High-resolution 3D imaging uncovers organ-specific vascular control of tissue aging

Chen, Junyu; Sivan, Unnikrishnan; Tan, Sin Lih; Lippo, Luciana; Angelis, Jessica De; Labella, Rossella; Singh, Amit; Chatzis, Alexandros; Cheuk, Stanley; Medhghalchi, Mino; Gil, Jesús; Holländer, Georg A.; Marsden, Brian D.; Williams, R. J. P.; Ramasamy, Saravana K.; Kusumbe, Anjali P.

doi:10.1126/sciadv.abd7819

Cited by 71 publications

(79 citation statements)

References 58 publications

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“…the vascular niches trigger the loss of functional hematopoietic stem cells and osteoprogenitors 58 . Indeed, general attrition of vascularisation has been recently reported occurring in multiple organs, including the liver 22 indicating that tissue microenvironments experience profound alterations with age. This is in line with the observation that ageing is accompanied by a decline in blood flow in the liver 59 .…”

Section: Discussionmentioning

confidence: 99%

Single-cell resolution unravels spatial alterations in metabolism, transcriptome and epigenome of ageing liver

Nikopoulou

Kleinenkuhnen

Sandoval

et al. 2021

Preprint

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Epigenetic ageing clocks have revealed that tissues within an organism can age with different velocity. However, it has not been explored whether cells of one type experience different ageing trajectories within a tissue depending on their location. Here, we employed lipidomics, spatial transcriptomics and single-cell ATAC-seq in conjunction with available single-cell RNA-seq data to address how cells in the murine liver are affected by age-related changes of the microenvironment. Integration of the datasets revealed zonation-specific and age-related changes in metabolic states, the epigenome and transcriptome. Particularly periportal hepatocytes were characterized by decreased mitochondrial function and strong alterations in the epigenetic landscape, while pericentral hepatocytes – despite accumulation of large lipid droplets – did not show apparent functional differences. In general, chromatin alterations did not correlate well with transcriptional changes, hinting at post-transcriptional processes that shape gene expression during ageing. Together, we provide evidence that changing microenvironments within a tissue exert strong influences on their resident cells that can shape epigenetic, metabolic and phenotypic outputs.

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Section: Discussionmentioning

confidence: 99%

Single-cell resolution unravels spatial alterations in metabolism, transcriptome and epigenome of ageing liver

Nikopoulou

Kleinenkuhnen

Sandoval

et al. 2021

Preprint

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“…Interestingly, they have also been shown to express the myofibroblastic marker α-SMA, an immunophenotypic feature that makes them an additional plausible source of activated myofibroblasts [ 8 , 43 , 78 ]. In this regard, several studies have indicated the evidence of a pericyte-to-myofibroblast transition in different fibrotic disorders including pulmonary, liver, kidney and myocardial fibrosis [ 81 , 82 , 83 , 84 ]. In addition, it has been recently demonstrated that pericyte-to-myofibroblast differentiation represents a primary hallmark of tissue fibrosis occurring during organ aging, with age-associated tissue-specific molecular changes in the endothelium driving the acquisition of a profibrotic phenotype in pericytes with progressive microvascular loss and tissue accumulation of myofibroblasts [ 84 ].…”

Section: The Pathogenic Role Of Vascular Wall-resident Cells In Systemic Sclerosis: Linking Vasculopathy To Fibrosismentioning

confidence: 99%

“…In this regard, several studies have indicated the evidence of a pericyte-to-myofibroblast transition in different fibrotic disorders including pulmonary, liver, kidney and myocardial fibrosis [ 81 , 82 , 83 , 84 ]. In addition, it has been recently demonstrated that pericyte-to-myofibroblast differentiation represents a primary hallmark of tissue fibrosis occurring during organ aging, with age-associated tissue-specific molecular changes in the endothelium driving the acquisition of a profibrotic phenotype in pericytes with progressive microvascular loss and tissue accumulation of myofibroblasts [ 84 ]. Of note, in skin- and muscle-wounding experiments, a disintegrin and metalloproteinase (ADAM)12+ lineage-derived pericytes were demonstrated to be able to migrate into the perivascular tissue and differentiate into myofibroblasts [ 85 ] and, in a similar way, pericytes were found to detach from the microvasculature, migrate into the interstitial space and express profibrotic proteins after spinal cord injury [ 86 , 87 ].…”

Section: The Pathogenic Role Of Vascular Wall-resident Cells In Systemic Sclerosis: Linking Vasculopathy To Fibrosismentioning

confidence: 99%

New Insights into Profibrotic Myofibroblast Formation in Systemic Sclerosis: When the Vascular Wall Becomes the Enemy

Romano

Rosa

Fioretto

et al. 2021

Life

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In systemic sclerosis (SSc), abnormalities in microvessel morphology occur early and evolve into a distinctive vasculopathy that relentlessly advances in parallel with the development of tissue fibrosis orchestrated by myofibroblasts in nearly all affected organs. Our knowledge of the cellular and molecular mechanisms underlying such a unique relationship between SSc-related vasculopathy and fibrosis has profoundly changed over the last few years. Indeed, increasing evidence has suggested that endothelial-to-mesenchymal transition (EndoMT), a process in which profibrotic myofibroblasts originate from endothelial cells, may take center stage in SSc pathogenesis. While in arterioles and small arteries EndoMT may lead to the accumulation of myofibroblasts within the vessel wall and development of fibroproliferative vascular lesions, in capillary vessels it may instead result in vascular destruction and formation of myofibroblasts that migrate into the perivascular space with consequent tissue fibrosis and microvessel rarefaction, which are hallmarks of SSc. Besides endothelial cells, other vascular wall-resident cells, such as pericytes and vascular smooth muscle cells, may acquire a myofibroblast-like synthetic phenotype contributing to both SSc-related vascular dysfunction and fibrosis. A deeper understanding of the mechanisms underlying the differentiation of myofibroblasts inside the vessel wall provides the rationale for novel targeted therapeutic strategies for the treatment of SSc.

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“…Analysis of vessel density and pericyte coverage in aged (12 month old) A/J, C57BL6/J and DBA/2J mice, which have a different life span, showed reduced vascular density in the hippocampus in old DBA/2J mice. Previous studies have shown that vessel density and pericyte coverage decreases during ageing in C57BL6/J mice, both in the brain and in peripheral organs with low regenerative capacity [ 34 , 35 ]. We did not detect reduced vascular density in brains of C57BL6/J mice.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the blood–brain barrier in genetically diverse laboratory mouse strains

Schaffenrath

Huang

Wyss

et al. 2021

Fluids Barriers CNS

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Background Genetic variation in a population has an influence on the manifestation of monogenic as well as multifactorial disorders, with the underlying genetic contribution dependent on several interacting variants. Common laboratory mouse strains used for modelling human disease lack the genetic variability of the human population. Therefore, outcomes of rodent studies show limited relevance to human disease. The functionality of brain vasculature is an important modifier of brain diseases. Importantly, the restrictive interface between blood and brain—the blood–brain barrier (BBB) serves as a major obstacle for the drug delivery into the central nervous system (CNS). Using genetically diverse mouse strains, we aimed to investigate the phenotypic and transcriptomic variation of the healthy BBB in different inbred mouse strains. Methods We investigated the heterogeneity of brain vasculature in recently wild-derived mouse strains (CAST/EiJ, WSB/EiJ, PWK/PhJ) and long-inbred mouse strains (129S1/SvImJ, A/J, C57BL/6J, DBA/2J, NOD/ShiLtJ) using different phenotypic arms. We used immunohistochemistry and confocal laser microscopy followed by quantitative image analysis to determine vascular density and pericyte coverage in two brain regions—cortex and hippocampus. Using a low molecular weight fluorescence tracer, sodium fluorescein and spectrophotometry analysis, we assessed BBB permeability in young and aged mice of selected strains. For further phenotypic characterization of endothelial cells in inbred mouse strains, we performed bulk RNA sequencing of sorted endothelial cells isolated from cortex and hippocampus. Results Cortical vessel density and pericyte coverage did not differ among the investigated strains, except in the cortex, where PWK/PhJ showed lower vessel density compared to NOD/ShiLtJ, and a higher pericyte coverage than DBA/2J. The vascular density in the hippocampus differed among analyzed strains but not the pericyte coverage. The staining patterns of endothelial arteriovenous zonation markers were similar in different strains. BBB permeability to a small fluorescent tracer, sodium fluorescein, was also similar in different strains, except in the hippocampus where the CAST/EiJ showed higher permeability than NOD/ShiLtJ. Transcriptomic analysis of endothelial cells revealed that sex of the animal was a major determinant of gene expression differences. In addition, the expression level of several genes implicated in endothelial function and BBB biology differed between wild-derived and long-inbred mouse strains. In aged mice of three investigated strains (DBA/2J, A/J, C57BL/6J) vascular density and pericyte coverage did not change—expect for DBA/2J, whereas vascular permeability to sodium fluorescein increased in all three strains. Conclusions Our analysis shows that although there were no major differences in parenchymal vascular morphology and paracellular BBB permeability for small molecular weight tracer between investigated mouse strains or sexes, transcriptomic differences of brain endothelial cells point to variation in gene expression of the intact BBB. These baseline variances might be confounding factors in pathological conditions that may lead to a differential functional outcome dependent on the sex or genetic polymorphism.

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High-resolution 3D imaging uncovers organ-specific vascular control of tissue aging

Cited by 71 publications

References 58 publications

Single-cell resolution unravels spatial alterations in metabolism, transcriptome and epigenome of ageing liver

Single-cell resolution unravels spatial alterations in metabolism, transcriptome and epigenome of ageing liver

New Insights into Profibrotic Myofibroblast Formation in Systemic Sclerosis: When the Vascular Wall Becomes the Enemy

Characterization of the blood–brain barrier in genetically diverse laboratory mouse strains

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