| Vision is the most important sensory perception of the humans.At least 80%of external input to brain is processed by the visual pathway.The retina is a thin,semitransparent,multilayered sheet of neural tissue located in the inner wall of the eyeball,which is the first station of vision formation.The function of retina is to convert optical signals into electrical signals,and transmit the signals to the brain through the optic nerve to form visual perception.Although in mammals,the retina has relatively conservative tissue structures,primates have macula and fovea which are a highly specialized area of the central retina that gives primates the ability to see fine details.The fovea enrichs a large number of cone cells responsible for photopic vision and color vision,and ganglion cells responsible for signal transmission.Any visual disease that affects the fovea area will cause significant visual decline.Therefore,it is of great biological significance to study the molecular characteristics of the macula and fovea in primates.Notwithstanding human and macaque retina share many similarities,such as genetics,anatomy,physiology and immunology,there are also differences between them,detailed molecular and cellular signatures between the different cell types in human and macaque retina remain elusive.In particular,whether various cell types in the human and macaque retina exhibit different molecular changes following aging is largely unknown.In addition,the differences in cell composition and gene expression between the fovea and the peripheral area of the primates retina are not well understood.Therefore,it is important to understand the cellular and gene expression changes in the human and non-human primate retina during aging process in fovea and periphery area respectively,so as to provide an important research basis for the treatment and intervention of age-related retinal diseases.We collected single-cell transcriptomic profiles of 119,520 cells,including 38,558 from six healthy human samples(one 8-day-old infant and,five adults aged between 35 and 87 years)and 80,962 from five macaque samples(one 2-year-old juvenile and four adults aged between 4 and 23 years).First,through data analysis and immunofluorescence validation,we identified a previously undescribed population of retinal cell types-OTX2/RLBP1 double positive cells.Secondly,the results of our study showed that the rods of both species could be divided into two special subsets,MYO9A+ rods and MYO9A-rods,but the composition proportion of the two rods subtypes was different between species.Combining ATAC-seq and immunofluorescence verification,we found that the formation of rod cell subtypes was probably regulated by transcription factor OTX2.Furthermore,the results illustreated that Muller glial and cone showed relatively consistent regional gene expression differences between the two species,and the distribution of horizontal cell subtypes differed between regions.All the differences were confirmed by immunofluorescence and RNA-Scope in situ hybridization.Not only that,through ATAC-seq,we also found that the regional differential gene expression of cone cells was likely to be affected by Muller glial.Thus,our results provide a detailed analysis of the differences and conservation in cellular composition and molecular characteristics of primate retinas.Aging affects retinal function and structure physiologically and pathologically.To clarify the cellular and molecular changes during aging,we systematically studied human retinal samples(between 35 and 87 years old).We categorized the five samples into three groups(35Y,adult group;52Y and 63Y,mid-age group;86Y and 87Y,aging group).It was found that during the aging process of human retina,rod cells were intolerant to aging,and MYO9A-rod cells were extremely sensitive to aging.However,because the proportion of MYO9A-rod cells in the macaque monkey retina was very low,the phenomenon was not detected in macaque.In addition,the up-regulated biological process of Muller glia during aging was different from other retinal cell types.The aging of retina was not only reflected in the changes of gene expression in various cell types,but also by changes in cell-to-cell communication.The expression of receptor-ligands between cells is significantly different between the adult group and the aging group.By integrating the aging gene set,we constructed a visualized model of human retinal aging,and found that the aging degree and rate of the foveal retina are greater than those in the peripheral retina.In addition,we discovered new molecular markers of retinal aging,explored the changes of the difference between fovea and periphery retina during the aging process.Therefore,the results of our study not only systematically analyzed the molecular characteristics of various cell types in the aging process of human retina,but also revealed the regional and cellular subtype specific variation of retinal aging.Based on the analysis of retinal aging process,we constructed an expression map of 178 disease-susceptibility genes of 55 human retinal diseases in human and macaque retinas.It was found that the disease genes expression pattern of two species shows the characteristics that conservation and specificity coexistence among two species.It implied that macaques used as a human visual disease model is conditional.Together,these results provide a solid basis for understanding the cellular and molecular mechanisms of human retinal diseases.In summary,we analyzed the cell composition and related molecular characteristics of the aging primate retina,and compared the conserved degree of cell composition and gene expression between human and macaque retina.We studied in detail the cellular and molecular events involved in retinal aging in primates.A multi-species map of human visual disease gene expression was establisted to provide a valuable resource for the future clinical treatment of retinal diseases and the delivery of targeted drugs. |
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