Cerebral ischemia, stem cells, immune response, inflammation, functional recovery

Stroke is the third most common cause of death in the UK and the single most common cause of severe disability with profound effects on patients, relatives and the economy (~£7 billion /year). With an increasing ageing population in the UK and a paucity of licensed therapies for stroke, new therapeutic strategies are needed to prevent brain damage after stroke. Our own and others have highlighted the potential of stem cell therapy for stroke (Patkar et al, 2012). Inflammatory changes are key players in cerebral ischemic pathogenesis (Fumagalli et al, 2011) and can be key to the success or demise of stem cell therapy (Ideguchi et al, 2008). In addition undifferentiated adult stem cells display immune-like functions that promote long-lasting neuroprotection (Knight et al, 2011).

Specific objectives: Two main questions will be addressed in this project:

1. How can we improve stem cell technology to overcome immunogenecity?
2. How can we improve immunomodulatory capacity of NPCs?

We will employ various genetically modified (GM) mouse strains (cytokine deficient, immunodeficient) in models of cerebral ischaemia to explore inflammatory effects on stem cell function. We will also genetically modify stem cells (e.g. cytokine receptor knockdown) to gain an understanding of immune -like functions of stem cells.

Briefly 3 month old male WT and GM mice will undergo middle cerebral artery occlusion with reperfusion and 48hours later mice will undergo stem cell transplantation of GM stem cells or WT stem cells. Behavioural recovery will be used to assess stem cell success after stroke over 4 weeks. Thereafter brains will be assessed for infarct volume, inflammatory response (expression of pro- and anti- inflammatory cytokines) and markers of brain plasticity and repair.

Expected results and Conclusions:These results are expected to reveal how we can modulate the immune system to improve stem cell function and also how we can improve stem cell technology to improve therapeutic potential of stem cells in stroke.

Fumagalli, S, Coles, J.A.C., Ejlerskov, P., Ortolano, F., Bushell, T.J., Brewer, J.M., De Simoni, M.G., Dever, G., Garside, P., Maffia, P., Carswell, H.V  In vivo Real Time Multiphoton Imaging of T Lymphocytes in Mouse Brain After Experimental Stroke. Stroke. (2011) 42; 1429-1436