Oral mucosal lamina propria progenitor cells as a novel and preferential source for treatment of Graft Vs Host Disease

Lead Research Organisation: Cardiff University
Department Name: School of Medicine

Abstract

Graft-Versus-Host-Disease (GVHD) is characterised by a direct attack on the patient?s body by immune cells present within transplanted donor blood stem cells. This disease is a major barrier to transplantation in that it leads to a high death rate. Bone marrow stem cells (BMSCs) can suppress this attack on the patient and reduce the incidence/severity of GVHD but there are problems with using these cells. We have identified within the mouth a novel population of progenitor (stem-like) cells (oral PCs) which are powerful suppressors of immune responses and are more effective than BMSCs, possibly due to something they secrete. This research will investigate in depth how these cells are able to exert their superior suppression on immune cells and how they are different to BMSCs. We will also utilise cutting edge technologies to identify what the soluble factors are so that these cells/factors can ultimately be utilised to help patients. Importantly, oral PCs have distinct advantages for therapeutic applications in that they come from an area of the mouth that is easily accessible and which will heal rapidly with no/minimal resultant scar formation for the patient. We believe that the increased potential of these oral PCs will make them a favoured source of cells for transplantation with blood stem cells in the treatment of GVHD and potentially a number of other diseases where the immune response is dysfunctional.

Technical Summary

Mortality due directly to chronic GVHD remains one of the major obstacles in allogeneic haematopoietic stem cell (HSC) transplantation. Research suggests that co-transplantation of mesenchymal stem cells (MSCs) during HSC transplantation results in a significant decrease in acute and chronic GVHD. However, MSC heterogeneity means that trial results are variable and also large cell numbers are required to deliver an immunosuppressive effect which can sometimes initiate an immune response. We have recently demonstrated the existence of a novel, neural crest-derived PC population resident within the lamina propria of the oral mucosa which have a unique immunomodulatory capacity. These clonally-derived oral mucosal lamina propria-progenitor cells (OMLP-PCs) have the ability to lower lymphocyte proliferation back to base levels in the presence of alloantigens, in a contact-independent manner and at ratios as low as 0.001% of OMLP-PCs to allogeneic lymphocytes (levels much lower than for MSCs). This suggests that OMLP-PCs may work via a different mechanism(s) to MSCs and would be potentially more potent/effective than MSCs in the treatment of GVHD. This application will complete the in vitro characterisation of the immunosuppressive potential of OMLP-PCs in direct comparison to MSCs and identify the soluble factors involved in this response. Ultimately this project is aimed at translating our basic research findings into innovative and improved pre-clinical developments for the treatment of GVHD.

Publications

10 25 50
 
Description Cardiff University (School of Dentistry)/external PhD scheme
Amount £92,566 (GBP)
Organisation Cardiff University 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2015 
End 09/2018
 
Description Confidence in Concept Award
Amount £50,000 (GBP)
Organisation Medical Research Council (MRC) 
Department MRC Confidence in Concept Scheme
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 11/2014 
End 10/2015
 
Description Life Science Bridging Fund
Amount £75,000 (GBP)
Funding ID LSBF/R3-004 
Organisation Government of Wales 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 11/2016 
End 10/2017
 
Description KI collaboration 
Organisation Karolinska Institute
Country Sweden, Kingdom of 
Sector Academic/University 
PI Contribution Sharing lab equipment, scientific expertise.
Collaborator Contribution Access to technical expertise, clinical insight into disease.
Impact Stem Cell Dev 2012 paper published
Start Year 2009
 
Description Oral Mucosal Lamina Propria Progenitor Cells as a therapy for acute kidney injury 
Organisation University of Edinburgh
Department BRE Centre for Fire Safety Engineering
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We are supplying the OMLP-PCs and Edinburgh are supplying the animal models of acute kidney injury and downstream analysis. This has been funded by the Life Science Bridging Fund in Wales.
Collaborator Contribution We are supplying the OMLP-PCs and Edinburgh are supplying the animal models of acute kidney injury and downstream analysis. This has been funded by the Life Science Bridging Fund in Wales.
Impact To early for any outputs yet
Start Year 2016
 
Title Oral Mucosal Stem Cells 
Description Isolation and characterisation of progenitor cells from the oral (buccal) mucosa 
IP Reference 2009249053 - Australia 
Protection Patent granted
Year Protection Granted 2014
Licensed No
Impact Not as yet
 
Title Oral Mucosal Stem Cells 
Description Isolation and characterisation of progenitor cells isolated from the oral (buccal) mucosa 
IP Reference 09761964.7 (EP 2296674) - Europe 
Protection Patent granted
Year Protection Granted 2014
Licensed No
Impact None as yet
 
Title Oral Mucosal Stem Cells 
Description Isolation, characterisation and use of Oral Mucosal Stem Cells. 
IP Reference CN102089424B - China 
Protection Patent granted
Year Protection Granted 2015
Licensed No
Impact -
 
Title Oral Mucosal Stem Cells 
Description Isolation, characterisation and use of Oral Mucosal Stem Cells. 
IP Reference JP5755138 - Japan 
Protection Patent granted
Year Protection Granted 2015
Licensed No
Impact -
 
Description Co-hosted the first every European Tissue Repair Society Summer School (London) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact A summer school to bring together about 20 postgraduate researchers from across Europe to learn, in an informal environment, about cutting edge advances in tissue repair and stem cells
Year(s) Of Engagement Activity 2016
 
Description Invited Lecture - Mesenchymal Stem Cell Biology Course, Karolinska Institutet, Stockholm, Sweden 20th March 2013 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Invited lecture with discussion afterwards

Developed research collaborations
Year(s) Of Engagement Activity 2013
 
Description Invited Lecture - Swansea University, Swansea, UK 11th April 2013 "Oral Progenitor Cells - a Novel Therapy for the Treatment of Immune-Related Disorders?" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Invited talk and discussion afterwards

Developed research collaborations
Year(s) Of Engagement Activity 2013
 
Description Lecture at Stem Cell Research Day (Cardiff University) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Paper Presentation
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Approximately 80 people (clinical and non-clinical) attended an internal workshop on stem cell research with Cardiff to gain an insight into each others research areas/expertise and to set up a network for future coordinated grant applications.

Circulation of relevant information around the network, establishment of peer-to-peer support.
Year(s) Of Engagement Activity 2013
 
Description Public lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact Public lecture for the Welsh Livery Guild on stem cells and the clinical potential for our ageing bodies
Year(s) Of Engagement Activity 2016
 
Description School visit (Cardiff) 
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 90 Year 5 pupils (3x 30) attended a hands on workshop (three stations - cell modelling, maggot racing, life sized operation game) on tissue engineering. Lots of discussion about science and potential career routes/prospects.

We have been invited back to present to other years. Twitter posts. This was number five of a whole series of planned visits to Schools in Cardiff.
Year(s) Of Engagement Activity 2014
 
Description Stem Cell Meeting (Cardif) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Approximately 70 people (clinical and non-clinical) attended an internal workshop on stem cell research with Cardiff to gain an insight into each others research areas/expertise and to set up a network for future coordinated grant applications.

Circulation of relevant information around the network, establishment of peer-to-peer support. An expansion of this meeting in 2013 to bring in other academic and industrial partners.
Year(s) Of Engagement Activity 2012
 
Description Stem Cell Research Day (2016) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Approximately 140 people (clinical and non-clinical) attended an internal workshop on stem cell research with Cardiff to gain an insight into each others research areas/expertise and to set up a network for future coordinated grant applications.
Year(s) Of Engagement Activity 2016