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M. Takeda, J. Jiao, K.–S. Cho, D.F. Chen; Glutamate Stimulates Neurogenesis and Photoreceptor Cell Regeneration in the Adult Mouse Retina . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3215.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: The retinas of adult mammals are unable to regenerate. Retinal Müller glia in higher vertebrates has been proposed to possess properties of endogenous progenitor cells and capable of generating new neurons after injury. However, signal that triggers neuro–regeneration from Müller glia remains unknown. Here, we ask whether Müller glia in the adult mouse retina can become progenitor cells and generate new neurons. Methods: Glutamate or its analogue with 5’–bromo–2’–deoxyuridine (BrdU) were injected into subretinal space of adult wild–type mice. The proliferation and differentiation capacities of BrdU+ cells were examined in vivo and in vitro. Immunohistochemistry was performed using antibodies to BrdU or various retinal cell–specific markers. The proliferative potential of Müller glia was also determined in purified cell cultures. Results: Glutamate, a neurotransmitter that accumulates after acute neural injury, stimulates adult murine Müller glia to de–differentiate and induces neurogenesis in vivo and in purified Müller glial cultures. A glutamate analogue that specifically targets astroglial cells also induced expression of progenitor cell markers in Müller glia and differentiation of progenitor–like cells into retina–specific neurons. In vivo, the glutamate analogue induced these progenitor–like cells to migrate to the outer nuclear layer, differentiate, and express mature photoreceptor cell markers. Conclusions: Glutamate stimulates directly Müller glia of adult mice to re–enter the cell cycle, exhibit progenitor cell properties, and generate retina–specific neurons. This capacity of glutamate to induce neurogenesis from dormant progenitors suggests a novel potential strategy for treating degenerative diseases without transplanting exogenous cells.
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