Müller Cells Dedifferentiation During Rat Retina Degeneration

Retina degeneration disease is the leading cause of blindness worldwide, which lack the suitable clinical treatment. Among several experimental approaches for the treatment of retina degeneration, stem cell-based therapy offers a novel therapeutic approach, based on the stratagem that transplanted progenitor cells could replace the lost photoreceptor cells during the degenerative process. In recent years several reports have been published in this field, proved that transplanted retina progenitor cells could integrate into host retina and differentiate into photoreceptors and play an effective way in rescuing vision in animal models of retinal degeneration. However cell-based therapeutic approaches have been limited to date due to the minimal survival and integration of donor cells into the ONL and their ability to participate into host retinal circuitry.With the scientific development, we know more and more about ourselves. It has long been believed that the adult mammalian central nervous system (CNS) lacked for neurogenesis, but in the last decade it has been proved that continuous neurogenesis occurs at two principal sites: the subventricular zone (SVZ) of the lateral ventricles and the hippocampus. Moreover, radial glia which arises from neuroepithelial cells around the time that neurons begin to appear has long been recognized as scaffolds for immature neurons migrating to the cortical plate during neurogenesis, while recent evidence suggests that the radial glia could participate in neural regeneration and showed multipotential character of neural stem cells in adult mammalian CNS. With regard to the retina, which is a part of the CNS, it has been indicated that Müller cells are the radial glia of the neural retina. Recent studies showed that they could behave as endogenous retina progenitor cells and show the proliferation and regenerating potentials in vitro or in vivo, under certain special conditions. These give people a new sight on treating retinal degeneration disease by using this group of cells. However, most of these in vivo studies performed on the mammalian model of acute retina injure, such as N-methy1-D-aspartate (NMDA) neurotoxin injury, laser injury and N-methy1-N-nitrosourea (MNU). These acute retina degenerations are rare in clinic. Till now no researches focus on the neurons progenitor potential of Müller cells in chronically retinal degeneration pathological process. Our lab found out that Chx10, which is a retina progenitor marker re-expressed during the peak time of retina degeneration of RCS rat and then drop down gradually. Based on all the researches above and the previous results in our lab, we make a hypothesis that Müller could be stimulated into cell cycle during the retina degeneration progress and retina stem cells transplantation.Based on the hypothesis above, our study initially focused on: 1) investigate whether Müller cells could show potential of regeneration during the pathological process of RCS rats; 2) transplant DiI labeled rat retina stem cells into subretinal space of RCS rat at day 30. Investigate grafts survival, migration, differentiation and rescue effects; 3) investigate whether Müller cells could be stimulated reenter cell cycle and dedifferentiate after retina stem cells transplantation. Our main results are showed as following:1. Müller cells could show potential of retina progenitor cells during the pathological process of RCS rats. 2. After transplantation, grafts cells could survival, migration and differentiation into photoreceptors. And the most important is that retina stem cells transplantation could rescue the vision function of RCS rat. 3. The proliferating Müller cells dedifferentiate and a sub set of these cells differentiated into photoreceptors after retina stem cells transplantation.In this study, we found evidence that Müller cells show part of their character of being a retinal progenitor cells during the chronically retina degeneration process in RCS rats. In addition, we found that Müller cells can be activated and differentiate into photoreceptors after retinal stem cells transplantation. Our research also point out a new way of understanding cell-based therapy, which not only replace the photoreceptor by exogenous donor cells but also stimulate endogenous progenitor cells into photoreceptor.