Pericyte dysfunction and loss of interpericyte tunneling nanotubes promote neurovascular deficits in glaucoma

Alarcón-Martínez, Luis; Shiga, Yukihiro; Villafranca‐Baughman, Deborah; Belforte, Nicolás; Quintero, Heberto; Dotigny, Florence; Vargas, Jorge L. Cueva; Polo, Adriana Di

doi:10.1073/pnas.2110329119

Cited by 44 publications

(47 citation statements)

References 59 publications

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“…Pericytes are mural cells that wrap around the endothelial cells that line capillary blood vessels. A recent study has found reduced capillary diameter and impaired blood flow at pericyte locations in mouse eyes with high IOP 70 .…”

Section: Discussionmentioning

confidence: 94%

Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma

Hamel

Rouhana

Yan

et al. 2022

Preprint

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Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide; however the molecular and cellular causes are not well understood. Elevated intraocular pressure (IOP) is a major risk factor, but many patients have normal IOP. Colocalization analysis of >130 POAG and 112 IOP GWAS loci and overlapping expression and splicing quantitative trait loci (e/sQTLs) in 49 GTEx tissues and retina proposed causal genes for 60% of the loci, that were enriched in extracellular matrix organization, cell adhesion, and vascular development. Analyzing single-nucleus RNA-seq of glaucoma-relevant eye tissues, we found that the colocalizing genes were enriched in known and less well-characterized cell types, including fibroblasts in the conventional and unconventional aqueous outflow pathways; vascular cells in the anterior segment; astrocytes and Müller glia in retina and optic nerve head (ONH); and smooth muscle and vascular endothelial cells in ONH. This study nominated IOP- dependent and independent regulatory mechanisms, genes, and cell types that may underlie POAG pathogenesis.

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Section: Discussionmentioning

confidence: 94%

Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma

Hamel

Rouhana

Yan

et al. 2022

Preprint

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“…OHT was induced by intracameral injection of magnetic microbeads, which were attracted to the iridocorneal angle with a magnet to block aqueous humor outflow and increase intraocular pressure (Figures 1C and 1D) (Ito et al, 2016). Mitochondrial movement was evaluated at 2 weeks after microbead injection because (1) high intraocular pressure is stable but no significant RGC loss is detected (Figure S1A) (Ito et al, 2016;Belforte et al, 2021;Alarcon-Martinez et al, 2022), and (2) Thy1-mediated transgene and protein expression do not differ from naive retinas at this time point (Belforte et al, 2021), confirming stable Thy1 promoter activity. Mitochondrial transport in intraretinal RGC axons was visualized using two-photon laser scanning microscopy (TPLSM) (Figure 1E), allowing minimally invasive trans-scleral imaging of mitochondria with single-axon resolution in living mice (Figure 1F; Videos S1 and S2).…”

Section: Impaired Anterograde Axonal Transport and Mitochondria Deple...mentioning

confidence: 99%

Restoration of mitochondria axonal transport by adaptor Disc1 supplementation prevents neurodegeneration and rescues visual function

et al. 2022

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“…The role of TNT at the blood-central nervous system barriers remains largely unknown. The role of interpericytes TNT (IP-TNT) in the regulation of neurovascular coupling under physiological conditions and their dysfunction in glaucoma were recently characterized in the mouse retina [ 33 , 41 ]. However, whether TNT play a role at human BBB-level remains unexplored.…”

Section: Discussionmentioning

confidence: 99%

Role of pericytes in blood–brain barrier preservation during ischemia through tunneling nanotubes

et al. 2022

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Crosstalk mechanisms between pericytes, endothelial cells, and astrocytes preserve integrity and function of the blood-brain-barrier (BBB) under physiological conditions. Long intercellular channels allowing the transfer of small molecules and organelles between distant cells called tunneling nanotubes (TNT) represent a potential substrate for energy and matter exchanges between the tripartite cellular compartments of the BBB. However, the role of TNT across BBB cells under physiological conditions and in the course of BBB dysfunction is unknown. In this work, we analyzed the TNT’s role in the functional dialog between human brain endothelial cells, and brain pericytes co-cultured with human astrocytes under normal conditions or after exposure to ischemia/reperfusion, a condition in which BBB breakdown occurs, and pericytes participate in the BBB repair. Using live time-lapse fluorescence microscopy and laser-scanning confocal microscopy, we found that astrocytes form long TNT with pericytes and endothelial cells and receive functional mitochondria from both cell types through this mechanism. The mitochondrial transfer also occurred in multicellular assembloids of human BBB that reproduce the three-dimensional architecture of the BBB. Under conditions of ischemia/reperfusion, TNT formation is upregulated, and astrocytes exposed to oxygen-glucose deprivation were rescued from apoptosis by healthy pericytes through TNT-mediated transfer of functional mitochondria, an effect that was virtually abolished in the presence of TNT-destroying drugs. The results establish a functional role of TNT in the crosstalk between BBB cells and demonstrate that TNT-mediated mitochondrial transfer from pericytes rescues astrocytes from ischemia/reperfusion-induced apoptosis. Our data confirm that the pericytes might play a pivotal role in preserving the structural and functional integrity of BBB under physiological conditions and participate in BBB repair in brain diseases.

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Pericyte dysfunction and loss of interpericyte tunneling nanotubes promote neurovascular deficits in glaucoma

Cited by 44 publications

References 59 publications

Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma

Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma

Restoration of mitochondria axonal transport by adaptor Disc1 supplementation prevents neurodegeneration and rescues visual function

Role of pericytes in blood–brain barrier preservation during ischemia through tunneling nanotubes

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