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Understanding how ageing impacts on vascular regeneration through the endothelial senescence associated secretory phenotype

Reference	BB/T000805/1
Principal Investigator / Supervisor	Professor Reinhold Medina
Co-Investigators / Co-Supervisors	Professor Alan Stitt
Institution	Queen's University of Belfast
Department	Sch of Medicine, Dentistry & Biomed Sci
Funding type	Research
Value (£)	428,815
Status	Current
Type	Research Grant
Start date	01/01/2020
End date	30/09/2023
Duration	45 months

Abstract

Ageing is associated with vasodegeneration. The classical view is that ageing induces cumulative damage in endothelial cells; however, vasorepair mechanisms also play an important role as evidence confirms that endothelial regeneration is slower in older than in younger mice. The homeostatic maintenance of a healthy vasculature depends on a population of reparative cells known as vascular stem cells or endothelial progenitor cells. In addition, there has been recent attention into the senescence associated secretory phenotype (SASP) as the new hallmark of cellular senescence. This study will investigate the SASP in both mouse in vivo and human in vitro models. We will define the composition and role of endothelial progenitor SASP in cellular senescence. Our lab investigates blood vessel regeneration, and we have isolated a subtype of endothelial progenitors known as endothelial colony forming cells (ECFCs). Compelling evidence from various labs including ours demonstrates the significant vasoreparative potential of ECFCs and here we will study these cells in the context of ageing. We have already adopted and optimised well-accepted models to study cellular senescence in ECFCs. First, we will use the TTP mouse model that has impaired inflammatory responses to investigate if reduced inflammatory SASP in vivo can translate into a higher frequency and quality of ECFCs. Second, we will perform Luminex assays, mass cytometry, and single cell RNA sequencing to characterise the SASP and associated cellular phenotype in human ECFCs undergoing cellular senescence in vitro. This characterisation will also include evaluation of the functional effects of SASP in proliferation, tube formation and paracrine senescence. Third, we will modulate the SASP by genetically or biochemically inhibiting molecular drivers RIG-I and IRF7, as a strategy to enhance vascular health and endothelial performance.

Summary

Ageing is the greatest risk factor for poor health and chronic diseases. While life expectancy continues to rise, health span is not improving at the same pace, and therefore there is a real need to increase the quality of life in the elderly population. Ageing impacts on every tissue in our body, and our lab is particularly interested in ageing of blood vessels. The idea of ageing in the vasculature is not new as there is an English saying from the 1600s stating, "A man is only as old as his arteries"; however, recent technological advances in science have opened new opportunities to understand the ageing of blood vessels at the molecular level. This study will employ state-of-the-art technology to investigate ageing in stem cells from blood vessels. These cells known as vascular stem cells or endothelial progenitor cells are responsible for repairing and maintaining a healthy vasculature. There is a theory of ageing suggesting that there is a loss of stem cells with age, while others propose that stem cells become dysfunctional or senescent. Here, we will elucidate how stem cells in blood vessels change during the ageing process. The ageing process in cells is called cellular senescence, and there is evidence to indicate that senescent cells adopt an inflammatory phenotype. The secretion of these inflammatory proteins is called SASP and reinforces the senescence programme. While this idea was demonstrated in human skin fibroblasts, it is not known if this applies to other tissues and cells. Here, we will investigate if inflammation and SASP drives cellular senescence in endothelial progenitors. Importantly, we aim to inhibit this SASP as a strategy to enhance vascular health. A multidisciplinary team comprising of stem cell biologists, vascular biologists, and inflammation biologists designed this project. Working together, we will investigate vascular ageing and endothelial senescence in vascular stem cells using state-of-the-art technologies. We will providethe first detailed molecular characterisation of SASP in endothelial progenitors. Furthermore, we will identify components of the SASP that could be modulated to promote vascular health. In addition, we will use a unique animal model to test the role of inflammation driving vascular ageing and vascular stem cell exhaustion. In summary, outcomes of this project will provide critical information in relation to how vascular ageing is driven by cellular senescence and inflammation in vascular stem cells.

Impact Summary

This project is basic biology research of ageing in blood vessels with potential economical and societal impact in the long term. We have identified these important stakeholders: 1. Anti-Aging Biotech Companies IMPACT: Results from this project will identify novel targets to delay ageing in blood vessels. Scientific evidence will provide proof-of-concept that modulation of certain molecular pathways enhances vascular health. PATHWAY: During the project, and as results become available, we will submit Innovative Disclosure Forms to the University to discuss IP potential with our Patents office. Once IP is protected, we will contact anti-aging companies to establish commercial partnerships. 2. The Cell Therapy Industry in the UK IMPACT: Our findings will provide important data to facilitate development pathways for vascular stem cell therapies while improving manufacture methodologies. All these will support the consolidation of UK stakeholders in industry and academy as leading players in the competitive market of Regenerative Medicine. PATHWAY: By the end of the project, we will organise a meeting with the Cell and Gene Therapy Catapult to discuss major relevant findings with potential to change current practices in vascular stem cell therapy product manufacture. 3. Queen's University Belfast and Northern Ireland economy IMPACT: This project can lead to the creation of a spin out company targeting ageing in blood vessels. Results from this project are critical to demonstrate feasibility of translating scientific findings into a spin out company and to attract R&D investment. PATHWAY: During the course of this project, we will organise meetings every 6 months with Queen's University Research and Enterprise IP and Innovation Department to discuss research developments, IP potential, and commercialisation strategy. 4. Ageing population IMPACT: If our hypothesis is right and results are positive, this project could become the foundation for the development of novelstrategies to increase the health of our blood vessels and therefore improve quality of life. PATHWAY: We will actively explore the potential to develop novel approaches for preventing ageing in blood vessels if scientific results are supportive. 5. General Public IMPACT: This project will help to increase the public awareness and understanding of biology of our blood vessels in relation to ageing and stem cells. PATHWAY: We will showcase results from this project in an educational event. UNISTEM is the European Stem Cell Awareness day and we have already been involved in organising this in Northern Ireland. We will include in the programme for UNISTEM 2020 a talk on 'How ageing affects stem cells in our blood vessels?'

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	Regenerative Biology, Stem Cells
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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