Kenneth N Grisé1,2, Nelson X Bautista3, Krystal Jacques4,5, Brenda L K Coles3,4, Derek van der Kooy3,4,5. 1. Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada. ken.grise@mail.utoronto.ca. 2. Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, M5S 3E1, Canada. ken.grise@mail.utoronto.ca. 3. Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada. 4. Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, M5S 3E1, Canada. 5. Institute of Medical Science, University of Toronto, Toronto, ON, M5S 1A8, Canada.
Abstract
BACKGROUND: Adult mammalian retinal stem cells (RSCs) readily proliferate, self-renew, and generate progeny that differentiate into all retinal cell types in vitro. RSC-derived progeny can be induced to differentiate into photoreceptors, making them a potential source for retinal cell transplant therapies. Despite their proliferative propensity in vitro, RSCs in the adult mammalian eye do not proliferate and do not have a regenerative response to injury. Thus, identifying and modulating the mechanisms that regulate RSC proliferation may enhance the capacity to produce RSC-derived progeny in vitro and enable RSC activation in vivo. METHODS: Here, we used medium-throughput screening to identify small molecules that can expand the number of RSCs and their progeny in culture. In vitro differentiation assays were used to assess the effects of synthetic glucocorticoid agonist dexamethasone on RSC-derived progenitor cell fate. Intravitreal injections of dexamethasone into adult mouse eyes were used to investigate the effects on endogenous RSCs. RESULTS: We discovered that high-affinity synthetic glucocorticoid agonists increase RSC self-renewal and increase retinal progenitor proliferation up to 6-fold without influencing their differentiation in vitro. Intravitreal injection of synthetic glucocorticoid agonist dexamethasone induced in vivo proliferation in the ciliary epithelium-the niche in which adult RSCs reside. CONCLUSIONS: Together, our results identify glucocorticoids as novel regulators of retinal stem and progenitor cell proliferation in culture and provide evidence that GCs may activate endogenous RSCs.
BACKGROUND: Adult mammalian retinal stem cells (RSCs) readily proliferate, self-renew, and generate progeny that differentiate into all retinal cell types in vitro. RSC-derived progeny can be induced to differentiate into photoreceptors, making them a potential source for retinal cell transplant therapies. Despite their proliferative propensity in vitro, RSCs in the adult mammalian eye do not proliferate and do not have a regenerative response to injury. Thus, identifying and modulating the mechanisms that regulate RSC proliferation may enhance the capacity to produce RSC-derived progeny in vitro and enable RSC activation in vivo. METHODS: Here, we used medium-throughput screening to identify small molecules that can expand the number of RSCs and their progeny in culture. In vitro differentiation assays were used to assess the effects of synthetic glucocorticoid agonist dexamethasone on RSC-derived progenitor cell fate. Intravitreal injections of dexamethasone into adult mouse eyes were used to investigate the effects on endogenous RSCs. RESULTS: We discovered that high-affinity synthetic glucocorticoid agonists increase RSC self-renewal and increase retinal progenitor proliferation up to 6-fold without influencing their differentiation in vitro. Intravitreal injection of synthetic glucocorticoid agonist dexamethasone induced in vivo proliferation in the ciliary epithelium-the niche in which adult RSCs reside. CONCLUSIONS: Together, our results identify glucocorticoids as novel regulators of retinal stem and progenitor cell proliferation in culture and provide evidence that GCs may activate endogenous RSCs.
Authors: Andreas Bringmann; Thomas Pannicke; Jens Grosche; Mike Francke; Peter Wiedemann; Serguei N Skatchkov; Neville N Osborne; Andreas Reichenbach Journal: Prog Retin Eye Res Date: 2006-07-12 Impact factor: 21.198
Authors: Chenbo Zeng; Fenghui Pan; Lynne A Jones; Miranda M Lim; Elizabeth A Griffin; Yvette I Sheline; Mark A Mintun; David M Holtzman; Robert H Mach Journal: Brain Res Date: 2010-01-11 Impact factor: 3.252