Heparin-binding EGF-like growth factor (HB-EGF) stimulates the proliferation of Müller glia-derived progenitor cells in avian and murine retinas.
Müller glia can be stimulated to de-differentiate, proliferate and form Müller glia-derived progenitor cells (MGPCs) that regenerate retinal neurons. In the zebrafish retina, heparin-binding EGF-like growth factor (HB-EGF) may be one of the key factors that stimulate the formation of proliferating MGPCs. Currently nothing is known about the influence of HB-EGF on the proliferative potential of Müller glia in retinas of birds and rodents. In the chick retina, we found that levels of both hb-egf and egf-receptor are rapidly and transiently up-regulated following NMDA-induced damage. Although intraocular injections of HB-EGF failed to stimulate cell-signaling or proliferation of Müller glia in normal retinas, HB-EGF stimulated proliferation of MGPCs in damaged retinas. By comparison, inhibition of the EGF-receptor (EGFR) decreased the proliferation of MGPCs in damaged retinas. HB-EGF failed to act synergistically with FGF2 to stimulate the formation of MGPCs in the undamaged retina and inhibition of EGF-receptor did not suppress FGF2-mediated formation of MGPCs. In the mouse retina, HB-EGF stimulated the proliferation of Müller glia following NMDA-induced damage. Furthermore, HB-EGF not only stimulated MAPK-signaling in Müller glia/MGPCs, but also activated mTor- and Jak/Stat-signaling. We propose that levels of expression of EGFR are rate-limiting to the responses of Müller glia to HB-EGF and the expression of EGFR can be induced by retinal damage, but not by FGF2-treatment. We conclude that HB-EGF is mitogenic to Müller glia in both chick and mouse retinas, and HB-EGF is an important player in the formation of MGPCs in damaged retinas.
Department of Neuroscience, College of Medicine, The Ohio State University, 4190 Graves Hall, 333 West 10th Ave, Columbus, OH 43210, USA.
Levi
L
Todd
Department of Neuroscience, College of Medicine, The Ohio State University, 4190 Graves Hall, 333 West 10th Ave, Columbus, OH 43210, USA.
Leo I
LI
Volkov
Department of Neuroscience, College of Medicine, The Ohio State University, 4190 Graves Hall, 333 West 10th Ave, Columbus, OH 43210, USA.
Chris
C
Zelinka
Department of Neuroscience, College of Medicine, The Ohio State University, 4190 Graves Hall, 333 West 10th Ave, Columbus, OH 43210, USA.
Natalie
N
Squires
Department of Neuroscience, College of Medicine, The Ohio State University, 4190 Graves Hall, 333 West 10th Ave, Columbus, OH 43210, USA. Electronic address: Andrew.Fischer@osumc.edu.
Andy J
AJ
Fischer
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002645:Chickens; D063928:Ependymoglial Cells / Q000166:cytology / Q000187:drug effects*; D066257:Heparin-binding EGF-like Growth Factor / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects*; D012160:Retina / Q000166:cytology* / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000378:metabolism; D015027:Zebrafish
D066257:Heparin-binding EGF-like Growth Factor
Müller glia; Progenitor; Proliferation; Retina