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New Research from the Kusumbe group at the Kennedy Institute of Rheumatology identifies vascular attrition, marked by pericyte to fibroblast differentiation, as a primary hallmark of aging and highlights organ-specific vascular changes with age.

A montage of images showing 3D scans of mouse spleens and kidneys
From left to right 1 - Tile scan 3D confocal image showing a mouse spleen with multicolour immunolabeling for endothelial cell and pericyte markers. Blue shows cell nuclei stained with TO-PRO-3. 2 - Tile scan 3D confocal image showing a mouse spleen with multicolour immunolabeling for endothelial cell and pericyte markers. 3 - Tile scan 3D confocal image showing a mouse kidney with multicolour immunolabeling for endothelial cell and pericyte markers. Blue shows cell nuclei stained with TO-PRO-3. 4 - Tile scan 3D confocal image showing a mouse kidney with multicolour immunolabeling for endothelial cell and pericyte markers.

Cellular and physiological activity in the body declines over time with age, resulting in a loss of tissue and organ function and the potential risk of major health conditions such as cancer or cardiovascular disease. What is less understood are age-related changes in the tissue microenvironment such as the blood vessels.

Blood vessels are an essential component in maintaining tissue function not only because they form vital transport routes around the body, but also because blood vessels engage in signalling with neighbouring cells within the tissues thereby governing their behaviour. For example, blood vessels provide nurturing niches for stem/progenitor cells and regulate their stemness and fate. Therefore, any vascular changes have the potential to reveal microenvironmental triggers impacting the aging process.

For the study which appears in Science Advances Anjali Kusumbe’s group examined 1000’s of confocal images across several murine and human organs. “The cellular aspects of aging have been extensively studied and we understand how they affect tissue function. Our goal was to understand age-related changes to blood vessels, the vascular system, by comparing young and aging tissues from several organs through 3D imaging.” said Anjali.

3D imaging showed the vascular microenvironments of the kidney, muscle, spleen, thymus, liver, lung, uterus, heart, bladder, brain, skin, and the gut. By comparing young and aging tissues from several organs the study revealed a loss of vascular abundance and differentiation of pericytes into fibroblasts as the key features of aging tissue. Pericytes are the cells lining the blood vessels and support vascular functions while fibroblasts are known drivers for disease conditions such as fibrosis and arthritis.

“This vascular attrition is seen at a much earlier stage in the life span of the tissues than the appearance of cellular hallmarks of aging and leads us to conclude that this is a primary hallmark of tissue and organ aging,” said Anjali. 

“We find that pericytes are not only the source of age-associated fibroblast accumulation but pericyte to fibroblast differentiation underlies the pathogenesis of fibrosis and rheumatoid arthritis” added Junyu Chen, first author on the paper and a Postdoctoral Fellow at the Kennedy Institute.

Interestingly, while most organs are affected, the highly remodelling organs such as skin, uterus and gut do not show vascular loss. Potentially by understanding the characteristics of these tissues, strategies to retain and maintain vasculature in aging might be discovered.

The full library of 3D vascular and tissue maps is being been made freely available by the Kennedy Institute of Rheumatology. It contains more than 1000 single-cell–resolution 3D maps with spatial information for exploration and quantitative analyses. The resource will serve as an essential research tool to understand tissue biology in various fields of physiology, aging, matrix, and vascular biology and to investigate functional pathophysiology and therapeutic effects. 

The study was funded by the Medical Research Council (MRC), Kennedy Trust for Rheumatology Research (KTRR) and the European Research Council (ERC).

 

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