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Tauroursodeoxycholic Acid Promotes Neuronal Survival and Proliferation of Tissue Resident Stem and Progenitor Cells in Retina of Adult Zebrafish

hepatic stellate cells. 17–19) Recent study also demonstrates that in the neurogenic niches of adult rat brain, administration of TUDCA induces in vivo proliferation of neural stem cells, 20) suggesting that TUDCA can elicit proliferation of tissue resident stem and progenitor cells in the central nervous system. Using adult zebrafish, we investigate the effect of TUDCA on proliferation of retinal stem and progenitors. In the intact retina, TUDCA enhanced proliferation of actively cycling progenitors, but not quiescent stem cells. Following constant light lesion, TUDCA exerted protective effect and attenuated loss of photoreceptors. Importantly, following stab wound lesion, TUDCA significantly increased the number of BrdU-labeled proliferative cells derived from reprogrammed Müller glia. These results highlight TUDCA as a potential pharmacological substance that promotes neural survival and proliferation of tissue resident stem and progenitor cells. Regenerative medicine aims to replenish damaged tissue. Boosting the capacity of intrinsic stem cells to proliferate is one key for successful regeneration. Adult zebrafish possess tissue resident stem and progenitor cells, which contribute to homeostatic growth and tissue regeneration. In the intact retina, Müller glia sporadically divide to generate fate restricted, proliferative precursors. Cell death reprograms Müller glia into stem cells that divide and produce multi-potent retinal progenitors. Using zebrafish, we evaluated the effect of taurine-con-jugated bile acid, Tauroursodeoxycholic acid (TUDCA) on retinal regeneration. In the intact retina, treatment with TUDCA significantly promotes proliferation of the fate restricted precursors, but has no effect on Müller glia. Following constant light exposure, TUDCA attenuates photoreceptor death, indicating that TUDCA is neuroprotective. Following a stab wound, which initiates death of retinal neurons and reprogramming of Müller glia, treatment with TUDCA significantly increases the number of proliferating cells. In the intact retina, TUDCA-induced proliferation was accompanied by decreased expression of cell cycle inhibitors. These results suggest that TUDCA promotes proliferation of actively-cycling stem and progenitors, identifying TUDCA as a potential reagent to promote regeneration of retinal neurons.