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PUBLIC RELEASE DATE:
2-Jul-2014

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Contact: Mary Leach
Mary_Leach@meei.harvard.edu
Massachusetts Eye and Ear Infirmary
www.twitter.com/MassEyeAndEar

Researchers regrow corneas -- first known tissue grown from an adult human stem cell

Limbal stem cells, identified with new marker, could reverse a leading cause of blindness

IMAGE: This is a restored functional cornea following transplantation of human ABCB5-positive limbal stem cells to limbal stem cell-deficient mice. Transplants consisting of human ABCB5-positive limbal stem cells resulted in restoration...

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Boston (July 2, 2014) – Boston researchers have identified a way to enhance regrowth of human corneal tissue to restore vision, using a molecule known as ABCB5 that acts as a marker for hard-to-find limbal stem cells. This work, a collaboration between the Massachusetts Eye and Ear/Schepens Eye Research Institute (Mass. Eye and Ear), Boston Children's Hospital, Brigham and Women's Hospital and the VA Boston Healthcare System, provides promise to burn victims, victims of chemical injury and others with damaging eye diseases. The research, published this week in Nature, is also one of the first known examples of constructing a tissue from an adult-derived human stem cell.

Limbal stem cells reside in the eye's basal limbal epithelium, or limbus, and help maintain and regenerate corneal tissue. Their loss due to injury or disease is one of the leading causes of blindness. In the past, tissue or cell transplants have been used to help the cornea regenerate, but it was unknown whether there were actual limbal stem cells in the grafts, or how many, and the outcomes were not consistent.

In this study, researchers were able to use antibodies detecting ABCB5 to zero in on the stem cells in tissue from deceased human donors and use them to regrow anatomically correct, fully functional human corneas in mice.

IMAGE: Composite image depicting the palisades of Vogt within the human limbus (left), ABCB5-positive limbal stem cells isolated from the palisades (right; ABCB5 -- green, nucleus -- red) and a restored...

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"Limbal stem cells are very rare, and successful transplants are dependent on these rare cells," says Bruce Ksander, Ph.D., of Mass. Eye and Ear, co-lead author on the study with post-doctoral fellow Paraskevi Kolovou, M.D. "This finding will now make it much easier to restore the corneal surface. It's a very good example of basic research moving quickly to a translational application."

ABCB5 was originally discovered in the lab of Markus Frank, M.D., of Boston Children's Hospital, and Natasha Frank, M.D., of the VA Boston Healthcare System and Brigham and Women's Hospital, co-senior investigators on the study, as being produced in tissue precursor cells in human skin and intestine. In the new work, using a mouse model developed by the Frank lab, they found that ABCB5 also occurs in limbal stem cells and is required for their maintenance and survival, and for corneal development and repair. Mice lacking a functional ABCB5 gene lost their populations of limbal stem cells, and their corneas healed poorly after injury.

"ABCB5 allows limbal stem cells to survive, protecting them from apoptosis [programmed cell death]," says Markus Frank. "The mouse model allowed us for the first time to understand the role of ABCB5 in normal development, and should be very important to the stem cell field in general." according to Natasha Frank.

IMAGE: This is an image depicting the palisades of Vogt within the human limbus. The human limbal architecture shows the palisades of Vogt in whole mounted tissue labeled with collagen VII...

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Markus Frank is working with biopharmaceutical industry to develop a clinical-grade ABCB5 antibody that would meet U.S. regulatory approvals. "A single lab cannot do a study like this," says Natasha Frank, also affiliated with the Harvard Stem Cell Institute. "It integrates genetics, knockout mice, antibodies, transplantation—a lot of technical expertise that we were lucky came together in a very nice way."

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Researchers include Bruce R. Ksander, Paraskevi E. Kolovou, Sean P. McGuire, Meredith S. Gregory, William J. B. Vincent and James D. Zieske (Schepens Eye Research Institute/Massachusetts Eye and Ear and Harvard Medical School); Brian J. Wilson, Karim R. Saab, and Jie Ma (Boston Children's Hospital), Qin Guo (Boston Chidren's Hospital, VA Boston Healthcare System), Victor L. Perez and Fernando Cruz-Guilloty (Bascom Palmer Eye Institute, University of Miami Miller School of Medicine), Winston W.Y. Kao and Mindy K. Call (University of Cincinnati Medical Center), Budd A. Tucker (Stephen A Wynn Institute for Vision Research, Carver College of Medicine, University of Iowa), Qian Zhan and George Murphy (Brigham and Women's Hospital), Kira L. Lathrop (University of Pittsburgh), Clemens Alt, Luke J. Mortensen and Charles P. Lin (Massachusetts General Hospital and Harvard Medical School), Markus H. Frank (Boston Children's Hospital, Brigham and Women's Hospital, Harvard Medical School) and Natasha Y. Frank (VA Boston Healthcare System, Boston Children's Hospital, Brigham and Women's Hospital, Harvard Medical School).

The research was supported by the National Institute of Neurological Disorders and Stroke (grant K08NS051349), the Veterans Administration (BLR&D 1I01BX000516 and VA RR&D 1I01RX000989), the Harvard Stem Cell Institute, the National Cancer Institute (R01CA113796, R01CA158467, R01CA138231), the Department of Defense (PR0332453), the National Institutes of Health (R01EY018624, P30EY014801, R01EY021768, R01CA138231, R01EB017274, U01HL100402, P41EB015903 and NIH New Innovator Award DP2OD007483), the Corley Research Foundation, the Western Pennsylvania Medical Eye Bank Core Grant for Vision Research (EY08098), the Howard Hughes Medical Institute and the Life Sciences Research Foundation.

About Mass. Eye and Ear

Mass. Eye and Ear clinicians and scientists are driven by a mission to find cures for blindness, deafness and diseases of the head and neck. After uniting with Schepens Eye Research Institute in 2011, Mass. Eye and Ear in Boston became the world's largest vision and hearing research center, offering hope and healing to patients everywhere through discovery and innovation. Mass. Eye and Ear is a Harvard Medical School teaching hospital and trains future medical leaders in ophthalmology and otolaryngology, through residency as well as clinical and research fellowships. Internationally acclaimed since its founding in 1824, Mass. Eye and Ear employs full-time, board-certified physicians who offer high-quality and affordable specialty care that ranges from the routine to the very complex. U.S. News & World Report's "Best Hospitals Survey" has consistently ranked the Mass. Eye and Ear Departments of Otolaryngology and Ophthalmology as among the top hospitals in the nation. For more information about life-changing care and research, or to learn how you can help, please visit MassEyeAndEar.org.

About Boston Children's Hospital

Boston Children's Hospital is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including seven members of the National Academy of Sciences, 14 members of the Institute of Medicine and 14 members of the Howard Hughes Medical Institute comprise Boston Children's research community. Founded as a 20-bed hospital for children, Boston Children's today is a 395-bed comprehensive center for pediatric and adolescent health care. Boston Children's is also the primary pediatric teaching affiliate of Harvard Medical School. For more information about research and clinical innovation at Boston Children's, visit: http://vectorblog.org.

About Brigham and Women's Hospital

Brigham and Women's Hospital (BWH) is a 793-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare. BWH has more than 3.5 million annual patient visits, is the largest birthing center in Massachusetts and employs nearly 15,000 people. The Brigham's medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in patient care, quality improvement and patient safety initiatives, and its dedication toresearch, innovation, community engagement and educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Brigham Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on human diseases, more than 1,000 physician-investigators and renowned biomedical scientists and faculty supported by nearly $650 million in funding. For the last 25 years, BWH ranked second in research funding from the National Institutes of Health (NIH) among independent hospitals. BWH continually pushes the boundaries of medicine, including building on its legacy in transplantation by performing a partial face transplant in 2009 and the nation's first full face transplant in 2011. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative. For more information, resources and to follow us on social media, please visit BWH's online newsroom.

About VA Boston Healthcare System

VA Boston Healthcare System (VA BHS) is the largest VA facility in New England encompassing three campuses and four community outpatient clinics within a 40-mile radius of the greater Boston area. VA BHS serves as a national Research and Development center for medical research and is a major tertiary care center for the VA New England Healthcare System Veterans Integrated Service Network (VISN). Research is an integral part of the VA's mission and plays a key role in enhancing the healthcare services provided to the Massachusetts veteran population. With 238 principal investigators, 1,200 staff with research credentials, and two National Centers for PTSD, VA BHS's research service is one of the largest in VHA. Over 800 research studies are currently being conducted in all disciplines.



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