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. 2024 Nov 30;10(1):60.
doi: 10.1038/s41514-024-00187-9.

SenMayo transcriptomic senescence panel highlights glial cells in the ageing mouse and human retina

Samyuktha Suresh #  1 , Gayathri Karthik #  1 , John F Ouyang  2 , Vicki Chrysostomou  1   3 , See Aik Tang  1 , Enrico Petretto  2   4 , Jonathan G Crowston  1   3   5 , Katharina C Bell  6   7   8
Affiliations

SenMayo transcriptomic senescence panel highlights glial cells in the ageing mouse and human retina

Samyuktha Suresh et al. NPJ Aging. .

Abstract

There is a growing need to better characterise senescent cells in the CNS and retina. The recently published SenMayo gene panel was developed to identify transcriptomic signatures of senescence across multiple organ systems, but the retina was not included. While other approaches have identified senescent signatures in the retina, these have largely focused on experimental models in young animals. We therefore conducted a detailed single-cell RNA-seq analysis to identify senescent cell populations in the retina of different aged mice and compared these with five comprehensive human and mouse retina and brain transcriptome datasets. Transcriptomic signatures of senescence were most apparent in mouse and human retinal glial cells, with IL4, 13 and 10 and the AP1 pathway being the most prominent markers involved. Similar levels of transcriptional senescence were observed in the retinal glia of young and old mice, whereas the human retina showed significantly increased enrichment scores with advancing age.

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Conflict of interest statement

Competing interests: The authors declare no competing interests. Ethics approval: All breeding and experimental procedures were undertaken in accordance with the Association for Research for Vision and Ophthalmology Statement for the Use of Animals in Ophthalmic and Research and were approved by the SingHealth Institutional Animal Care and Use Committee (2019/SHS/1534).

Figures

Fig. 1
Fig. 1. “SenMayo-hi” cells detected in the mouse retina mainly correspond with retinal glial cells.
a UMAP plot of murine retina samples collected from 3-, 12-, and 24-month-old mice representing an ageing series. Cells detected include neurons such as Rods, Cones, Retinal Ganglion Cells (RGCs), Bipolar cells (BCs), Amacrine Cells (ACs), Horizontal cells (HCs), glia including Mueller Glia (MG), Astrocytes (Asc) and Microglia (Mic), Endothelial cell, Pericytes (ECs & Pericytes) and retinal blood cells (Ret blood). b Density plot showing the cell type distribution of SenMayo gene panel enrichment scores obtained using the escape package. Mic cells score the highest. c UMAP highlighting the SenMayo-hi cells, which correspond to Mac, Mic, Asc and Endothelial cells. d Percentage of SenMayo-hi cells per cell type. e SenMayo-hi cells also score high for GenAge and CellAge. Inset- Violin plot shows the upregulation of Tgfb2 gene expression in SenMayo-hi cells in the mouse retina. f Chord diagram representing ligand-receptor (L-R) signalling pathways in the mouse retina, that includes signalling both from and to the SenMayo-hi cells. These cells mainly interact with themselves, suggesting a strong signalling network within this category.
Fig. 2
Fig. 2. SenMayo-hi cells detected in the retinal microglia (Mic).
a UMAP plot of SenMayo-hi cells in the Mic subcluster. b Top 30 enriched biological processes (BP) in SenMayo-hi Mic, with senescence and immune response-related processes highlighted in blue (FDR < 0.01). See the Supplementary Table 4a for a full list. c Top 20 genes upregulated in the SenMayo-hi Mic (vs SenMayo-low Mic). d Top 30 enriched pathways in SenMayo-hi Mic with senescence-related pathways highlighted in blue (FDR < 0.01). See the Supplementary Table 4b for a full list. e Violin plots depicting increased expression of genes related to AP1 pathway, IL4/13 and IL10signalling in SenMayo-hi Mic.
Fig. 3
Fig. 3. SenMayo-hi cells detected in the retinal Mueller glia (MG).
a UMAP plot of SenMayo-hi cells in the MG subcluster. b Top 30 enriched biological processes (BP) in SenMayo-hi MG with senescence and glial response processes highlighted in blue (FDR < 0.01). See the Supplementary Table 6a for a full list. c Top 20 genes upregulated in the SenMayo-hi MG (vs SenMayo-low MG). d Top 30 enriched pathways in SenMayo-hi MG with senescence-related pathways highlighted in blue (FDR < 0.01). See the Supplementary Table 6b for a full list. e Violin plots depicting increased expression of genes related to AP1 pathway and interleukin 4/13 signalling in SenMayo-hi MG.
Fig. 4
Fig. 4. Microglia and other glial cells comprise most of the SenMayo-hi cells in the human retina.
a UMAP plot depicting cell types in the human retina (GEO: GSE148077). Cells detected include Rods, Cones, Retina Ganglion cells (RGCs), Bipolar cells (BCs), Amacrine cells (ACs), Horizontal cells (HCs), Mueller glia (MG), Astrocytes (Asc), Microglia (Mic) and Endothelial cells & Pericytes (ECs and Pericytes). b SenMayo enrichment score (ES) distribution in the human retina by cell type. c UMAP plot of human retina depicting SenMayo-hi cells. Mic cells score the highest. d Percentage of SenMayo-hi cells in different cell types in the human retina. e SenMayo-hi cells also score high for GenAge and CellAge gene sets. f Violin plots show the upregulation of MIF and AXL in SenMayo-hi cells in the human retina.
Fig. 5
Fig. 5. Comparison of SenMayo-hi glia in mouse and human retina datasets shows conserved interleukin signalling in all glial cells and AP1 pathway enrichment in microglia specifically.
a Scatter plot comparing log fold change of genes in SenMayo-hi microglia (Mic) (against SenMayo-low Mic) in mouse and human retina. b Scatter plot comparing log fold change of genes in SenMayo-hi Mueller glia (MG) in mouse and human retina (against SenMayo-low Mueller glia). c Dotplot of enriched pathways in human SenMayo-hi Mic with pathways that are also enriched in mouse Mic highlighted and labelled in red (FDR < 0.01) See Supplementary Table 9a for a full list. d Dotplot of enriched pathways in human SenMayo-hi MG with pathways that are also enriched in mouse MG highlighted and labelled in red (FDR < 0.01) See Supplementary Table 9b for a full list. e and f Selected common interaction pathways in mouse and human SenMayo-hi cells include APP and PSAP pathways. In both e mouse and f human many interactions of SenMayo-hi cells include signalling to other SenMayo-hi glia.
Fig. 6
Fig. 6. SenMayo panel enrichment with age in the retina.
SenMayo enrichment scores (ES) in the a mouse microglia and b mouse Mueller glia clusters show no trend to increase with age. Increased SenMayo enrichment scores with age in c human microglia (significant increase) d Mueller glia (significant increase between both 60 s and 70 s vs 50 s). SenMayo genes that are increased with age in e human microglia and f Mueller glia.
Fig. 7
Fig. 7. Age-related changes in the mouse retina.
IPA canonical pathway comparison analysis of DEGs from 12-mo vs 3-mo and 24-mo vs 3-mo a Mueller glia, b rod photoreceptors c cone photoreceptors and d Bipolar cells (p-value < 0.05).
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