Understanding how ageing impacts on vascular regeneration through the endothelial senescence associated secretory phenotype
Lead Research Organisation:
Queen's University Belfast
Department Name: Sch of Medicine, Dentistry & Biomed Sci
Abstract
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 provide the 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.
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 provide the 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.
Technical Summary
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.
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.
Planned Impact
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 novel strategies 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?'
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 novel strategies 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?'
Organisations
Publications
Stravalaci M
(2021)
The Long Pentraxin PTX3 as a New Biomarker and Pharmacological Target in Age-Related Macular Degeneration and Diabetic Retinopathy.
in Frontiers in pharmacology
Lechner J
(2022)
Advances in cell therapies using stem cells/progenitors as a novel approach for neurovascular repair of the diabetic retina.
in Stem cell research & therapy
Kurzawa-Akanbi M
(2022)
Retinal pigment epithelium extracellular vesicles are potent inducers of age-related macular degeneration disease phenotype in the outer retina.
in Journal of extracellular vesicles
Guduric-Fuchs J
(2021)
miR-130a activates the VEGFR2/STAT3/HIF1a axis to potentiate the vasoregenerative capacity of endothelial colony-forming cells in hypoxia.
in Molecular therapy. Nucleic acids
Chambers SEJ
(2021)
Current concepts on endothelial stem cells definition, location, and markers.
in Stem cells translational medicine
Bertelli PM
(2022)
Long term high glucose exposure induces premature senescence in retinal endothelial cells.
in Frontiers in physiology
Description | This project investigates the ageing process in the cells within our blood vessels. We have characterised at the molecular level the senescence program in human endothelial cells. Our findings suggests that cellular senescence programs are distinct according to cell types, and endothelial cells have distinct senescence gene signatures. We are currently evaluating some of these molecular cell ageing targets to extend life-span and health span of endothelial cells. |
Exploitation Route | Biomarkers of determine the age status of blood vessels. Development of therapies or approaches to maintain a youthful vasculature. Identification of molecular pathways that can be targeted by senolytic drugs to removed dysfunctional aged endothelial cells from vasculature. |
Sectors | Healthcare Pharmaceuticals and Medical Biotechnology |
Description | Our finding have uncovered new biology surrounding cell ageing. Findings have been used at outreach activities to increase awareness of 'healthy ageing' while engaging with Schools and the general public. In particular high school students from Unistem 2023 event have shown a keen interest in ageing biology and a career in science. |
First Year Of Impact | 2023 |
Sector | Education |
Impact Types | Cultural |
Title | Supplementary information files for Retinal pigment epithelium extracellular vesicles are potent inducers of age-related macular degeneration disease phenotype in the outer retina |
Description | Supplementary files for article Retinal pigment epithelium extracellular vesicles are potent inducers of age-related macular degeneration disease phenotype in the outer retina Age-related macular degeneration (AMD) is a leading cause of blindness. Vision loss is caused by the retinal pigment epithelium (RPE) and photoreceptors atrophy and/or retinal and choroidal angiogenesis. Here we use AMD patient-specific RPE cells with the Complement Factor H Y402H high-risk polymorphism to perform a comprehensive analysis of extracellular vesicles (EVs), their cargo and role in disease pathology. We show that AMD RPE is characterised by enhanced polarised EV secretion. Multi-omics analyses demonstrate that AMD RPE EVs carry RNA, proteins and lipids, which mediate key AMD features including oxidative stress, cytoskeletal dysfunction, angiogenesis and drusen accumulation. Moreover, AMD RPE EVs induce amyloid fibril formation, revealing their role in drusen formation. We demonstrate that exposure of control RPE to AMD RPE apical EVs leads to the acquisition of AMD features such as stress vacuoles, cytoskeletal destabilization and abnormalities in the morphology of the nucleus. Retinal organoid treatment with apical AMD RPE EVs leads to disrupted neuroepithelium and the appearance of cytoprotective alpha B crystallin immunopositive cells, with some co-expressing retinal progenitor cell markers Pax6/Vsx2, suggesting injury-induced regenerative pathways activation. These findings indicate that AMD RPE EVs are potent inducers of AMD phenotype in the neighbouring RPE and retinal cells. |
Type Of Material | Database/Collection of data |
Year Produced | 2023 |
Provided To Others? | Yes |
URL | https://repository.lboro.ac.uk/articles/dataset/Supplementary_information_files_for_Retinal_pigment_... |
Description | Educational Event PINT OF SCIENCE Belfast 2023 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Pint of Science is a worldwide science festival which brings researchers and scientists to local pubs/cafes to share their scientific discoveries with the general public. This year over 400 cities across 26 countries participated. 36 cities in the UK were involved. In Belfast, Pint of Science 2023, was organised by Reinhold Medina from WWIEM in the Black Box pub, with the theme of POSITIVE AGEING, with over 100 people attending. Colleagues from Centre for Public Health, our guest speaker from University of Cambridge, and panel of older experts all delivered an excellent evening of informative science. |
Year(s) Of Engagement Activity | 2023 |
Description | Invited Speaker at the Gordon Research Conference 'Endothelial cell phenotypes in health and disease' in Spain (29 Jun 2022) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Scientific Conference to discuss latest research in Vascular Biology |
Year(s) Of Engagement Activity | 2022 |
Description | Invited speaker at the Virtual Academic Program 'Lectures in Stem Cell and Regenerative Medicine' organised by the Department of Translational and Regenerative Medicine, PGIMER, Chandigarh, India (1 Nov 2022) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Undergraduate students |
Results and Impact | 120 people attended the Virtual seminar program on Stem Cells, and actively engaged during the Q&A session |
Year(s) Of Engagement Activity | 2022 |
Description | Speaker and organiser of UniStem Belfast 2023 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Researchers at Queen's University Belfast and others around Europe celebrated UniStem Day 2023 on Friday 10th March, bringing together universities and school pupils to foster learning, discovery and debate in the field of stem cell research and regenerative medicine - and hopefully inspiring the scientists of tomorrow. This event showcased our cutting edge research and explore the mechanisms behind scientific breakthroughs, engaging pupils with the concepts and methodologies involved but also providing an insight into the daily work of a researcher so that pupils will gain an appreciation for a career in scientific research. UniStem Day has now grown to include over 74 universities in over 60 cities. |
Year(s) Of Engagement Activity | 2023 |
URL | https://unistem.unimi.it/category/unistem-day-2023/ |
Description | Visiting virtual lecture 'Cell Therapies for Blood Vessel Regeneration: Potential Applications in Eye Disease' to the Undergraduate Program organised by the Department of Ophthalmology, Faculty of Medicine, University of Hasanuddin, Indonesia. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Undergraduate students |
Results and Impact | 157 undergraduate students attended this virtual seminar on stem cells |
Year(s) Of Engagement Activity | 2022 |