WP2: Maximizing Regeneration after Brain Lesions: The Role of Stem Cells and Inflammation after Stroke: WP2 will be led by Professor Hoehn with four incoming ESRs/ERs into his MPI laboratory and two outgoing ESRs/ERs. This complex project requires the collaborative effort of several partners. While all MRI is performed in Cologne, optical imaging is optimized in collaboration with the partner at Leiden and PERC. Detailed physiological monitoring and animal handling is supported by Medres at Cologne. Data analysis will be supported by icoMetrix. It is further of interest to include the UA laboratory to assess regeneration potential of this approach on models of AD. Professor Hoehn will also work in the labs of PERC as an ER (>10) to bring together the cell labelling strategies, design the stem cell fate experiments and to correlate the fMRI and optical imaging data. Stem cell transplantations in the brain have been shown in several experimental animal studies of cerebral lesions to have a therapeutic effect on functional outcome improvement. Outcome improvement has been demonstrated using behavioural tests of the sensorimotor system and recently by fMRI. However, most studies have used stem cells of different origin or of different predifferentiation stage, making results difficult to compare due to varying protocols. This includes variation of time point of implantation after lesion induction. In parallel, recent intensive studies have shown a dual role of inflammation during response of the brain to the occurrence of a lesion. While it is believed that microglia and macrophages (M1 type) have a detrimental role on the lesion and further aggravate functional deficits, recent investigations have indicated that this is only the case during the early, subacute phase of the lesion evolution. In a second, somewhat later phase, activated microglia and M2 macrophages are actually needed for a robust regenerative process. There is further indication for an interaction between the grafted stem cells and the activated microglia, possibly influencing substantially the survival and activity of the graft and its therapeutic potential. It therefore becomes of increasing interest to analyze the temporal profile of the inflammatory reaction to an induced cerebral lesion. Better understanding of the shift between the detrimental and constructive inflammatory phases is needed to develop a robust and efficient stem cell mediated regeneration therapy. Although this description applies to many brain diseases including neurodegenerative diseases (such as AD and Parkinson’s Diseases), a vast number of studies on the topic of stem cell mediated regeneration has been performed on cerebral ischemia, in particular stroke. Thus, stroke makes an ideal disease model to study the interaction of grafted stem cells and inflammation, together with the fact that excellent, clinically relevant animal models of stroke are established.