Single-cell transcriptome analysis of the Akimba mouse retina reveals cell-type-specific insights into the pathobiology of diabetic retinopathy

Abstract

Aims/hypothesis

Diabetic retinopathy is a common complication of diabetes and a leading cause of visual impairment and blindness. Despite recent advances, our understanding of its pathophysiology remains incomplete. The aim of this study was to provide deeper insight into the complex network of molecular and cellular changes that underlie diabetic retinopathy by systematically mapping the transcriptional changes that occur in the different cellular compartments of the degenerating diabetic mouse retina.

Methods

Single-cell RNA sequencing was performed on retinal tissue from 12-week-old wild-type and Akimba (Ins2Akita×Vegfa+/) mice, which are known to replicate features of clinical diabetic retinopathy. This resulted in transcriptome data for 9474 retinal cells, which could be annotated to eight distinct retinal cell types. Using STRING analysis, we studied differentially expressed gene networks in neuronal, glial and immune cell compartments to create a comprehensive view on the pathological changes that occur in the Akimba retina. Using subclustering analysis, we further characterised macroglial and inflammatory cell subpopulations. Prominent findings were confirmed at the protein level using immunohistochemistry, western blotting and ELISA.

Results

At 12 weeks, the Akimba retina was found to display degeneration of rod photoreceptors and presence of inflammatory cells, identified by subclustering analysis as monocyte, macrophage and microglial populations. Analysis of differentially expressed genes in the rod, cone, bipolar cell and macroglial compartments indicated changes in cell metabolism and ribosomal gene expression, gliosis, activation of immune system pathways and redox and metal ion dyshomeostasis. Experiments at the protein level supported a metabolic shift from glycolysis to oxidative phosphorylation (glyceraldehyde 3-phosphate dehydrogenase), activation of microglia/macrophages (isolectin-B4), metal ion and oxidative stress response (metallothionein and haem oxygenase-1) and reactive macroglia (glial fibrillary acidic protein and S100) in the Akimba retina, compared with wild-type mice. Our single-cell approach also indicates macroglial subpopulations with distinct fibrotic, inflammatory and gliotic profiles.

Conclusions/interpretation

Our study identifies molecular pathways underlying inflammatory, metabolic and oxidative stress-mediated changes in the Akimba mouse model of diabetic retinopathy and distinguishes distinct functional subtypes of inflammatory and macroglial cells.

Data availability

RNA-seq data have been deposited in the ArrayExpress database at EMBL-EBI (www.ebi.ac.uk/arrayexpress) under accession number E-MTAB-9061.

Graphical abstract

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Data availability

RNA-seq data have been deposited in the ArrayExpress database at EMBL-EBI (www.ebi.ac.uk/arrayexpress) under accession number E-MTAB-9061.

Abbreviations

BMP:

Bone morphogenetic protein

CC:

Canonical correlation

CNS:

Central nervous system

ECM:

Extracellular matrix

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GFAP:

Glial fibrillary acidic protein

GO:

Gene Ontology

HO-1:

Haem oxygenase-1

IGFBP:

IGF binding proteins

KEGG:

Kyoto Encyclopedia of Genes and Genomes

MT:

Metallothionein

OXPHOS:

Oxidative phosphorylation

RPE:

Retinal pigment epithelium

scRNAseq:

Single-cell RNA sequencing

STZ:

Streptozotocin

t-SNE:

t-Distributed Stochastic Neighbor Embedding

VEGF:

Vascular endothelial growth factor

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Acknowledgements

The authors wish to thank A. De Vriese, V. Vanheukelom and H. Moreau from Oxurion NV, L. Noterdaeme from KU Leuven, and B. Tembuyser and T. Van Brussel from VIB Center for Cancer Biology for their technical support. Some of the data were presented as an abstract at the 2019 European Association for Vision and Eye Research and European Association for the Study of Diabetic Eye Complications meetings.

Authors’ relationships and activities

IVH, TTH, TVB, KB, IE and MP are current employees at Oxurion NV; JHMF serves as a consultant to Oxurion NV. The other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Funding

LDG is a postdoctoral fellow supported by the Flemish Research Foundation (FWO Vlaanderen). The computational resources used in this work were provided by the Flemish Supercomputer Center (VSC), funded by the Hercules Foundation and the Flemish Government, Department of Economy, Science and Innovation (EWI). The funding agencies were not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication.

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IVH designed the study, performed experiments, analysed data and wrote the manuscript. LDG performed experiments, analysed data and wrote the manuscript. TTH, TVB, KB, IE, BB and EM performed experiments, analysed data and revised the manuscript. DL, LM and JHMF designed the study and revised the manuscript. MP designed the study, analysed data and wrote the manuscript. All authors approve the final version of the manuscript. MP is responsible for the integrity of the work as a whole.

Corresponding author

Correspondence to Michaël Porcu.

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Van Hove, I., De Groef, L., Boeckx, B. et al. Single-cell transcriptome analysis of the Akimba mouse retina reveals cell-type-specific insights into the pathobiology of diabetic retinopathy. Diabetologia (2020). https://doi.org/10.1007/s00125-020-05218-0

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Keywords

  • Akimba mouse
  • Diabetic retinopathy
  • Retina
  • Retinal degeneration
  • Single-cell transcriptomics