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Matthew Kent, Dominic Didiano, James Patton; Identification of novel factors to initiate retina regeneration in zebrafish. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3101.
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Regeneration remains a key goal in treating retina diseases. Zebrafish spontaneously regenerate the retina in response to damage whereas regeneration in mammals and humans is largely blocked. We sought to determine factors that could induce retina regeneration in both fish and mice. Previously, we showed that antagonizing the GABAA receptor could induce a proliferative response in proliferating progenitor cells derived from Müller glia (MG). We have now shown that inhibition of GABA signaling can induce a proliferative response in mice and we are actively engaged in identifying other factors that can induce regeneration, including GABA-ρ receptor antagonists and intravitreal injection of exosomes from various cell lines.
GABA – Fish were intravitreally injected with either PBS, gabazine, TPMPA (GABA-ρ antagonist), or the combination. At 48 hours post injection, retinas were fixed, sectioned, and immunostained with antibodies against PCNA. Cell nuclei were stained with TOPRO-3 and the number of proliferating cells analyzed.Exosomes - Fish were intravitreally injected with exosomes purified from over 30 different cell lines and induction of proliferation was determined by immunostaining with antibodies against PCNA.
GABA – The number of PCNA-positive cells was significantly greater when the combination of gabazine and TPMPA was injected, compared to either gabazine or TPMPA alone (p<0.0001). Although single injections of gabazine and TPMPA induced proliferation, no significant difference was observed between the two.Exosomes – Induction of a proliferative response upon injection of exosomes was cell-line dependent with some cells inducing a significant increase in PCNA positive cells and others showing no difference compared to PBS-injections. Exosomes from C6 glioma cells consistently induced the most robust regenerative response (p<0.0001).
MG-mediated regeneration can be initiated by altering the activity of various types of GABA receptors, not just GABAA receptors. In addition, factors in C6-derived exosomes are capable of initiating regeneration.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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