In vivo Identification and Characterization of Synovial Membrane Mesenchymal Stem Cells

Lead Research Organisation: University of Aberdeen
Department Name: Biomedical Sciences

Abstract

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Technical Summary

The use of mesenchymal stem cells (MSCs) as an alternative to mature cells for cell-based tissue repair is aggressively sought because more versatile and amenable to upscaling. We have identified and characterized multipotent MSCs from the adult human synovial membrane (SM). Such MSCs were derived from mixed populations of adherent SM cells following in vitro expansion. Expansion in mixed cell populations, however, alters the biological behaviour of SM MSCs and may be a source of variability in clinical applications. The purification of MSCs from the fresh SM digest, desirable to increase the consistency of MSC preparations and their efficacy, is currently impeded by the lack of specific markers.

In this project we propose a strategy to identify marker sets specific for uncultured SM MSCs, which would allow their direct purification from fresh SM digests as well as their identification in vivo within the tissue. To achieve this, we will sort the uncultured SM digest using combinations of negative markers (expressed by differentiated cell types) as well as positive candidate markers, associated with stem cells in other tissues/organs/systems. Individually, however, these markers are not specific for MSCs. To identify a specific MSC molecular profile, we will compare the transcriptome of the MSC-enriched fraction with that of the unsorted and negatively sorted (MSC-depleted) cell populations. These marker sets will be validated by comparing the purified cell populations with the unsorted cell populations for clonogenicity, kinetics of growth and multipotentcy using standardized quantitative in vitro and in vivo assays. The identified markers will also be used to localize the native MSCs within the intact SM and to investigate their stem cell function within the joint by prospectively monitoring their fate coupling cell-tracking techniques with marker analysis in a mouse model of mechanical joint surface injury.

Publications

10 25 50

publication icon
Augello A (2010) The regulation of differentiation in mesenchymal stem cells. in Human gene therapy

publication icon
Bluteau G (2008) Stem cells for tooth engineering. in European cells & materials

publication icon
De Bari C (2008) Cell therapy: a challenge in modern medicine. in Bio-medical materials and engineering

publication icon
De Bari C (2007) Mesenchymal stem cells in rheumatology: a regenerative approach to joint repair. in Clinical science (London, England : 1979)

publication icon
De Bari C (2010) Mesenchymal stem cells from development to postnatal joint homeostasis, aging, and disease. in Birth defects research. Part C, Embryo today : reviews

publication icon
De Bari C (2006) The stem cell niche: a new target in medicine in Current Opinion in Orthopaedics

 
Description OARSI Research and Training Committee
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
 
Description Scientific Advisory Panel of Action Medical Research, UK
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description Arthritis Research UK Tissue Engineering Centre (£6m across four centres - £2.5m ARUK/£3.4m HEIs)
Amount £546,000 (GBP)
Organisation Versus Arthritis 
Department Arthritis Research UK Tissue Engineering Centre
Sector Academic/University
Country United Kingdom
Start 04/2011 
End 04/2016
 
Description Equipment Grant
Amount £60,000 (GBP)
Organisation Versus Arthritis 
Start 06/2008 
End 05/2009
 
Description MRC Centre Grant
Amount £1,900,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description PhD Studentship
Amount £82,000 (GBP)
Organisation Versus Arthritis 
Start 10/2007 
End 09/2010
 
Description Project Grant
Amount £163,301 (GBP)
Organisation Versus Arthritis 
Start 12/2010 
End 06/2015
 
Description Project Grant
Amount £201,718 (GBP)
Funding ID 19667 
Organisation Versus Arthritis 
Start 11/2011 
End 05/2016
 
Description Technology Cell Therapy Programme Grant/Technology Strategy Board (TSB) and EPSRC
Amount £595,254 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 12/2009 
End 03/2013
 
Title Development and validation of a novel in vivo mouse joint surface injury model with age and strain-dependent outcome 
Description A new mouse model of joint surface injusy has been developed, and validated via peer review process. It consists of making a controlled injury to the joint surface in mice, which has an outcome that is dependent on mouse strain and age. The injury heals in young DBA/1 mice and not in age-matched C57BL/6 mice; notably, it does heal in elderly DBA/1 mice. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact This is a novel exciting in vivo model to investigate cellular and molecular mechanisms that underlie healing in order to trigger regeneration in animals that instead fail to heal. The model was published in Osteoarthritis and Cartilage (19070514). 
 
Title Mesenchymal stem cells 
Description These are primary mesenchymal stem cells that are derived from adult human surgical waste tissues. They are obtained after informed consent (ethics in place). 
Type Of Material Cell line 
Provided To Others? No  
Impact These adult stem cells are used for research purposes in skeletal tissue engineering and regenerative medicine. Their use will hopefully advance the field towards the development of stem cell therapy in clinic. 
 
Description Arthritis Research UK Centre of Excellence of Tissue Engineering 
Organisation Newcastle University
Country United Kingdom 
Sector Academic/University 
PI Contribution I am contributing my bench-to-bedside expertise in the field of tissue engineering and cell-based therapy for skeletal tissues, with a specific focus onto joint surface. I am also sharing within the Centre animal models for pre-clinical assessments.
Collaborator Contribution The partnership is dramatically increasing the volume of bench-to-bedside translational research in my lab with fruitful collaborative links across the multi-institutional Centre of Excellence.
Impact An output resulting directly from this collaboration was the recent award of the Centre of Excellence in Tissue Engineering for Osteoarthritis from the Arthritis Research UK on a competitive basis. The total award is 2.5 million over 5 years. The Centre includes Newcastle University (leading Institution), Aberdeen University, Keele University and York University. The remit of the Centre is to refine current cell-based therapy and develop novel tissue engineering approaches for prevention and treatment of early osteoarthritis. I am PI at Aberdeen (£545,000).
Start Year 2010
 
Description Cellular and molecular pathophysiology of postnatal joint homeostasis, remodelling and repair 
Organisation Queen Mary University of London
Department Barts and The London School of Medicine and Dentistry
Country United Kingdom 
Sector Academic/University 
PI Contribution I look at stem cell niches and their molecular regulation in joint homeostasis, remodelling and repair and I can offer my expertise in stem cell biology which dovetails very well with Dr Dell'Accio's expertise in cartilage biology and interest in studying the molecular mechanisms that are underlying joint surface regeneration or development of osteoarthritis.
Collaborator Contribution I share with Dr F Dell'Accio an animal model of joint surface injury where I look at cellular mechanisms and particularly stem cell niches in the joint (synovium, bone marrow and periosteum), while Dr Dell'Accio looks at the molecular signals activated within the articular cartilage by injury.
Impact In 2007 Dr Dell'Accio was awarded by the Arthritis Research Campaign a PhD studentship to study CXC chemokines signalling cartilage repair (£82,084; I am co-applicant). Recently, I have been awarded a 3-year project grant by Arthritis Research UK to investigate joint stem cell niches to prevent and treat osteoarthritis (£163,301; Dr Dell'Accio is a co-applicant). Other notable outputs include the following publications: 17465820 16893455 18438861 19070514
 
Description High pressure freezing of skeletal tissues and cells 
Organisation University of Aberdeen
Department Department of Medicine and Therapeutics
Country United Kingdom 
Sector Academic/University 
PI Contribution I have been delighted to provide my expertise in stem cell biology and niches to secure funding for this fundamental equipment that minimises artefacts due to fixation and allows detailed morphological study of tissues and cells.
Collaborator Contribution The collaboration has secured funding for the acquisition of an equipment for high pressure freezing of skeletal tissues and cells. This equipment will help investigate the anatomical definition of stem cell niches in the joint.
Impact The collaboration across PIs in the Musculoskeletal Programme at the Institute of Medical Sciences of the University of Aberdeen resulted in a successful bid for an equipment grant to the Arthritis Research Campaign led by Professor M Helfrich (£60,000 awarded in 2008; I am co-applicant).
Start Year 2007
 
Description Innovative cell-based technologies for bone regeneration (REGENBONE) 
Organisation University of Aberdeen
Department Institute of Medical Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Expertise in bone biology and stem cell biology in tissue engineering and skeletal regenerative medicine
Collaborator Contribution Expertise in biomaterial science and electric fields in tissue engineering
Impact This collaboration with Dr Iain Gibson and Professor Colin McGaig at the IMS has secured funding for a Technology Cell Therapy Programme Grant by TSB/EPSRC to develop and validate preclinically a bone patch for non-unions. I am a PI on the grant together with Dr Gibson. This R&D proposal includes 2 biotech companies, ApaTech and B1 Medical.
Start Year 2008
 
Description New diagnostic and treatment approaches in organ and stem cell transplantation 
Organisation King's College London
Department MRC Centre for Transplantation
Country United Kingdom 
Sector Public 
PI Contribution I provided my expertise in experimental models of stem cell transplantation.
Collaborator Contribution My research programme benefitted from the knowledge, expertise and tools of top scientists in immunology and this has stimulated my interests to investigate interactions between stem cells and the immune system.
Impact When I was at KCL, I was part of a multidisciplinary consortium led by Prof S Sacks that resulted in a successful bid to the MRC for the establishment of a Centre at KCL to develop new diagnostic and treatment approaches in organ and stem cell transplantation.
Start Year 2006
 
Description Stem cells in tooth morphogenesis and engineering 
Organisation University of Zurich
Country Switzerland 
Sector Academic/University 
PI Contribution My expertise in stem cell biology and tissue engineering
Collaborator Contribution My research has received benefit by extending the portfolio of tools to investigate stem cell niches in vivo.
Impact Following publications: 18671204 18582856 18572158 18054913 17764674
Start Year 2006
 
Description The enthesis in spondyloarthritis: interactions between immunology and biomechanics 
Organisation Catholic University of Louvain
Country Belgium 
Sector Academic/University 
PI Contribution Within this multidisciplinary consortium led by Professor R Lories from the University of Leuven (Belgium), my contribution will be the investigation of the role of stem cell niches in animal models of enthesitis.
Collaborator Contribution Expertise in animal models and biomechanics of enthesitis.
Impact Prof Lories led a successful bid to the Flanders Research Foundation for a collaborative travel grant (€62,500 over 5 years) that includes as co-applicants myself from Aberdeen, Prof McGonagle from Leeds, and Prof Elewaut from Ghent to study enthesitis from multiple angles.
Start Year 2008
 
Description National media 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact Following my inaugural lecture at the University of Aberdeen in November 2008, I was approached by media to discuss specifically my MRC funded research aiming at developing novel cell-based biological approaches for the repair or regeneration of musculoskeletal tissues such as articular cartilage.

I had a very enjoyable experience.
Year(s) Of Engagement Activity 2008
 
Description Press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Following the press relase in May 2009, I was approached by national media to discuss the possibility of stem cell therapy reaching patients to treat or prevent osteoarthritis.

I released several interviews to local radios and media for lay dissemination to the public.
Year(s) Of Engagement Activity 2009
 
Description VVIP visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact The Aberdeen Centre for Arthritis and Musculoskeletal Health hosted a visit of HRH the Duchess of Rothesay and Chancellor of the University of Aberdeen at the Institute of Medical Sciences. The visit was organised by Arthritis Research UK and National Osteoporosis Society to showcase the clinical and research activities taking place at the University of Aberdeen and NHS Grampian.
Year(s) Of Engagement Activity 2017