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      Combined Transplantation of Olfactory Ensheathing Cells With Rat Neural Stem Cells Enhanced the Therapeutic Effect in the Retina of RCS Rats


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          Retinal degenerative diseases (RDDs) are the leading causes of blindness and currently lack effective treatment. Cytotherapy has become a promising strategy for RDDs. The transplantation of olfactory ensheathing cells (OECs) or neural stem cells (NSCs) has recently been applied for the experimental treatment of RDDs. However, the long-term outcomes of single-cell transplantation are poor. The combined transplantation of multiple types of cells might achieve better effects. In the present study, OECs [containing olfactory nerve fibroblasts (ONFs)] and NSCs were cotransplanted into the subretinal space of Royal College of Surgeons (RCS) rats. Using electroretinogram (ERG), immunofluorescence, Western blot, and in vitro Transwell system, the differences in the electrophysiological and morphological changes of single and combined transplantation as well as the underlying mechanisms were explored at 4, 8, and 12 weeks postoperation. In addition, using the Transwell system, the influence of OECs on the stemness of NSCs was discovered. Results showed that, compared to the single transplantation of OECs or NSCs, the combined transplantation of OECs and NSCs produced greater improvements in b-wave amplitudes in ERGs and the thickness of the outer nuclear layer at all three time points. More endogenous stem cells were found within the retina after combined transplantation. Glial fibrillary acidic protein (GFAP) expression decreased significantly when NSCs were cotransplanted with OECs. Both the vertical and horizontal migration of grafted cells were enhanced in the combined transplantation group. Meanwhile, the stemness of NSCs was also better maintained after coculture with OECs. Taken together, the results suggested that the combined transplantation of NSCs and OECs enhanced the improvement in retinal protection in RCS rats, providing a new strategy to treat RDDs in the future.

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          Stimulation of functional neuronal regeneration from Müller glia in adult mice

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            Microglia-Müller glia cell interactions control neurotrophic factor production during light-induced retinal degeneration.

            Activation of microglia commonly occurs in response to a wide variety of pathological stimuli including trauma, axotomy, ischemia, and degeneration in the CNS. In the retina, prolonged or high-intensity exposure to visible light leads to photoreceptor cell apoptosis. In such a light-reared retina, we found that activated microglia invade the degenerating photoreceptor layer and alter expression of neurotrophic factors such as nerve growth factor (NGF), ciliary neurotrophic factor (CNTF), and glial cell line-derived neurotrophic factor (GDNF). Because these neurotrophic factors modulate secondary trophic factor expression in Müller glial cells, microglia-Müller glia cell interaction may contribute to protection of photoreceptors or increase photoreceptor apoptosis. In the present study, we demonstrate the possibility that such functional glia-glia interactions constitute the key mechanism by which microglia-derived NGF, brain-derived neurotrophic factor (BDNF), and CNTF indirectly influence photoreceptor survival, although the receptors for these neurotrophic factors are absent from photoreceptors, by modulating basic fibroblast growth factor (bFGF) and GDNF production and release from Müller glia. These observations suggest that microglia regulate the microglia-Müller glia-photoreceptor network that serves as a trophic factor-controlling system during retinal degeneration.
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              Restoration of vision after de novo genesis of rod photoreceptors in mammalian retinas

              In zebrafish, Müller glial cells (MGs) are a source of retinal stem cells that can replenish damaged retinal neurons and restore vision 1 . In mammals, however, MGs lack regenerative capability as they do not spontaneously re-enter the cell cycle to generate a population of stem/progenitor cells that differentiate into retinal neurons. The regenerative machinery may exist in the mammalian retina, however, as retinal injury can stimulate MG proliferation followed by limited neurogenesis 2–7 . The fundamental question remains whether MG-derived regeneration can be exploited to restore vision in mammalian retinas. Previously, we showed that gene transfer of β-catenin stimulates MG proliferation in the absence of injury in mouse retinas 8 . Here, we report that following gene transfer of β-catenin, cell-cycle-reactivated MGs can be reprogrammed into rod photoreceptors via a subsequent gene transfer of transcription factors that are essential for rod cell fate specification and determination. MG-derived rods restored visual responses in Gnat1rd17 :Gnat2cpfl3 double mutant mice, a model of congenital blindness 9,10 , throughout the visual pathway from the retina to the primary visual cortex. Together, our results provide evidence of vision restoration after de novo MG-derived genesis of rod photoreceptors in mammalian retinas.

                Author and article information

                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                24 March 2020
                : 14
                [1] 1Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University) , Chongqing, China
                [2] 2Key Lab of Visual Damage and Regeneration & Restoration of Chongqing , Chongqing, China
                [3] 3Department of Ophthalmology, The 6th Medical Center of PLA General Hospital , Beijing, China
                Author notes

                Edited by: Gary S. L. Peh, Singapore Eye Research Institute (SERI), Singapore

                Reviewed by: Biju Thomas, University of Southern California, United States; Karen L. Lankford, Yale University, United States

                These authors have contributed equally to this work

                This article was submitted to Cellular Neuropathology, a section of the journal Frontiers in Cellular Neuroscience

                Copyright © 2020 Zhai, Gao, Qu, Li, Zeng, Li, Xu and Yin.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 7, Tables: 0, Equations: 0, References: 46, Pages: 15, Words: 0
                Funded by: National Key Research and Development Program of China Stem Cell and Translational Research 10.13039/501100013290
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Funded by: Southwest Hospital 10.13039/501100011476
                Original Research

                retinal degenerative diseases,neural stem cells,olfactory ensheathing cells,combined transplantation,rcs rats


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