Abstract
BackgroundAdult 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.MethodsHere, 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.ResultsWe 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.ConclusionsTogether, 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.
Highlights
Adult mammalian retinal stem cells (RSCs) readily proliferate, self-renew, and generate progeny that differentiate into all retinal cell types in vitro
Medium-throughput screening identifies several unique compound classes that expand retinal stem and progenitor cells in culture To identify compounds that can expand retinal stem and progenitor cell number, we developed a mediumthroughput screening (MTS) pipeline that combined a method for the generation and seeding of retinal stem and progenitor cells with medium-throughput image analysis
Glucocorticoid agonists stimulate mouse retinal stem and progenitor cell proliferation in vitro via both glucocorticoid receptor and mineralocorticoid receptor signaling Here, we investigated the cell biological effects that underpinned the ability of the synthetic GC agonists and other hit molecules to effect the increases in RSPC number detected via MTS
Summary
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. CE RSCs continue to be investigated as an exogenous source for cell replacement therapy and a potential source of endogenous retinal regeneration [5, 25] attempts to activate adult mammalian RSCs in vivo have not been effective, an outcome that is attributed to the presence of quiescence factors in the RSC niche [26, 27]
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