Neurotransmitter signalling to two types of oligodendrocyte precursor cell in remyelination

Lead Research Organisation: University of Cambridge
Department Name: Veterinary Medicine

Abstract

For nerve fibres in the brain and spinal cord (the central nervous system, or CNS) to work properly, and enable us to feel, move, talk, see, think etc., they need to be covered by a sheath called myelin. In many neurological diseases myelin is lost and nerve fibres cannot conduct impulses properly, and may even die. Just as a skin wound can heal, myelin injuries can be healed spontaneously by stem cells present in the CNS. However, this repair process, called remyelination, often fails. Scientists are therefore studying how CNS stem cells can be encouraged to heal myelin injury more efficiently. In this project we will determine the role of two distinct CNS stem cells that we have recently identified in remyelination.

When myelin is first produced in the developing brain the process is influenced by small molecules released from neurons, called neurotransmitters. However, it is unknown whether these neurotransmitters can influence remyelination. In this project we will study how remyelination by one or both types of stem cell is regulated by neurotransmitters. The results of this project will help in devising new remyelination therapies.

Technical Summary

Demyelination has profound consequences for the efficiency of action potential conduction along axons, and for axonal integrity. In the CNS demyelination can be followed by a regenerative process called remyelination. However, in many myelin diseases (e.g. multiple sclerosis, trauma, stroke, cerebral palsy) remyelination is inadequate. Consequently, treatment of myelin diseases requires the development of remyelination-enhancing therapies, of which there are currently none. Remyelination is mediated by an endogenous population of stem/precursor cells called oligodendrocyte precursor cells (OPCs). We have recently shown that there are two populations of OPCs with distinct electrophysiological phenotypes: one type expresses voltage-gated sodium channels, fires action potentials and receives synaptic input, whereas the other type does not. At present it is not known whether both types of OPC become activated following demyelination and are able to differentiate into remyelinating oligodendrocytes. Furthermore, normal myelination has been shown to be influenced by axonal action potentials and neurotransmitter signalling, but at present there is no knowledge available regarding the effect of neurotransmitters on remyelination. This project will address the important questions of which OPC type should be targeted for remyelination-enhancing therapies, and whether modulation of neurotransmitter signalling could be used to enhance remyelination.

Publications

10 25 50
 
Description Allen Distinguished Investigator Award
Amount $1,300,000 (USD)
Organisation Paul G. Allen Family Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2016 
End 03/2021
 
Description Cambridge Centre for Myelin Repair (renewal)
Amount £1,641,443 (GBP)
Funding ID 50 
Organisation Multiple Sclerosis Society 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2016 
End 10/2020
 
Description Lister Institute research prize
Amount £200,000 (GBP)
Organisation Lister Institute of Preventive Medicine 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2015 
End 09/2021
 
Description Neuronal regulation of CNS myelin plasticity
Amount € 1,999,729 (EUR)
Funding ID 771411 MyelinPlasticity 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 01/2018 
End 05/2023
 
Description Repurposing AMPAkines for enhancing myelin regeneration in multiple sclerosis
Amount £130,000 (GBP)
Funding ID 204488/Z/16/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2017 
End 03/2019
 
Description Royal Society Equipment grant RG2010R1 (The role of NRG, voltage-gated sodium channels and intracellular signalling in myelination)
Amount £13,240 (GBP)
Funding ID RG2010R1 
Organisation The Royal Society 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2010 
End 08/2011
 
Description UK MS Society Centre of Excellence Programme (PI): Cambridge Centre for Myelin Repair - Combatting progression in MS - when and how?
Amount £1,850,000 (GBP)
Organisation Multiple Sclerosis Society 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2021 
End 03/2026
 
Description Wellcome Trust Research Career Development Fellowship in Basic Biomedical Science; 091543 (Determinants of oligodendrocyte cell fate in development and disease)
Amount £932,296 (GBP)
Funding ID 091543/Z/10/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2011 
End 12/2015
 
Title Light activating box - sutiable for an incubator 
Description It is a platform of blue LED lights that have heat removing block on top. They are build in a circuit and connected to a power source that controls the intensity of light, duration and frequency, further connected to a timer that allows for 12hrs cycles. This box allows for light activation of cells in culture. This box is useful when studying light activation of proteins and photo toxicity in culture, as it is suitable for being inside an incubator. This was done in collaboration with the electrical workshop in the University of Cambridge. 
Type Of Material Technology assay or reagent 
Year Produced 2011 
Provided To Others? Yes  
Impact Other groups have asked for the drawings of this box and how to build it. We have supplied it to reaserach groups in USA. 
 
Description Collaboration with Andras Lakatos for Paper in Nature Communications (2014) "Reactivity of astrocytes - regulation of synaptic inputs" 
Organisation National Institute for Health Research
Department NIHR Cambridge Biomedical Research Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution We performed electrophysiological recordings, identified candidates to look into from our single-cell functional analysis.
Collaborator Contribution The Lakatos group conceived the project, performed the surgeries and generated transgenic animals
Impact Publication of Paper in Nature Communications (2014) "Reactivity of astrocytes - regulation of synaptic inputs"
Start Year 2011
 
Description Collaboration with Kristian Franze, Environmental influence of neuronal development 
Organisation University of Cambridge
Department Department of Physiology, Development and Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution We performed electrophysiological recordings, identified candidates to look into from our single-cell functional analysis. We also generated primary neuronal cell cultures.
Collaborator Contribution The Franze group generated cell matrices, measured stiffness and altered the culture environment to determine it effect on neuronal maturation.
Impact Paper on Environmental influence of neuronal development
Start Year 2013
 
Description Early maturation and distinct tau pathology in iPS derived neurons from patients with MAPT mutations. 
Organisation University of Cambridge
Department Department of Clinical Neurosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We performed electrophysiological recording on neurons, we identified that MAPT neurons matured faster than neurons derived from healthy controls. We helped with the writing of the manuscript, figure making and data analysis.
Collaborator Contribution They taught us to generate neurons from IPCS, they performed intital characterization and data analysis
Impact Iovino M, Agathou S, Martin R, Gonzales Rueda A, Borroni B, Lynch T, Gaffney D, Vallier L, Paulsen O, Káradóttir R, Spillantini MG (2015). Early maturation and distinct tau pathology in iPS derived neurons from patients with MAPT mutations. Brain 138(11):3345-59.
Start Year 2012
 
Description Electrical properties of neurons and oligodendrocytes derived from human embryonic stem cells 
Organisation University of Cambridge
Department Department of Clinical Neurosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We both share scientific interest in neuronal stem cells. My laboratory has the experience on the electrical properties of neuronal cells, with the main focus on the electrical properties of oligodendrocytes. The laboratory of Professor Siddharthan Chandran at the Department of Clinical Neurosciences, University of Cambridge has expertise in human embryonic stem cells. Combining our knowledge has resulted in two publications (as listed below), furthermore we are currently expanding this work to address the electrical properties of human oligodendrocytes.
Collaborator Contribution Provided us with the opportunity to study the electrical properties of human neuronal cells and most importantly, human oligodendrocyte precursor cells (OPCs), which is extremely important to assert which animal model currently available to study the properties of these cell best represents the human OPCs.
Impact Outcome resulted from this collaboration the following publications; Stacpoole SR, Bilican B, Webber DJ, Luzhynskaya A, He XL, Compston A, Karadottir R, Franklin RJ, Chandran S (2011). Efficient derivation of NPCs, spinal motor neurons and midbrain dopaminergic neurons from hESCs at 3% oxygen. Nat. Protoc. 6(8):1229 Stacpoole S.R., Bilican B., Webber, D.J., Luzhynskaya, A., He, X.L., Compston, A., Karadottir, R., Franklin, R.J., Chandran, S. (2011). Derivation of neural precursor cells from human ES cells at 3% O(2) is efficient, enhances survival and presents no barrier to regional specification and functional differentiation. Cell Death Differ. 6(18):1016- 23
Start Year 2010
 
Description Mechanical properties of CNS tissue in health and disease 
Organisation University of Cambridge
Department Physics of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution As mentioned above, we both share scientific interest in white matter disease. We have set up multi-disciplinary approach to study remyelination. My laboratory has the experience to work with white matter, CNS tissue, animals and the knowledge of the biological properties of the white matter and repair. The laboratory of Jochen Guck at The Cambridge Centre for the Physics of Medicine has the knowledge of atom force microscope and measurements of tissue mechanics. Combining our knowledge has resulted in a publication of the difference mechanical properties of white and grey matter in the rat cerebellum (J. Biomech. 2010), which now forms the bases of a PhD project which started in 2010.
Collaborator Contribution We are both interested in myelin repair and the concept of a difference in tissue mechanics in health and disease is a new idea to us. As currently we focus on biological factors of repair; however mechanical factors also play a role. Thus this collaboration has widened our horizon and possible approach to study white matter disease. We have recently published a paper together in J. Biomech. 2010 titled "Mechanical difference between white and gray matter in the rat cerebellum measured by scanning force microscopy". Which demonstrates: 1. it is possible to measure the CNS mechanical differences 2. That there are measurable differences between different layers of the brain and 3 we can measure at high enough resolution to measure mechanical properties in white matter lesions. This was the background of a new PhD project " a nanoscience approach to mechanosensing in the central nervous system" - jointly supervised.
Impact Outcome resulted from this collaboration the following publication: Christ AF, Franze K, Gautier H, Moshayedi P, Fawcett J, Franklin RJM, Karadottir RT, Guck J. Mechanical difference between white and gray matter in the rat cerebellum measured by scanning force microscopy. J Biomech. 2010 16;43(15):2986-92. PMID: 20656292 [PubMed - in process] This is a multi- disciplinary approach as we combine cell physiology with atom force microscopy. Therefore the disciplines are cell physilogy and physics
Start Year 2009
 
Description Neuronal activity regulates remyelination via glutamate signaling to oligodendrocyte progenitors 
Organisation Imperial College London
Department Imperial College Trust
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution We had made a discovery that OPCs receives synaptic inputs from demyelinated axons, and this synaptic communication is essential for remyelination. We identified proteins that we can look at in the lesions, and these proteins were investigated in Prof. Richard Reynolds laboratory. We preformed analysis of the images Richard's lab sent us. This led to a submission of a paper in Gautier et al., Nat. Communications 2015.
Collaborator Contribution Prof. Richard Reynolds laboratory supplied MS tissue samples and performed immunohistology and confocal imaging of these samples for the manuscript relating to the effect of neuronal activity in remyelination
Impact Gautier HO, Evans K, Lundgaard I, James F, Lao-Peregrin C, Franklin RJM & Káradóttir R (2015). Neuronal activity regulates remyelination via glutamate signaling to oligodendrocyte progenitors. Nature Communications 6: 8518
Start Year 2014
 
Description Prof Tim Bussey, Prof Lisa Saksida, Department of Psychology, University of Cambridge 
Organisation University of Cambridge
Department Department of Chemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution In order to investigate the learning dependent changes in myelination we are collaborating with Prof Tim Bussey and Prof Lisa Saksida at the Department of Psychology in Cambridge. This collaboration allows us to use touchscreen testing boxes for mice, which enable us to train and test the animals on cognitive paradigms such as spatial working memory, and are directly translatable to human studies which use testing batteries such as the CANTAB.
Collaborator Contribution Prof Bussey and Prof Saksida have helped with the study design and intellectual discussions, provided support with the animal testing and task programming via their team members and enable us to breed and test animals under their license.
Impact It is a collaboration with the field of Neuroscience, but multidisciplinary in that it involves the collaboration of the Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute and the Department of Psychology, both at the University of Cambridge. As this is a big project, involving many steps, so far the experiments are still ongoing and we are expecting to have preliminary results by the end of the year.
Start Year 2015
 
Description Wellcome Trust - MRC Cambridge Stem Cell Institute 
Organisation University of Cambridge
Department Cambridge Stem Cell Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution My laboratory provides both training and collaboration on isolation of neuronal stem cell from the brain, patch-clamp recordings (in both cell culture and brain slices), imaging (calcium, time-lapse and confocal).
Collaborator Contribution Being part of the WT-MRC Cambridge Stem Cell Institute, has been an excellent platform to interact with other investigators interested in stem cell biology and given me access to MRC and Wellcome Trust funded PhD students selected on the 4 year PhD programme in Stem Cell Biology, organised by the initiative. Furthermore, a successful collaboration with Professor Siddharthan Chandran, that resulted in two publication (listed below) came about through our interaction in events organised by the initiative.
Impact Outcome resulted from this collaboration the following publications; Stacpoole SR, Bilican B, Webber DJ, Luzhynskaya A, He XL, Compston A, Karadottir R, Franklin RJM, Chandran S (2011). Efficient derivation of NPCs, spinal motor neurons and midbrain dopaminergic neurons from hESCs at 3% oxygen. Nat. Protoc. 6(8):1229 Stacpoole S.R., Bilican B., Webber, D.J., Luzhynskaya, A., He, X.L., Compston, A., Karadottir, R., Franklin, R.J.M., Chandran, S. (2011). Derivation of neural precursor cells from human ES cells at 3% O(2) is efficient, enhances survival and presents no barrier to regional specification and functional differentiation. Cell Death Differ. 6(18):1016- 23
Start Year 2008
 
Description Action Medical Research Charity meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Around 50 persons attended this meeting which was to inform fundraising volunteers for Action Medical Research about the type of research the charity funds. My presentation was shown great interest demonstrated by multiple questions and discussions afterwards that further continued with individual participants

I was requested to come and speak at AMR fundraising event.
Year(s) Of Engagement Activity 2010
 
Description Allen Institute Talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact As Allen Distinguished Investigator, I described how the tools that are available now are helping to support neuroscience, immunology and psychiatric disease research better than ever before.
Year(s) Of Engagement Activity 2020
URL https://alleninstitute.org/news-press/articles/science-matters-understanding-brain-better
 
Description Boston Globe 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Boston Globe interview
Year(s) Of Engagement Activity 2015
 
Description British Neuroscience Association news magazine 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Interview for the quarterly British Neuroscience Association news magazine
Year(s) Of Engagement Activity 2015
 
Description Cambridge - TV 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Cambridge TV interview
Year(s) Of Engagement Activity 2015
 
Description Cambridge MS research day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Around 100 MS patients, physiotherapists and nurses attendend this meeting where scientist working on MS reserach present their newest work for lay audience

Audience suffering from MS congratulated us on our work and for making "complicated" science accessible. In general the audience was very complimentary to our presentations.
Year(s) Of Engagement Activity 2012
 
Description Cambridge Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact The event took place at St Catharine's College, Cambridge,
30 students from years 10 and 11 attendant the event, and the students seem to enjoy the presentation


none
Year(s) Of Engagement Activity 2011
 
Description Cambridge Science Festival - Stem cells: unravelling brain disease 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Cambridge Science Festival - Stem cells: unravelling brain disease - a public talk,
Year(s) Of Engagement Activity 2015
 
Description Icelandic national new paper Fréttatíminn 
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 Public/other audiences
Results and Impact Icelandic national new paper Fréttatíminn interview
Year(s) Of Engagement Activity 2015
 
Description Icelandic national news paper - Morgunbladid 
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 Other audiences
Results and Impact This was national new paper interview - Icelandic interview for Morgunbladid
Year(s) Of Engagement Activity 2015
 
Description Icelandic national television service RUV 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Icelandic national television service RUV News interview
Year(s) Of Engagement Activity 2014
 
Description Invited talk for Action Medical Research charity lunch meeting in Peterborough 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact around 50 people attented the lunch where I held my presentation, which evoked long discussions into medical research and white matter disease in particular. Followed by me reciving few emails afterwards from members in the audience.

Around 50 people attended the lunch where I held my presentation, which evoked long discussions into medical research and white matter disease in particular. After the event I received some emails afterwards from members in the audience, commenting and asking questions regarding the talk.
Year(s) Of Engagement Activity 2010
 
Description Kastljos - RUV -Icelandic national television service RUV 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact TV interview for a news specialist program - similar to Newsnight - but for the national television in Iceland
Year(s) Of Engagement Activity 2015
 
Description National radio Ras2 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact National radio Ras2 interview
Year(s) Of Engagement Activity 2015
 
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 International
Primary Audience Public/other audiences
Results and Impact University of Cambridge made a press release on our paper (Gautier et al., Nat. Communications 2015), this press release was taken up by other press releases and talked - highlighted on number of international science media web pages
Year(s) Of Engagement Activity 2015
URL http://www.cam.ac.uk/research/news/calling-for-help-damaged-nerve-cells-communicate-with-stem-cells
 
Description Radio Interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Radio interview at the Icelandic National Radio station, so the target audience was the general public

Was invited to give lecture to Neurologists in Iceland
Year(s) Of Engagement Activity Pre-2006,2006,2008,2011
 
Description Women in Science 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact This event was organaised by The Norwegian Academy of Science and Letters and the title was "Bridging science and carriere development: Women in frontline science - what is their experience?" 10-11 November 2011 .

I was invited as a speaker to speak about my research and personal drive to juggle science and familiy. The title of my talk was "Oligedendrocyte: The most vulnerable cell in the brain. "

After my talk I spoke with a number of postdocs and PhD students. In addition, I formed a collaboration with Kristine Walhovd and I was offered 10% professorship at the Univeristy of Oslo.
Year(s) Of Engagement Activity 2011
 
Description public lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact ERA-Net NEURON II Foresight symposium due to the european month of the brain - this was the public lecture open to all member of the public. Those that attended where scientists from various background, policy makers, politicians and the general public

Number of emails after the talk from the general audience about my work and white matter disease and I was invited for a radio interview.
Year(s) Of Engagement Activity 2013
URL http://www.neuron-eranet.eu/_media/Symposium_Reykjavik_2013.pdf