Intercellular communication analysis of the human retinal pigment epithelial and choroidal cells predicts pathways associated with aging, cellular senescence and age-related macular degeneration

Abstract

The retinal pigment epithelium (RPE) and the choroid are ocular tissues with fundamental roles in supporting neuroretinal function. The pathogenesis of age-related macular degeneration (AMD), a leading cause of irreversible blindness for which aging is the highest risk factor is closely linked with progressive impairment of various functions of these tissues. Cellular senescence, marked by cell cycle arrest and secretion of proinflammatory factors, is known to be associated with aging and has been proposed as a potential driver of AMD. Here, we investigated the role played by intercellular communication in the RPE/choroid within the context of aging, senescence and AMD. We inferred cell–cell interactions in the RPE/choroid by applying CellChat and scDiffCom on a publicly available scRNA-seq dataset from three human donors with and without AMD. We identified age-regulated ligand and receptor genes by using limma on a separate publicly available bulk microarray dataset providing RPE/choroid samples at multiple time points. Cellular senescence was investigated by assigning a score to each cell and each sample of these scRNA-seq and microarray datasets, respectively, based on the expression of key signature genes determined by a previous senescence meta-analysis. We identified VEGF-, BMP-and tenascin-mediated pathways supporting some of the strongest cell–cell interactions between RPE cells, fibroblasts and choroidal endothelial cells and as strong intercellular communication pathways related to both aging and senescence. Their signaling strength was enhanced between subpopulations of cells having high senescence scores. Predominant ligands of these pathways were upregulated with age whereas predominant receptors were downregulated. Globally, we also observed that cells from AMD samples presented slightly bigger senescence scores than normal cells and that the senescence score positively correlated with age in bulk samples (R = 0.26, value of p < 0.01). Hence, our analysis provides novel information on RPE/choroid intercellular communication that gives insights into the connection between aging, senescence and AMD.

CircMETTL3 inhibits H2O2-induced senescence, oxidative stress, and DNA damage in ARPE-19 cells via miR-100/BMPR2 axis

“…In order to further elucidate the molecular mechanism of miR-100 in AMD, we identi ed BMPR2, the downstream target of miR-100, using StarBase and TargetScan. Dhirachaikulpanich et al revealed that decreased expression of BMPR2 receptor in human choroidal endothelial cells during aging [27]. In this study, depletion of BMPR2 accelerates senescence, oxidative stress, and DNA damage in H 2 O 2treated ARPE-19 cells.…”

A tissue ubiquitous gene set for cellular senescence

“…Figure 2i-j show example interaction plots in the human trachea tissue. T cells and epithelial cells are among the top interaction targets of SnCs 12,29 (Figure 2k), consistent across human and mouse (correlation=0.417, Figure 2l, Supplementary Table S4). Several key pathways known as hallmarks of cellular senescence are consistently enriched across tissues (Figure 2m), including COLLAGEN, which is responsible for extracellular matrix remodeling and enlarged phenotypes of senescent cells 30-32 ; LAMININ, corresponding to the loss of laminin B1 that compromises nuclear integrity in senescent cells 1,33 ; MHC-I, which is elevated in senescent cells 34,35 ; and MIF, which is involved in senescence-associated inflammation and oxidative stress response pathways 36,37 .…”

Molecular hallmarks of ageing in amyotrophic lateral sclerosis

“…Senescent cells are metabolically active and can communicate with, and influence the behaviour of, neighbouring cells through paracrine signalling [ 231 ]. Senescence is also an important part of inter-cellular communication and ageing [ 232 ] via SASP [ 233 ]. As well as the secretion of pro-inflammatory molecules, senescent cells also communicate with other cells via membrane-bound intercellular bridges or ‘tunnelling nanotubes’, that facilitate direct physical connections between cells [ 234 ].…”