Ephrin-A2 and -A3 are negative regulators of the regenerative potential of Möller cells.

Ruilin ZHU; Kin-Sang CHO; Dong Feng CHEN; Liu YANG

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Ephrin-A2 and -A3 are negative regulators of the regenerative potential of Möller cells.

Author: Ruilin ZHU ^{1
,

2
,

3} ; Kin-Sang CHO ⁴ ; Dong Feng CHEN ⁵ ; Liu YANG ¹ ;
Author Information

1. Department of Ophthalmology, Peking University First Hospital
2. Key Laboratory of Vision Loss and Restoration, Ministry of Education, Beijing, China
3. Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
4. Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
5. Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
Publication Type:Journal Article
MeSH: Animals; Cell Differentiation; genetics; physiology; Ephrin-A2; genetics; metabolism; Ephrin-A3; genetics; metabolism; Fluorescent Antibody Technique; Mice; Mice, Inbred C57BL; Mice, Knockout; Real-Time Polymerase Chain Reaction; Receptor, EphA4; genetics; metabolism; Retina; cytology; metabolism; Reverse Transcriptase Polymerase Chain Reaction; Stem Cells; cytology; metabolism
From: Chinese Medical Journal 2014;127(19):3438-3442
CountryChina
Language:English
Abstract:
BACKGROUNDIn a previous study, we demonstrated that ephrin-A2 and -A3 negatively regulate the growth of neural progenitor cells in the central nervous system. Adult mice deficient in ephrin-A2 and -A3 (A2(-/-)A3(-/-)) displayed active ongoing neurogenesis throughout the brain, and mice deficient in ephrin-A3 alone showed increased proliferation of ciliary epithelium derived retinal stem cells. This study aimed to detect that the increase in proliferation and neurogenic potential of Müller cells is influenced by the absence of ephrin-A2 and -A3.
METHODSWe assessed the retinal and Müller cell expression of ephrin-As and their receptor and neural progenitor cell markers by immunostaining and real-time PCR. We cultured purified primary Müller cells derived from wild-type and A2(-/-)A3(-/-) mice in a defined culture medium that enables trans-differentiation of Müller cells into retinal neurons. To evaluate proliferating Müller cells in vivo, we injected 5'-ethylnyl-2'-deoxiuridine (EdU) intraperitoneally to adult mice.
RESULTSExpression of ephrin-A2/A3 and their receptor EphA4 were detected in the retinas of adult mice, with EphA4 expression particularly enriched in Müller cells. Müller cells of A2(-/-)A3(-/-) mice exhibited significantly elevated expression of retinal progenitor cell markers, Pax6 and Chx10, when compared with those from wild-type mice. Moreover, a higher percentage of Müller cells of A2(-/-)A3(-/-) mice trans-differentiated and became recoverin+ and β-III-tublin+ in the culture than those from wild type mice. Strikingly, an increased number of EdU+ retinal cells was detected in the retinas of adult A2(-/-)A3(-/-) mice as compared with wild-type mice.
CONCLUSIONSEphrin-A2 and -A3 are negative regulators of the proliferative and neurogenic potentials of Müller cells. Manipulating ephrin-A signaling may thus represent a novel strategy for stimulating neuroregeneration from endogenous progenitors to participate in retinal repair in case of disease or damage.