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Vitronectin (VTN) is a blood protein produced mainly by the liver. We show that VTN leaks from the bloodstream into the injury site and neighboring subventricular zone (SVZ) following ischemic stroke (middle cerebral artery occlusion, MCAO) in adult mice. MCAO is known to increase neurogenesis after stroke. VTN inhibits this response in females, but not in males, as shown by ~70% more stroke-induced SVZ neurogenesis in female VTN−/− mice at 14 d. In female VTN−/− mice, stroke-induced expression of interleukin-6 (IL-6) at 24 h was reduced in the SVZ. The closely related leukemia inhibitory factor (LIF) or pro-neurogenic ciliary neurotrophic factor (CNTF) were not affected. The female-specific effect of VTN on IL-6 expression was not due to sex hormones, as shown by ovariectomy and castration. IL-6 injection next to the SVZ reversed the MCAO-induced increase in neurogenesis seen in VTN−/− mice. Our in vitro and vivo data suggest that plasma VTN activates focal adhesion kinase (FAK) in the SVZ following MCAO, which reduces IL-6 expression in astrocytes but increases it in other cells such as microglia/macrophages. Inducible conditional astrocytic FAK deletion increased MCAO-induced IL-6 expression in females at 24 h and blocked MCAO-induced neurogenesis at 14 d, confirming a key detrimental role of IL-6. Collectively, these data suggest that leakage of VTN into the SVZ reduces the neurogenic response to stroke in female mice by promoting IL-6 expression. Reducing VTN or VTN signaling may be an approach to promote neurogenesis for neuroprotection and cell replacement after stroke in females.

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Introduction: Astrocytopathy is known to be an early feature of different neuroinflammatory diseases. However, the impact of astrocyte loss and repopulation on the development and progression of demyelinating lesions in complex etiologies, such as multiple sclerosis, is difficult to determine. To more easily analyse astrocyte- oligodendrocyte-interactions during lesion formation and progression in the human brain, diseases like Central pontine myelinolysis (CPM) can be used as a less complex model of demyelinating disorders. CPM is a rare neurological condition characterized by damage to the myelin sheath of pontine nerves after osmotic shifts in serum. Astrocytopathy is regarded to be the first event in the pathogenesis of CPM lesions. Methods: Histological investigation of autopsy tissue from human CPM patients was performed. Lesions were staged considering the myelination and the appearance of different astrocyte subtypes, which was used to judge behaviour of the astrocytic compartment. Further, dynamics of oligodendrocyte loss and repopulation were analysed and compared to the astrocytic repopulation. Results: Early-staged lesions were largely demyelinated and showed an overall reduction of astrocyte densities. The few astrocytes present showed a bipolar morphology and were APQ4-negative, indicating an immature state. Intermediate- stage lesions were still largely demyelinated, but had increased overall densities of astrocytes, which did not yet reflect densities observed in the perilesion. Astrocytes appeared mostly ramified and AQP4-positive, indicating maturity. Nevertheless, bipolar astrocytes were still observable, indicating that repopulation was not yet finalized. Late-stage CPM-lesions were at least partially remyelinated. Astrocytes were detectable in overall densities comparable to the perilesion and showed a ramified (or even reactive morphology), as well as regular expression of AQP4. Investigating the oligodendrocytes, intralesional densities were reduced in early- and intermediate-stage lesions when compared to the perilesion. Re-increase in oligodendrocyte densities was first observable in late-stage lesions, but did not reach perilesional levels. Conclusion: The study at hand indicates that the recovery of demyelinated osmolyte- induced pontine lesions follows a distinct time-course. Repopulation of the lesion with oligodendrocytes is not carried out until lesions are completely repopulated with functional resident astrocytes, as indicated by the ramified morphology and the expression of AQP4. Further studies will be needed to determine, whether the appearance of immature astrocytes, indicating an ongoing repopulation of lesions with astrocytes, correlates with an inefficient repair of demyelinated lesions.:List of Abbreviations.................................................................................................................6 1 Introduction................................................................................................................7 1.1 Osmotic Demyelinating Syndrome......................................................................... 7 1.2 Clinical manifestation............................................................................................. 9 1.3 Diagnosis and Management of CPM.....................................................................11 1.4 Aetiology of Central Pontine Myelinolysis.................................. ......................... 14 1.5 The brain, its adaptation to hyponatraemia and response to correction – pathophysiology of CPM............................................................................................16 1.6 Pathology of myelin............................................................................................. 19 1.6.1 Astrocytopathy and oligodendrocytopathy.................................................................................................20 1.7 Aims of the study................................................................................................. 23 2 Material und Methods............................................................................................. 24 2.1 Patient tissue........................................................................................................ 24 2.2 Histology and immunohistochemistry................................................................................................24 2.2.1 Basic concepts........................................................................................... ......24 2.2.2 Hematoxylin and Eosin (HE)............................................................................. 26 2.2.3 Luxol Fast Blue/ Periodic Acid Schiff stain........................................................27 2.2.4 Immunohistochemistry. Application and Protocol.............................................28 2.3 Implementation.................................................................................................... 31 2.4 Estimation of demyelination................................................................................. 32 2.5 Analysis of cell density and proliferation.............................................................. 32 2.6 Data plotting and statistical analysis.................................................................... 32 3 Results..................................................................................................................... 33 3.1 Patient cohort....................................................................................................... 33 3.2 Characteristics of demyelination.......................................................................... 35 3.3 CPM lesion and disease staging.......................................................................... 37 3.4 Astrocytes within human CPM lesions................................................................. 42 3.4.1 Astrocyte densities are decreased in early CPM lesions....................................42 3.4.2 Astrocytes in CPM– morphological distinctions.................................................45 3.5 Oligodendrocyte densities within human CPM lesions.........................................48 3.6 Macrophages and activated microglia.................................................................. 54 3.6.1 KiM1P – a marker for infiltrating macrophages and activated microglia............54 3.6.2 Proliferating Iba1+ cells are observed in all lesion stages..................................58 4 Discussion................................................................................................................ 61 4.1 Lesion Staging...................................................................................................... 61 4.2 Astrocytes in the pathogenesis of CPM............................................................... 65 4.3 Oligodendrocyte pathology in CPM..................................................................... 69 4.4 Mechanisms of regeneration in human CPM lesions............................................72 4.5 Summary, interpretation and limitations of our study............................................78 5 Conclusion and Outlook.......................................................................................... 80 6 Bibliography............................................................................................................. 82 7 List of Tables.............................................................................................................91 8 List of Figures.......................................................................................................... 92 9 Appendix.................................................................................................................. 94 9.1 Declaration of Authenticity.....................................................................................94 9.2 Acknowledgements...............................................................................................95

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京都大学 / 新制・課程博士 / 博士(医学) / 甲第23804号 / 医博第4850号 / 新制||医||1058(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 井上 治久, 教授 林 康紀, 教授 竹内 理 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM