alpha-aminoadipate induces progenitor cell properties of Muller glia in adult mice

作者:Takeda Masumi; Takamiya Akira; Jiao Jian Wei; Cho Kin Sang; Trevino Simon G; Matsuda Takahiko; Chen Dong F*
来源:Investigative Ophthalmology & Visual Science, 2008, 49(3): 1142-1150.
DOI:10.1167/iovs.07-0434

摘要

PURPOSE. Retinal Muller 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 Muller glia in adult mice, by studying their behavior during glutamate stimulation.
METHODS. Various concentrations of glutamate and its analogue alpha-aminoadipate, which specifically binds Muller glia, were injected subretinally in adult mice. Proliferating retinal cells were labeled by subretinal injection of 5'-bromo-2'-deoxyuridine (BrdU) followed by immunohistochemistry. Muller cell fates were analyzed in retinal sections by using double immunolabeling with primary antibodies against Muller and other retina-specific cell markers. The effects of glutamate and alpha-aminoadipate were also determined in purified Muller cell cultures.
RESULTS. Although high levels of glutamate induce retinal damage, subtoxic levels of glutamate directly stimulate Muller glia to re-enter the cell cycle and induce neurogenesis in vivo and in purified Muller cell cultures. alpha-Aminoadipate, which selectively target glial cells, also induced expression of progenitor cell markers by Muller cells in vitro or stimulated Muller cell migration to the outer nuclear layer (ONL) and to differentiate into photoreceptors in vivo.
CONCLUSIONS. Mature Muller 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.

  • 出版日期2008-3