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    CCL11 differentially affects post-stroke brain injury and neuroregeneration in mice depending on age
    (MDPI, 2020) Lieschke, Simone; Zechmeister, Bozena; Haupt, Matteo; Zheng, Xuan; Jin, Fengyan; Hein, Katharina; Weber, Martin S.; Hermann, Dirk M.; Bähr, Mathias; Kılıç, Ertuğrul; Doeppner, Thorsten R.
    CCL11 has recently been shown to differentially affect cell survival under various pathological conditions including stroke. Indeed, CCL11 promotes neuroregeneration in neonatal stroke mice. The impact of CCL11 on the adult ischemic brain, however, remains elusive. We therefore studied the effect of ectopic CCL11 on both adolescent (six-week) and adult (six-month) C57BL6 mice exposed to stroke. Intraperitoneal application of CCL11 significantly aggravated acute brain injury in adult mice but not in adolescent mice. Likewise, post-stroke neurological recovery after four weeks was significantly impaired in adult mice whilst CCL11 was present. On the contrary, CCL11 stimulated gliogenesis and neurogenesis in adolescent mice. Flow cytometry analysis of blood and brain samples revealed a modification of inflammation by CCL11 at subacute stages of the disease. In adolescent mice, CCL11 enhances microglial cell, B and T lymphocyte migration towards the brain, whereas only the number of B lymphocytes is increased in the adult brain. Finally, the CCL11 inhibitor SB297006 significantly reversed the aforementioned effects. Our study, for the first time, demonstrates CCL11 to be a key player in mediating secondary cell injury under stroke conditions. Interfering with this pathway, as shown for SB297006, might thus be an interesting approach for future stroke treatment paradigms.
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    Extracellular vesicles derived from neural progenitor cells--a preclinical evaluation for stroke treatment in mice
    (Springer, 2021) Zheng, Xuan; Zhang, Lin; Kuang, Yaoyun; Venkataramani, Vivek; Jin, Fengyan; Hein, Katharina; Zafeiriou, Maria Patapia; Lenz, Christof; Moebius, Wiebke; Kılıç, Ertuğrul; Hermann, Dirk Matthias; Weber, Martin S.; Urlaub, Henning; Zimmermann, Wolfram Hubertus; BäHR, Mathias; Doeppner, Thorsten Roland
    Stem cells such as mesenchymal stem cells (MSCs) enhance neurological recovery in preclinical stroke models by secreting extracellular vesicles (EVs). Since previous reports have focused on the application of MSC-EVs only, the role of the most suitable host cell for EV enrichment and preclinical stroke treatment remains elusive. The present study aimed to evaluate the therapeutic potential of EVs derived from neural progenitor cells (NPCs) following experimental stroke. Using the PEG technique, EVs were enriched and characterized by electron microscopy, proteomics, rt-PCR, nanosight tracking analysis, and Western blotting. Different dosages of NPC-EVs displaying a characteristic profile in size, shape, cargo protein, and non-coding RNA contents were incubated in the presence of cerebral organoids exposed to oxygen-glucose deprivation (OGD), significantly reducing cell injury when compared with control organoids. Systemic administration of NPC-EVs in male C57BL6 mice following experimental ischemia enhanced neurological recovery and neuroregeneration for as long as 3 months. Interestingly, the therapeutic impact of such NPC-EVs was found to be not inferior to MSC-EVs. Flow cytometric analyses of blood and brain samples 7 days post-stroke demonstrated increased blood concentrations of B and T lymphocytes after NPC-EV delivery, without affecting cerebral cell counts. Likewise, a biodistribution analysis after systemic delivery of NPC-EVs revealed the majority of NPC-EVs to be found in extracranial organs such as the liver and the lung. This proof-of-concept study supports the idea of EVs being a general concept of stem cell-induced neuroprotection under stroke conditions, where EVs contribute to reverting the peripheral post-stroke immunosuppression.
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    Extracellular vesicles derived from neural progenitor cells--a preclinical evaluation for stroke treatment in mice (vol 12, pg 185, 2021)
    (Springer, 2022) Zheng, Xuan; Zhang, Lin; Kuang, Yaoyun; Venkataramani, Vivek; Jin, Fengyan; Hein, Katharina; Zafeiriou, Maria Patapia; Lenz, Christof; Moebius, Wiebke; Kılıç, Ertuğrul; Hermann, Dirk Matthias; Weber, Martin S.; Urlaub, Henning; Zimmermann, Wolfram Hubertus; BäHR, Mathias; Doeppner, Thorsten Roland
    In the version of this article initially published, there were errors on pages 5 and 6.
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    Lithium modulates miR-1906 levels of mesenchymal stem cell-derived extracellular vesicles contributing to poststroke neuroprotection by toll-like receptor 4 regulation
    (Wiley, 2021) Haupt, Matteo; Zheng, Xuan; Kuang, Yaoyun; Lieschke, Simone; Janssen, Lisa; Bosche, Bert; Jin, Fengyan; Hein, Katharina; Kılıç, Ertuğrul; Venkataramani, Vivek; Hermann, Dirk M.; Bahr, Mathias; Doeppner, Thorsten R.
    Lithium is neuroprotective in preclinical stroke models. In addition to that, poststroke neuroregeneration is stimulated upon transplantation of mesenchymal stem cells (MSCs). Preconditioning of MSCs with lithium further enhances the neuroregenerative potential of MSCs, which act by secreting extracellular vesicles (EVs). The present work analyzed, whether MSC preconditioning with lithium modifies EV secretion patterns, enhancing the therapeutic potential of such derived EVs (Li-EVs) in comparison with EVs enriched from native MSCs. Indeed, Li-EVs significantly enhanced the resistance of cultured astrocytes, microglia, and neurons against hypoxic injury when compared with controls and to native EV-treated cells. Using a stroke mouse model, intravenous delivery of Li-EVs increased neurological recovery and neuroregeneration for as long as 3 months in comparison with controls and EV-treated mice, albeit the latter also showed significantly better behavioral test performance compared with controls. Preconditioning of MSCs with lithium also changed the secretion patterns for such EVs, modifying the contents of various miRNAs within these vesicles. As such, Li-EVs displayed significantly increased levels of miR-1906, which has been shown to be a new regulator of toll-like receptor 4 (TLR4) signaling. Li-EVs reduced posthypoxic and postischemic TLR4 abundance, resulting in an inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) signaling pathway, decreased proteasomal activity, and declined both inducible NO synthase and cyclooxygenase-2 expression, all of which culminating in reduced levels of poststroke cerebral inflammation. Conclusively, the present study for the first time demonstrates an enhanced therapeutic potential of Li-EVs compared with native EVs, interfering with a novel signaling pathway that yields both acute neuroprotection an enhanced neurological recovery.