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

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.

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.

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.