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ARS2 is required for retinal progenitor cell S-phase progression and Müller glial cell fate specification.
摘要： During a developmental period that extends postnatally in the mouse, proliferating multipotent retinal progenitor cells produce one of seven major cell types (rod, cone, bipolar, horizontal, amacrine, ganglion, and Müller glial cells) as they exit the cell cycle in consecutive waves. Cell production in the retina is tightly regulated by intrinsic, extrinsic, spatial, and temporal cues and is coupled to the timing of cell cycle exit. ARS2 (also known as SRRT) is a component of the nuclear cap-binding complex involved in RNA Polymerase II transcription, and is required for cell cycle progression. We show that postnatal RPCs require ARS2 for proper progression through S phase, and ARS2 disruption leads to early exit from the cell cycle. Furthermore, we observe an increase in the proportion of cells expressing a rod photoreceptor marker, and a loss of Müller glia marker expression, indicating a role for ARS2 in regulating cell fate specification or differentiation. Knockdown of FLASH, which interacts with ARS2 and is required for cell cycle progression and 3’-end processing of replication-dependent histone transcripts, phenocopies ARS2 knockdown. These data implicate ARS2/FLASH-mediated histone mRNA processing in regulating RPC cell cycle kinetics and neuroglial cell fate specification during postnatal retinal development.
关键词： photoreceptor cells,Müller cells,retina,retinal progenitor cells,cell cycle,Ars2
更新于2025-09-19 17:15:36
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Otx2 enhances transdifferentiation of Müller cells-derived retinal stem cells into photoreceptor-like cells
摘要： Retinal Müller glial cells have the potential of neurogenic retinal progenitor cells, and could reprogram into retinal‐specific cell types such as photoreceptor cells. How to promote the differentiation of Müller cells into photoreceptor cells represents a promising therapy strategy for retinal degeneration diseases. This study aimed to enhance the transdifferentiation of rat Müller cells‐derived retinal stem cells (MC‐RSCs) into photoreceptor‐like cells and explore the signalling mechanism. We dedifferentiated rat Müller cells into MC‐RSCs which were infected with Otx2 overexpression lentivirus or control. The positive rate of photoreceptor‐like cells among MC‐RSCs treated with Otx2 overexpression lentivirus was significantly higher compared to control. Furthermore, pre‐treatment with Crx siRNA, Nrl siRNA, or GSK‐3 inhibitor SB‐216763 reduced the positive rate of photoreceptor‐like cells among MC‐RSCs treated with Otx2 overexpression lentivirus. Finally, Otx2 induced photoreceptor precursor cells were injected into subretinal space of N‐methyl‐N‐nitrosourea induced rat model of retinal degeneration and partially recovered retinal degeneration in the rats. In conclusion, Otx2 enhances transdifferentiation of MC‐RSCs into photoreceptor‐like cells and this is associated with the inhibition of Wnt signalling. Otx2 is a potential target for gene therapy of retinal degenerative diseases.
关键词： Müller cells,photoreceptor cells,stem cells,Wnt signalling,Otx2
更新于2025-09-10 09:29:36
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Inner Segment Remodeling and Mitochondrial Translocation in Cone Photoreceptors in Age-Related Macular Degeneration With Outer Retinal Tubulation
摘要： PURPOSE. To quantify impressions of mitochondrial translocation in degenerating cones and to determine the nature of accumulated material in the subretinal space with apparent inner segment (IS)-like features by examining cone IS ultrastructure. METHODS. Human donor eyes with advanced age-related macular degeneration (AMD) were screened for outer retinal tubulation (ORT) in macula-wide, high-resolution digital sections. Degenerating cones inside ORT (ORT cones) and outside ORT (non-ORT cones) from AMD eyes and unaffected cones in age-matched control eyes were imaged using transmission electron microscopy. The distances of mitochondria to the external limiting membrane (ELM), cone IS length, and cone IS width at the ELM were measured. RESULTS. Outer retinal tubulation and non-ORT cones lose outer segments (OS), followed by shortening of IS and mitochondria. In non-ORT cones, IS broaden. Outer retinal tubulation and non-ORT cone IS myoids become undetectable due to mitochondria redistribution toward the nucleus. Some ORT cones were found lacking IS and containing mitochondria in the outer fiber (between soma and ELM). Unlike long, thin IS mitochondria in control cones, ORT and non-ORT IS mitochondria are ovoid or reniform. Shed IS, some containing mitochondria, were found in the subretinal space. CONCLUSIONS. In AMD, macula cones exhibit loss of detectable myoid due to IS shortening in addition to OS loss, as described. Mitochondria shrink and translocate toward the nucleus. As reflectivity sources, translocating mitochondria may be detectable using in vivo imaging to monitor photoreceptor degeneration in retinal disorders. These results improve the knowledge basis for interpreting high-resolution clinical retinal imaging.
关键词： ellipsoid,outer retinal tubulation,age-related macular degeneration,histology,photoreceptors,cones,myoid,transmission electron microscopy,Müller cells
更新于2025-09-10 09:29:36
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Müller Cell Regulated Microglial Activation and Migration in Rats With N-Methyl-N-Nitrosourea-Induced Retinal Degeneration
摘要： During the pathogenesis of retinitis pigmentosa (RP), the roles of retinal microglial cells after activation have not been fully elucidated. Herein, experimental RP was induced in Sprague Dawley rats by intraperitoneal injection of N-methyl-N-nitrosourea (MNU) at 50 mg/kg, and the effects of MNU on the retinas were evaluated, respectively, by retinal histology and electroretinography recordings at serial time points. Time-dependent and gradual loss of photoreceptor cells, disrupted arrangement of the outer nuclear layer (ONL), and significant reductions in both a-wave and b-wave amplitudes were observed. Morphology changes were observed in retinal microglial cells; meanwhile, with time, the number of Iba1-positive microglia and their infiltration into the ONL gradually increased. Furthermore, physical interaction of microglial-Müller cell processes following microglial activation was observed after MNU injection. In addition, Müller cells increased CX3CL1 secretion, enhanced microglial cell migration, and upregulated the CX3CR1 expression of the latter. Our observations implied that, during the pathogenesis of RP by MNU, microglial cells exhibit a prominent morphology change and Müller cells can induce activated microglia infiltration by increasing secretion of the chemotaxis factor, CX3CL1, and promoting the migration of retinal microglial cells. This novel finding highlights a potential therapeutic target aimed at regulating the microglial response.
关键词： N-methyl-N-nitrosourea,microglia,retinitis pigmentosa,Müller cells,crosstalk
更新于2025-09-04 15:30:14