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(Investigative Ophthalmology and Visual Science. 2008;49:1142-1150.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.07-0434
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{alpha}-Aminoadipate Induces Progenitor Cell Properties of Müller Glia in Adult Mice

Masumi Takeda,1,2,3 Akira Takamiya,1,2,3 Jian-wei Jiao,1,2 Kin-Sang Cho,1,2 Simon G. Trevino,1 Takahiko Matsuda,4 and Dong F. Chen1,2

1From the The Schepens Eye Research Institute and the 2Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts; the 3Department of Ophthalmology, Asahikawa Medical College, Asahikawa, Japan; and the 4Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts.

PURPOSE. Retinal Müller glia in higher vertebrates have been reported to possess progenitor cell properties and the ability to generate new neurons after injury. This study was conducted to determine the signals that can activate this dormant capacity of Müller glia in adult mice, by studying their behavior during glutamate stimulation.

METHODS. Various concentrations of glutamate and its analogue {alpha}-aminoadipate, which specifically binds Müller glia, were injected subretinally in adult mice. Proliferating retinal cells were labeled by subretinal injection of 5'-bromo-2'-deoxyuridine (BrdU) followed by immunohistochemistry. Müller cell fates were analyzed in retinal sections by using double immunolabeling with primary antibodies against Müller and other retina-specific cell markers. The effects of glutamate and {alpha}-aminoadipate were also determined in purified Müller cell cultures.

RESULTS. Although high levels of glutamate induce retinal damage, subtoxic levels of glutamate directly stimulate Müller glia to re-enter the cell cycle and induce neurogenesis in vivo and in purified Müller cell cultures. {alpha}-Aminoadipate, which selectively target glial cells, also induced expression of progenitor cell markers by Müller cells in vitro or stimulated Müller cell migration to the outer nuclear layer (ONL) and to differentiate into photoreceptors in vivo.

CONCLUSIONS. Mature Müller glia in adult mice can be induced to dedifferentiate, migrate, and generate new retinal neurons and photoreceptor cells by {alpha}-aminoadipate or glutamate signaling. The results of this study suggest a novel potential strategy for treating retinal neurodegeneration, including retinitis pigmentosa and age-related macular degeneration, without transplanting exogenous cells.






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Copyright © 2008 by the Association for Research in Vision and Ophthalmology