alpha-Aminoadipate induces progenitor cell properties of Müller glia in adult mice.
OBJECTIVE
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.
Takeda
Masumi
M
The Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
Takamiya
Akira
A
Jiao
Jian-Wei
JW
Cho
Kin-Sang
KS
Trevino
Simon G
SG
Matsuda
Takahiko
T
Chen
Dong F
DF
D015074:2-Aminoadipic Acid / Q000494:pharmacology*; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D019084:Fluorescent Antibody Technique, Indirect; D018698:Glutamic Acid / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000166:cytology* / Q000378:metabolism; D051603:Recoverin / Q000378:metabolism; D012160:Retina / Q000166:cytology*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
C020932:11-cis-retinal-binding protein; D002352:Carrier Proteins; D018691:Excitatory Amino Acid Antagonists; D051603:Recoverin; D015074:2-Aminoadipic Acid; D018698:Glutamic Acid; D001973:Bromodeoxyuridine