Meredith S Gregory - Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary and Harvard Medical School, Boston, Massachusetts 02114, USA
William J B Vincent - Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary and Harvard Medical School, Boston, Massachusetts 02114, USA
Victor L Perez - Bascom Palmer Eye Institute and the Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
Fernando Cruz-Guilloty - Bascom Palmer Eye Institute and the Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
Winston W Y Kao - Department of Ophthalmology, University of Cincinnati Medical Center, Cincinnati, Ohio 45229, USA
Mindy K Call - Department of Ophthalmology, University of Cincinnati Medical Center, Cincinnati, Ohio 45229, USA
Budd A Tucker - 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
Qian Zhan - Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA
George F Murphy - Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA
Kira L Lathrop - Department of Ophthalmology, University of Pittsburgh School of Medicine & Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, Pennsylvania 15213, USA
Clemens Alt - Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
Luke J Mortensen - Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
Charles P Lin - Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
James D Zieske - Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary and Harvard Medical School, Boston, Massachusetts 02114, USA
Markus H Frank - 1] Transplant Research Program, Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts 02115, USA Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02138, USA
Natasha Y Frank - 1] Department of Medicine, VA Boston Healthcare System, Boston, Massachusetts 02130, USA Transplant Research Program, Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts 02115, USA Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02138, USA Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA
Resource Type: Journal article
Publication Details: Nature (London), Vol.511(7509), pp.353-357
DOI: 10.1038/nature13426
PMID: 25030174
PMCID: PMC4246512
NLM abbreviation: Nature
ISSN: 1476-4687
eISSN: 1476-4687
Publisher: England
Grant note: R01EY018624 / NEI NIH HHS P41 EB015903 / NIBIB NIH HHS P30 EY008098 / NEI NIH HHS Howard Hughes Medical Institute U01 HL100402 / NHLBI NIH HHS P30EY014801 / NEI NIH HHS I01 RX000989 / RRD VA R01 CA138231 / NCI NIH HHS P30 EY014801 / NEI NIH HHS R01CA138231 / NCI NIH HHS R01CA113796 / NCI NIH HHS R01 CA113796 / NCI NIH HHS P41EB015903 / NIBIB NIH HHS I01 BX000516 / BLRD VA P30 EY003790 / NEI NIH HHS K08 NS051349 / NINDS NIH HHS R01 EY018624 / NEI NIH HHS EY08098 / NEI NIH HHS R01 EB017274 / NIBIB NIH HHS R01CA158467 / NCI NIH HHS DP2 OD007483 / NIH HHS U01HL100402 / NHLBI NIH HHS R01 CA158467 / NCI NIH HHS R01EY021768 / NEI NIH HHS DP2OD007483 / NIH HHS K08NS051349 / NINDS NIH HHS R01 EY021768 / NEI NIH HHS
Language: English
Date published: 07/17/2014
Academic Unit: Ophthalmology and Visual Sciences
Record Identifier: 9983980092402771

Metrics

40 Record Views

218 Times Cited - Web of Science