Skip to main content
Top
Published in: European Journal of Medical Research 1/2024

Open Access 01-12-2024 | Diabetic Retinopathy | Research

Deciphering Müller cell heterogeneity signatures in diabetic retinopathy across species: an integrative single-cell analysis

Authors: Xiyuan Deng, Ya Mo, Xiuying Zhu

Published in: European Journal of Medical Research | Issue 1/2024

Login to get access

Abstract

Diabetic retinopathy (DR), a leading cause of visual impairment, demands a profound comprehension of its cellular mechanisms to formulate effective therapeutic strategies. Our study presentes a comprehensive single-cell analysis elucidating the intricate landscape of Müller cells within DR, emphasizing their nuanced involvement. Utilizing scRNA-seq data from both Sprague–Dawley rat models and human patients, we delineated distinct Müller cell clusters and their corresponding gene expression profiles. These findings were further validated through differential gene expression analysis utilizing human transcriptomic data. Notably, certain Müller cell clusters displayed upregulation of the Rho gene, implying a phagocytic response to damaged photoreceptors within the DR microenvironment. This phenomenon was consistently observed across species. Additionally, the co-expression patterns of RHO and PDE6G within Müller cell clusters provided compelling evidence supporting their potential role in maintaining retinal integrity during DR. Our results offer novel insights into the cellular dynamics of DR and underscore Müller cells as promising therapeutic targets for preserving vision in retinal disorders induced by diabetes.
Appendix
Available only for authorised users
Literature
1.
go back to reference Teo ZL, Tham YC, Yu M, et al. Global prevalence of diabetic retinopathy and projection of burden through 2045: systematic review and meta-analysis. Ophthalmology. 2021;128(11):1580–91.PubMedCrossRef Teo ZL, Tham YC, Yu M, et al. Global prevalence of diabetic retinopathy and projection of burden through 2045: systematic review and meta-analysis. Ophthalmology. 2021;128(11):1580–91.PubMedCrossRef
2.
go back to reference ValdezGuerrero AS, Quintana-Pérez JC, Arellano-Mendoza MG, Castañeda-Ibarra FJ, Tamay-Cach F, Alemán-González-Duhart D. Diabetic retinopathy: important biochemical alterations and the main treatment strategies. Can J Diabetes. 2021;45(6):504–11.PubMedCrossRef ValdezGuerrero AS, Quintana-Pérez JC, Arellano-Mendoza MG, Castañeda-Ibarra FJ, Tamay-Cach F, Alemán-González-Duhart D. Diabetic retinopathy: important biochemical alterations and the main treatment strategies. Can J Diabetes. 2021;45(6):504–11.PubMedCrossRef
4.
go back to reference Newman E, Reichenbach A. The Müller cell: a functional element of the retina. Trends Neurosci. 1996;19(8):307–12.PubMedCrossRef Newman E, Reichenbach A. The Müller cell: a functional element of the retina. Trends Neurosci. 1996;19(8):307–12.PubMedCrossRef
6.
go back to reference Barber AJ, Antonetti DA, Gardner TW. Altered expression of retinal occludin and glial fibrillary acidic protein in experimental diabetes. the penn state retina research group. Investig Ophthalmol vis sci. 2000;41(11):3561–8. Barber AJ, Antonetti DA, Gardner TW. Altered expression of retinal occludin and glial fibrillary acidic protein in experimental diabetes. the penn state retina research group. Investig Ophthalmol vis sci. 2000;41(11):3561–8.
7.
go back to reference Lieth E, Barber AJ, Xu B, et al. Glial reactivity and impaired glutamate metabolism in short-term experimental diabetic retinopathy penn state retina research group. Diabetes. 1998;47(5):815–20.PubMedCrossRef Lieth E, Barber AJ, Xu B, et al. Glial reactivity and impaired glutamate metabolism in short-term experimental diabetic retinopathy penn state retina research group. Diabetes. 1998;47(5):815–20.PubMedCrossRef
8.
go back to reference Chen W, Gardeux V, Meireles-Filho A, Deplancke B. Profiling of single-cell transcriptomes. Cur Protoc Mouse Biology. 2017;7(3):145–75.CrossRef Chen W, Gardeux V, Meireles-Filho A, Deplancke B. Profiling of single-cell transcriptomes. Cur Protoc Mouse Biology. 2017;7(3):145–75.CrossRef
11.
go back to reference Qiu X, Hill A, Packer J, Lin D, Ma YA, Trapnell C. Single-cell mRNA quantification and differential analysis with census. Nat Methods. 2017;14(3):309–15.PubMedPubMedCentralCrossRef Qiu X, Hill A, Packer J, Lin D, Ma YA, Trapnell C. Single-cell mRNA quantification and differential analysis with census. Nat Methods. 2017;14(3):309–15.PubMedPubMedCentralCrossRef
12.
13.
go back to reference Vento-Tormo R, Efremova M, Botting RA, et al. Single-cell reconstruction of the early maternal–fetal interface in humans. Nature. 2018;563(7731):347–53.PubMedPubMedCentralCrossRef Vento-Tormo R, Efremova M, Botting RA, et al. Single-cell reconstruction of the early maternal–fetal interface in humans. Nature. 2018;563(7731):347–53.PubMedPubMedCentralCrossRef
14.
go back to reference Ritchie ME, Phipson B, Wu D, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7): e47.PubMedPubMedCentralCrossRef Ritchie ME, Phipson B, Wu D, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7): e47.PubMedPubMedCentralCrossRef
15.
go back to reference Li HD, Lin CX, Zheng J. GTFtools: a software package for analyzing various features of gene models. Bioinformatics. 2022;38(20):4806–8.PubMedCrossRef Li HD, Lin CX, Zheng J. GTFtools: a software package for analyzing various features of gene models. Bioinformatics. 2022;38(20):4806–8.PubMedCrossRef
16.
go back to reference Chen K, Wang Y, Huang Y, et al. Cross-species scRNA-seq reveals the cellular landscape of retina and early alterations in type 2 diabetes mice. Genomics. 2023;115(4): 110644.PubMedCrossRef Chen K, Wang Y, Huang Y, et al. Cross-species scRNA-seq reveals the cellular landscape of retina and early alterations in type 2 diabetes mice. Genomics. 2023;115(4): 110644.PubMedCrossRef
17.
go back to reference Frey F, Idema T. More than just a barrier: using physical models to couple membrane shape to cell function. Soft Matter. 2021;17(13):3533–49.PubMedCrossRef Frey F, Idema T. More than just a barrier: using physical models to couple membrane shape to cell function. Soft Matter. 2021;17(13):3533–49.PubMedCrossRef
19.
go back to reference Zhang Y, Yang X, Deng X, et al. Single-cell transcriptomics-based multidisease analysis revealing the molecular dynamics of retinal neurovascular units under inflammatory and hypoxic conditions. Exp Neurol. 2023;362: 114345.PubMedCrossRef Zhang Y, Yang X, Deng X, et al. Single-cell transcriptomics-based multidisease analysis revealing the molecular dynamics of retinal neurovascular units under inflammatory and hypoxic conditions. Exp Neurol. 2023;362: 114345.PubMedCrossRef
20.
go back to reference Rosato C, Bettegazzi B, Intagliata P, et al. Redox and calcium alterations of a müller cell line exposed to diabetic retinopathy-like environment. Front Cell Neurosci. 2022;16: 862325.PubMedPubMedCentralCrossRef Rosato C, Bettegazzi B, Intagliata P, et al. Redox and calcium alterations of a müller cell line exposed to diabetic retinopathy-like environment. Front Cell Neurosci. 2022;16: 862325.PubMedPubMedCentralCrossRef
21.
go back to reference Netti V, Fernández J, Melamud L, et al. Aquaporin-4 removal from the plasma membrane of human Müller cells by aqp4-igg from patients with neuromyelitis optica induces changes in cell volume homeostasis: the first step of retinal injury? Mol Neurobiol. 2021;58(10):5178–93.PubMedCrossRef Netti V, Fernández J, Melamud L, et al. Aquaporin-4 removal from the plasma membrane of human Müller cells by aqp4-igg from patients with neuromyelitis optica induces changes in cell volume homeostasis: the first step of retinal injury? Mol Neurobiol. 2021;58(10):5178–93.PubMedCrossRef
22.
go back to reference Toft-Kehler AK, Skytt DM, Kolko M. A perspective on the Müller Cell-neuron metabolic partnership in the inner retina. Mol Neurobiol. 2018;55(6):5353–61.PubMedCrossRef Toft-Kehler AK, Skytt DM, Kolko M. A perspective on the Müller Cell-neuron metabolic partnership in the inner retina. Mol Neurobiol. 2018;55(6):5353–61.PubMedCrossRef
23.
go back to reference Di Pierdomenico J, Martínez-Vacas A, Hernández-Muñoz D, et al. Coordinated intervention of microglial and Müller cells in light-induced retinal degeneration. Invest Ophthalmol Vis Sci. 2020;61(3):47.PubMedPubMedCentralCrossRef Di Pierdomenico J, Martínez-Vacas A, Hernández-Muñoz D, et al. Coordinated intervention of microglial and Müller cells in light-induced retinal degeneration. Invest Ophthalmol Vis Sci. 2020;61(3):47.PubMedPubMedCentralCrossRef
24.
go back to reference Liu B, Hunter DJ, Rooker S, et al. Wnt signaling promotes Müller cell proliferation and survival after injury. Invest Ophthalmol Vis Sci. 2013;54(1):444–53.PubMedCrossRef Liu B, Hunter DJ, Rooker S, et al. Wnt signaling promotes Müller cell proliferation and survival after injury. Invest Ophthalmol Vis Sci. 2013;54(1):444–53.PubMedCrossRef
25.
go back to reference Tang L, Xu GT, Zhang JF. Inflammation in diabetic retinopathy: possible roles in pathogenesis and potential implications for therapy. Neural Regen Res. 2023;18(5):976–82.PubMedCrossRef Tang L, Xu GT, Zhang JF. Inflammation in diabetic retinopathy: possible roles in pathogenesis and potential implications for therapy. Neural Regen Res. 2023;18(5):976–82.PubMedCrossRef
26.
28.
go back to reference Li X, Zhu J, Zhong Y, et al. Targeting long noncoding RNA-AQP4-AS1 for the treatment of retinal neurovascular dysfunction in diabetes mellitus. EBioMedicine. 2022;77: 103857.PubMedPubMedCentralCrossRef Li X, Zhu J, Zhong Y, et al. Targeting long noncoding RNA-AQP4-AS1 for the treatment of retinal neurovascular dysfunction in diabetes mellitus. EBioMedicine. 2022;77: 103857.PubMedPubMedCentralCrossRef
31.
go back to reference Wang W, LeBlanc ME, Chen X, et al. Pathogenic role and therapeutic potential of pleiotrophin in mouse models of ocular vascular disease. Angiogenesis. 2017;20(4):479–92.PubMedPubMedCentralCrossRef Wang W, LeBlanc ME, Chen X, et al. Pathogenic role and therapeutic potential of pleiotrophin in mouse models of ocular vascular disease. Angiogenesis. 2017;20(4):479–92.PubMedPubMedCentralCrossRef
33.
go back to reference Sakamoto K, Kadomatsu K. Midkine in the pathology of cancer, neural disease, and inflammation. Pathol Int. 2012;62(7):445–55.PubMedCrossRef Sakamoto K, Kadomatsu K. Midkine in the pathology of cancer, neural disease, and inflammation. Pathol Int. 2012;62(7):445–55.PubMedCrossRef
34.
go back to reference Gao H, Luodan A, Huang X, Chen X, Xu H. Müller glia-mediated retinal regeneration. Mol Neurobiol. 2021;58(5):2342–61.PubMedCrossRef Gao H, Luodan A, Huang X, Chen X, Xu H. Müller glia-mediated retinal regeneration. Mol Neurobiol. 2021;58(5):2342–61.PubMedCrossRef
35.
go back to reference Campbell WA, Fritsch-Kelleher A, Palazzo I, Hoang T, Blackshaw S, Fischer AJ. Midkine is neuroprotective and influences glial reactivity and the formation of Müller glia-derived progenitor cells in chick and mouse retinas. Glia. 2021;69(6):1515–39.PubMedPubMedCentralCrossRef Campbell WA, Fritsch-Kelleher A, Palazzo I, Hoang T, Blackshaw S, Fischer AJ. Midkine is neuroprotective and influences glial reactivity and the formation of Müller glia-derived progenitor cells in chick and mouse retinas. Glia. 2021;69(6):1515–39.PubMedPubMedCentralCrossRef
36.
go back to reference Nagashima M, D’Cruz TS, Danku AE, et al. Midkine-a Is required for cell cycle progression of müller glia during neuronal regeneration in the vertebrate retina. J Neurosci. 2020;40(6):1232–47.PubMedPubMedCentralCrossRef Nagashima M, D’Cruz TS, Danku AE, et al. Midkine-a Is required for cell cycle progression of müller glia during neuronal regeneration in the vertebrate retina. J Neurosci. 2020;40(6):1232–47.PubMedPubMedCentralCrossRef
38.
go back to reference Sanie-Jahromi F, Zia Z, Afarid M. A review on the effect of garlic on diabetes, BDNF, and VEGF as a potential treatment for diabetic retinopathy. Chin Med. 2023;18(1):18.PubMedPubMedCentralCrossRef Sanie-Jahromi F, Zia Z, Afarid M. A review on the effect of garlic on diabetes, BDNF, and VEGF as a potential treatment for diabetic retinopathy. Chin Med. 2023;18(1):18.PubMedPubMedCentralCrossRef
39.
go back to reference Mettu PS, Allingham MJ, Cousins SW. Incomplete response to anti-VEGF therapy in neovascular AMD: exploring disease mechanisms and therapeutic opportunities. Prog Retin Eye Res. 2021;82: 100906.PubMedCrossRef Mettu PS, Allingham MJ, Cousins SW. Incomplete response to anti-VEGF therapy in neovascular AMD: exploring disease mechanisms and therapeutic opportunities. Prog Retin Eye Res. 2021;82: 100906.PubMedCrossRef
40.
go back to reference Morales M, Findley AP, Mitchell DM. Intercellular contact and cargo transfer between Müller glia and to microglia precede apoptotic cell clearance in the developing retina. Development (Cambridge, England). 2024;151(1). Morales M, Findley AP, Mitchell DM. Intercellular contact and cargo transfer between Müller glia and to microglia precede apoptotic cell clearance in the developing retina. Development (Cambridge, England). 2024;151(1).
41.
go back to reference Bejarano-Escobar R, Sánchez-Calderón H, Otero-Arenas J, Martín-Partido G, Francisco-Morcillo J. Müller glia and phagocytosis of cell debris in retinal tissue. J Anat. 2017;231(4):471–83.PubMedPubMedCentralCrossRef Bejarano-Escobar R, Sánchez-Calderón H, Otero-Arenas J, Martín-Partido G, Francisco-Morcillo J. Müller glia and phagocytosis of cell debris in retinal tissue. J Anat. 2017;231(4):471–83.PubMedPubMedCentralCrossRef
42.
go back to reference Bailey TJ, Fossum SL, Fimbel SM, Montgomery JE, Hyde DR. The inhibitor of phagocytosis, O-phospho-L-serine, suppresses Müller glia proliferation and cone cell regeneration in the light-damaged zebrafish retina. Exp Eye Res. 2010;91(5):601–12.PubMedPubMedCentralCrossRef Bailey TJ, Fossum SL, Fimbel SM, Montgomery JE, Hyde DR. The inhibitor of phagocytosis, O-phospho-L-serine, suppresses Müller glia proliferation and cone cell regeneration in the light-damaged zebrafish retina. Exp Eye Res. 2010;91(5):601–12.PubMedPubMedCentralCrossRef
43.
go back to reference Sakami S, Imanishi Y, Palczewski K. Müller glia phagocytose dead photoreceptor cells in a mouse model of retinal degenerative disease. FASEB J. 2019;33(3):3680–92.PubMedCrossRef Sakami S, Imanishi Y, Palczewski K. Müller glia phagocytose dead photoreceptor cells in a mouse model of retinal degenerative disease. FASEB J. 2019;33(3):3680–92.PubMedCrossRef
44.
go back to reference Couturier A, Blot G, Vignaud L, et al. Reproducing diabetic retinopathy features using newly developed human induced-pluripotent stem cell-derived retinal Müller glial cells. Glia. 2021;69(7):1679–93.PubMedPubMedCentralCrossRef Couturier A, Blot G, Vignaud L, et al. Reproducing diabetic retinopathy features using newly developed human induced-pluripotent stem cell-derived retinal Müller glial cells. Glia. 2021;69(7):1679–93.PubMedPubMedCentralCrossRef
45.
go back to reference El-Hattab AW, Craigen WJ, Scaglia F. Mitochondrial DNA maintenance defects. Biochim Biophys Acta. 2017;1863(6):1539–55.CrossRef El-Hattab AW, Craigen WJ, Scaglia F. Mitochondrial DNA maintenance defects. Biochim Biophys Acta. 2017;1863(6):1539–55.CrossRef
46.
go back to reference Todd L, Fischer AJ. Hedgehog signaling stimulates the formation of proliferating Müller glia-derived progenitor cells in the chick retina. Development. 2015;142(15):2610–22.PubMedPubMedCentral Todd L, Fischer AJ. Hedgehog signaling stimulates the formation of proliferating Müller glia-derived progenitor cells in the chick retina. Development. 2015;142(15):2610–22.PubMedPubMedCentral
47.
go back to reference Afonina IS, Müller C, Martin SJ, Beyaert R. Proteolytic processing of interleukin-1 family cytokines: variations on a common theme. Immunity. 2015;42(6):991–1004.PubMedCrossRef Afonina IS, Müller C, Martin SJ, Beyaert R. Proteolytic processing of interleukin-1 family cytokines: variations on a common theme. Immunity. 2015;42(6):991–1004.PubMedCrossRef
48.
go back to reference Xiong JH, Chen JL, Liang JY, Zhang FF, Cheng SM. Identification of hub genes correlated with diabetic retinopathy via bioinformatics methods. Eur Rev Med Pharmacol Sci. 2023;27(11):4876–82.PubMed Xiong JH, Chen JL, Liang JY, Zhang FF, Cheng SM. Identification of hub genes correlated with diabetic retinopathy via bioinformatics methods. Eur Rev Med Pharmacol Sci. 2023;27(11):4876–82.PubMed
49.
go back to reference You ZP, Zhang YL, Li BY, Zhu XG, Shi K. Bioinformatics analysis of weighted genes in diabetic retinopathy. Invest Ophthalmol Vis Sci. 2018;59(13):5558–63.PubMedCrossRef You ZP, Zhang YL, Li BY, Zhu XG, Shi K. Bioinformatics analysis of weighted genes in diabetic retinopathy. Invest Ophthalmol Vis Sci. 2018;59(13):5558–63.PubMedCrossRef
Metadata
Title
Deciphering Müller cell heterogeneity signatures in diabetic retinopathy across species: an integrative single-cell analysis
Authors
Xiyuan Deng
Ya Mo
Xiuying Zhu
Publication date
01-12-2024
Publisher
BioMed Central
Published in
European Journal of Medical Research / Issue 1/2024
Electronic ISSN: 2047-783X
DOI
https://doi.org/10.1186/s40001-024-01847-y

Other articles of this Issue 1/2024

European Journal of Medical Research 1/2024 Go to the issue