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Öğe Adipose-derived mesenchymal stem cells reduce autophagy in stroke mice by extracellular vesicle transfer of miR-25(Taylor & Francis Ltd, 2020) Kuang, Yaoyun; Zheng, Xuan; Zhang, Lin; Ai, Xiaoyu; Venkataramani, Vivek; Kılıç, Ertuğrul; Hermann, Dirk M.; Majid, Arshad; Baehr, Mathias; Doeppner, Thorsten R.Grafted mesenchymal stem cells (MSCs) yield neuroprotection in preclinical stroke models by secreting extracellular vesicles (EVs). The neuroprotective cargo of EVs, however, has not yet been identified. To investigate such cargo and its underlying mechanism, primary neurons were exposed to oxygen-glucose-deprivation (OGD) and cocultured with adipose-derived MSCs (ADMSCs) or ADMSC-secreted EVs. Under such conditions, both ADMSCs and ADMSC-secreted EVs significantly reduced neuronal death. Screening for signalling cascades being involved in the interaction between ADMSCs and neurons revealed a decreased autophagic flux as well as a declined p53-BNIP3 activity in neurons receiving either treatment paradigm. However, the aforementioned effects were reversed when ADMSCs were pretreated with the inhibitor of exosomal secretion GW4869 or when Hrs was knocked down. In light of miR-25-3p being the most highly expressed miRNA in ADMSC-EVs interacting with the p53 pathway, further in vitro work focused on this pathway. Indeed, a miR-25-3p oligonucleotide mimic reduced cell death, whereas the anti-oligonucleotide increased autophagic flux and cell death by modulating p53-BNIP3 signalling in primary neurons exposed to OGD. Likewise, native ADMSC-EVs but not EVs obtained from ADMSCs pretreated with the anti-miR-25-3p oligonucleotide (ADMSC-EVs(anti-miR-25-3p)) confirmed the aforementioned in vitro observations in C57BL/6 mice exposed to cerebral ischemia. The infarct size was reduced, and neurological recovery was increased in mice treated with native ADMSC-EVs when compared to ADMSC-EVs(anti-miR-25-3p). ADMSCs induce neuroprotection by improved autophagic flux through secreted EVs containing miR-25-3p. Hence, our work uncovers a novel key factor in naturally secreted ADMSC-EVs for the regulation of autophagy and induction of neuroprotection in a preclinical stroke model.Öğe 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 RolandStem 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.Öğe 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 RolandIn the version of this article initially published, there were errors on pages 5 and 6.Öğe Extracellular vesicles from hypoxia-preconditioned microglia promote angiogenesis and repress apoptosis in stroke mice via the TGF-beta/Smad2/3 pathway(Springer Nature, 2021) Zhang, Lin; Wei, Wei; Ai, Xiaoyu; Kılıç, Ertuğrul; Hermann, Dirk M.; Venkataramani, Vivek; Baehr, Mathias; Doeppner, Thorsten R.Systemic transplantation of oxygen-glucose deprivation (OGD)-preconditioned primary microglia enhances neurological recovery in rodent stroke models, albeit the underlying mechanisms have not been sufficiently addressed. Herein, we analyzed whether or not extracellular vesicles (EVs) derived from such microglia are the biological mediators of these observations and which signaling pathways are involved in the process. Exposing bEnd.3 endothelial cells (ECs) and primary cortical neurons to OGD, the impact of EVs from OGD-preconditioned microglia on angiogenesis and neuronal apoptosis by the tube formation assay and TUNEL staining was assessed. Under these conditions, EV treatment stimulated both angiogenesis and tube formation in ECs and repressed neuronal cell injury. Characterizing microglia EVs by means of Western blot analysis and other techniques revealed these EVs to be rich in TGF-beta 1. The latter turned out to be a key compound for the therapeutic potential of microglia EVs, affecting the Smad2/3 pathway in both ECs and neurons. EV infusion in stroke mice confirmed the aforementioned in vitro results, demonstrating an activation of the TGF-beta/Smad2/3 signaling pathway within the ischemic brain. Furthermore, enriched TGF-beta 1 in EVs secreted from OGD-preconditioned microglia stimulated M2 polarization of residing microglia within the ischemic cerebral environment, which may contribute to a regulation of an early inflammatory response in postischemic hemispheres. These observations are not only interesting from the mechanistic point of view but have an immediate therapeutic implication as well, since stroke mice treated with such EVs displayed a better functional recovery in the behavioral test analyses. Hence, the present findings suggest a new way of action of EVs derived from OGD-preconditioned microglia by regulating the TGF-beta/Smad2/3 pathway in order to promote tissue regeneration and neurological recovery in stroke mice.Öğe Inhibition of fatty acid synthesis aggravates brain injury, reduces blood-brain barrier integrity and impairs neurological recovery in a murine stroke model(Frontiers Media SA, 2021) Janssen, Lisa; Ai, Xiaoyu; Zheng, Xuan; Wei, Wei; Çağlayan, Ahmet Burak; Kılıç, Ertuğrul; Wang, Ya-chao; Hermann, Dirk M.; Venkataramani, Vivek; Baehr, Mathias; Doeppner, Thorsten R.Inhibition of fatty acid synthesis (FAS) stimulates tumor cell death and reduces angiogenesis. When SH-SY5Y cells or primary neurons are exposed to hypoxia only, inhibition of FAS yields significantly enhanced cell injury. The pathophysiology of stroke, however, is not only restricted to hypoxia but also includes reoxygenation injury. Hence, an oxygen-glucose-deprivation (OGD) model with subsequent reoxygenation in both SH-SY5Y cells and primary neurons as well as a murine stroke model were used herein in order to study the role of FAS inhibition and its underlying mechanisms. SH-SY5Y cells and cortical neurons exposed to 10 h of OGD and 24 h of reoxygenation displayed prominent cell death when treated with the Acetyl-CoA carboxylase inhibitor TOFA or the fatty acid synthase inhibitor cerulenin. Such FAS inhibition reduced the reduction potential of these cells, as indicated by increased NADH(2)(+)/NAD(+) ratios under both in vitro and in vivo stroke conditions. As observed in the OGD model, FAS inhibition also resulted in increased cell death in the stroke model. Stroke mice treated with cerulenin did not only display increased brain injury but also showed reduced neurological recovery during the observation period of 4 weeks. Interestingly, cerulenin treatment enhanced endothelial cell leakage, reduced transcellular electrical resistance (TER) of the endothelium and contributed to poststroke blood-brain barrier (BBB) breakdown. The latter was a consequence of the activated NF-kappa B pathway, stimulating MMP-9 and ABCB1 transporter activity on the luminal side of the endothelium. In conclusion, FAS inhibition aggravated poststroke brain injury as consequence of BBB breakdown and NF-kappa B-dependent inflammation.Öğe 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.
