Novel strategies for promoting CNS repair through manipulation of FGF signalling and heparan sulphate proteoglycans

Lead Research Organisation: University of Glasgow
Department Name: College of Medical, Veterinary &Life Sci

Abstract

One of the major limitations in the repair of the damaged CNS is scarring. This is induced in tissue after injury and involves the brain's major support cell (or glial cell), the astrocyte. One repair strategy for CNS injury is to transplant the patient's own glial cells (harvested from peripheral nerves) into the injury site to promote nerve regrowth. There are two possible candidates for cell transplantation, glia from the nose, olfactory ensheathing cells (OECs) and glia of peripheral nerves, Schwann cells. We have found that Schwann cells, but not OECs, induce astrocytic scarring both in experiments in dishes and animal models of injury. Our recent work has shown that Schwann cells secrete complex sugar molecules that enhance the action of specific growth factors, leading to scarring. OECs do not secrete the same sugar structures and, therefore, do not induce scarring, even though they secrete the growth factors known to influence scarring. We have recently developed a number of approaches. The aim of this application is to exploit this new information by developing and testing novel methods to interfere with complex sugar regulation of growth factor signalling in rat models. If successful, this work will lead to design of strategies to manipulate the inhibitory environment induced in humans after injury and promote CNS repair.

Technical Summary

After injury, the central nervous system (CNS) undergoes an astrocyte stress response characterized by reactive astrocytosis/proliferation and scar formation (resulting in a boundary around the injury site). This response is widely considered to be a major inhibitory mechanism for CNS repair. We discovered that astrocytes exhibit this stress response in vitro when in contact with Schwann cells (SCs) but not when in contact with olfactory ensheathing cells (OECs), even though both cell types are very similar antigenically, morphologically and in their ability to remyelinate axons with peripheral type myelin. This difference is due to factor(s) secreted by SCs but absent from OECs. SCs are regarded as strong candidates for glial transplantation to enhance CNS repair, because of ready availability from peripheral nerves, but suffer from the drawback of inducing these astrocytic reactions. Thus, approaches which resolve this problem would have considerable significance in potential therapeutic applications. We have recently defined the molecular mechanisms mediating this effect, revealing a crucial involvement of heparan sulphate proteoglycan (HSPG) regulation of fibroblast growth factor 9 signaling. Our data have, thus, uncovered a novel signaling axis that differentially regulates the astrocyte stress response by OECs compared with SCs. In the current proposal, we plan to exploit these new molecular insights to develop and test molecular interventions to control SC astrocytic responses, firstly in the in vitro model as a screening tool. Selected strategies will then be tested in a biologically relevant, medium through-put in vivo model of CNS cellular interaction involving glial cell transplantation. These studies will provide proof-of-concept for novel strategies to enhance CNS repair by manipulating the inhibitory environment induced after injury, and will be the essential prelude to subsequent translational research aimed at enhancing functional CNS repair.

Planned Impact

The project will have significant impact by enhancing a number of research capacities relating to cell transplantation, and ultimately the improving of health, as set out in our Impact Pathway document. The regulation of astrocytosis by the novel interventions we will develop could have economic impact on health and social wellbeing for a number of diseases in which astrocytosis impedes repair. These include spinal cord injury, Multiple sclerosis, Alexander's disease, Parkinson's disease, ALS etc. Effective therapeutic strategies have the potential to reduce the large negative economic impacts of these devastating diseases.

Our impact plans cover general dissemination of the work, engaging with societal and commercial partners, and evaluating IP, and have specific measurable objectives, as detailed in the full Impact Pathways plan. We will actively disseminate information about our research efforts to academia (publications, conferences, seminars), industry (meetings, joint projects) and the general public (press releases, schools visits, engaging with disease societies). Regarding potential exploitation of IP, there is significant potential for outputs from this project. We will actively monitor our research output and draft publications for potential IP opportunities, and protect these where relevant by liaising with the Universities' technology transfer office.

Publications

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Barnett SC (2013) Myelination: do astrocytes play a role? in The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry

 
Description MRC
Amount £240,193 (GBP)
Funding ID MR/K014366/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 06/2013 
End 05/2015
 
Description PhD studentship MRS
Amount £110,825 (GBP)
Organisation Medical Research Scotland 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2015 
End 09/2019
 
Description Project grant
Amount £160,000 (GBP)
Organisation Multiple Sclerosis Society 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2017 
End 03/2018
 
Title Agents for the prevention and/or treatment of central nervous system damage. 
Description The use of heparin mimetics in the repair of the CNS and PNS. 
IP Reference 14/440,005 
Protection Patent granted
Year Protection Granted 2015
Licensed Yes
Impact grant funding
 
Title Heparin derivatives for use in the inhibition of astrocytosis 
Description modified heparans can prevent astroglyosis 
IP Reference 1219696.0 
Protection Patent application published
Year Protection Granted 2012
Licensed Yes
Impact none
 
Description Annual Meeting of the German priority programme on glial heterogeneity 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Was a grant reviewer on an European programm for research in germany. meeting was held in Annual Meeting of the German priority programme on glial heterogeneity in Homberg
Year(s) Of Engagement Activity 2015
 
Description Franco-Scottish seminar - Towards repair in Multiple Sclerosis, 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact predict sprkred discussion

will give in 2 weeks
Year(s) Of Engagement Activity 2014
URL http://www.royalsoced.org.uk/events/event.php?id=373
 
Description Invited Speaker for the ISN-ESN Myelin Biology: unraveling functions, mechanisms and therapies satellite meeting in Paris, August 2017. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presented work
Year(s) Of Engagement Activity 2017
URL https://www.neurochemistry.org/biennial-meeting/satellite-meetings.html
 
Description Invited speaker "Modeling Nervous System Diseases" 52nd Argentine Congress of Neurology, Mar de plata Argentina, 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact To describe my work using MSCs for spinal cord injury.
Year(s) Of Engagement Activity 2016
 
Description Invited speaker for Glasgow Neuro Interest Group, 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact To describe my work to medical students with an interest in spinal cord injury. To encourage medical students to interact with basic scientists.
Year(s) Of Engagement Activity 2016
 
Description MDC, Berlin, Germany, 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact stimulated discussion

had application for a position on future grant
Year(s) Of Engagement Activity 2012
 
Description University of Liverpool, Liverpool BNA local group, 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact this was directed to postgraduate and undergraduate students who asked questions

just continued to infrom others of work
Year(s) Of Engagement Activity 2014