Researcher:
Sarıkaya, Deniz

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Undergraduate Student

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Deniz

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Sarıkaya

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Sarıkaya, Deniz

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2019 - 201912020 - 20223

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Researcher Of Publications: search.filters.isAuthorOfPublication.729ffefa-b9f1-45b2-97fe-0d90073f7a34

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    Extracellular vesicles derived from bone marrow mesenchymal stem cells enhance myelin maintenance after cortical injury in aged rhesus monkeys
    (Elsevier, 2021) Go, Veronica; Zhou, Yuxin; Bowley, Bethany G. E.; Pessina, Monica A.; Rosene, Douglas L.; Zhang, Zheng Gang; Chopp, Michael; Finklestein, Seth P.; Medalla, Maria; Buller, Benjamin; Moore, Tara L.; N/A; Sarıkaya, Deniz; Undergraduate Student; School of Medicine; N/A
    Cortical injury, such as stroke, causes neurotoxic cascades that lead to rapid death and/or damage to neurons and glia. Axonal and myelin damage in particular, are critical factors that lead to neuronal dysfunction and impair recovery of function after injury. These factors can be exacerbated in the aged brain where white matter damage is prevalent. Therapies that can ameliorate myelin damage and promote repair by targeting oligodendroglia, the cells that produce and maintain myelin, may facilitate recovery after injury, especially in the aged brain where these processes are already compromised. We previously reported that a novel therapeutic, Mesenchymal Stem Cell derived extracellular vesicles (MSC-EVs), administered intravenously at both 24 h and 14 days after cortical injury, reduced microgliosis (Go et at, 2019), reduced neuronal pathology (Medalla et al. 2020), and improved motor recovery (Moore et al. 2019) in aged female rhesus monkeys. Here, we evaluated the effect of MSC-EV treatment on changes in oligodendrocyte maturation and associated myelin markers in the sublesional white matter using immunohistochemistry, confocal microscopy, stereology, qRT-PCR, and ELISA. Compared to vehicle control monkeys, EV-treated monkeys showed a reduction in the density of damaged oligodendrocytes. Further, EV-treatment was associated with enhanced myelin maintenance, evidenced by upregulation of myelin-related genes and increases in actively myelinating oligodendrocytes in sublesional white matter. These changes in myelination correlate with the rate of motor recovery, suggesting that improved myelin maintenance facilitates this recovery. Overall, our results suggest that EVs act on oligodendrocytes to support myelination and improves functional recovery after injury in the aged brain. Significance: We previously reported that EVs facilitate recovery of function after cortical injury in the aged monkey brain, while also reducing neuronal pathology (Medalla et al. 2020) and microgliosis (Go et al. 2019). However, the effect of injury and EVs on oligodendrocytes and myelination has not been characterized in the primate brain (Doewar et al. 1999; Sozem et al. 2013). In the present study, we assessed changes in myelination after cortical injury in aged monkeys. Our results show, for the first time, that MSC-EVs support recovery of function after cortical injury by enhancing myelin maintenance in the aged primate brain.
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    Targeting the blood–brain barrier disruption in hypertension by ALK5/TGF-В type I receptor inhibitor SB-431542 and dynamin inhibitor dynasore
    (Elsevier, 2022) Ayvaz, Ecem; Yılmaz, Canan Uğur; Girouard, Helene; Atış, Müge; Akcan, Uğur; Altunsu, Deniz; Sarıkaya, Deniz; Temizyürek, Arzu; Ahıshalı, Bülent; Kaya, Mehmet; PHD Student; PHD Student; PHD Student; Undergraduate Student; Other; Faculty Member; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Health Sciences; Graduate School of Health Sciences; Graduate School of Health Sciences; School of Medicine; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; 9509; 10486
    Introduction: In this study, we aimed to target two molecules, transforming growth factor-beta (TGF-beta) and dynamin to explore their roles in blood-brain barrier (BBB) disruption in hypertension. Methods: For this purpose, angiotensin (ANG) II-induced hypertensive mice were treated with SB-431542, an inhibitor of the ALK5/TGF-beta type I receptor, and dynasore, an inhibitor of dynamin. Albumin-Alexa fluor 594 was used to assess BBB permeability. The alterations in the expression of claudin-5, caveolin (Cav)-1, glucose transporter (Glut)-1, and SMAD4 in the cerebral cortex and the hippocampus were evaluated by quantification of immunofluorescence staining intensity.Results: ANG II infusion increased BBB permeability to albumin-Alexa fluor 594 which was reduced by SB431542 (P < 0.01), but not by dynasore. In hypertensive animals treated with dynasore, claudin-5 immunofluorescence intensity increased in the cerebral cortex and hippocampus while it decreased in the cerebral cortex of SB-431542 treated hypertensive mice (P < 0.01). Both dynasore and SB-431542 prevented the increased Cav-1 immunofluorescence intensity in the cerebral cortex and hippocampus of hypertensive animals (P < 0.01). SB431542 and dynasore decreased Glut-1 immunofluorescence intensity in the cerebral cortex and hippocampus of mice receiving ANG II (P < 0.01). SB-431542 increased SMAD4 immunofluorescence intensity in the cerebral cortex of hypertensive animals, while in the hippocampus a significant decrease was noted by both SB-431542 and dynasore (P < 0.01).Conclusion: Our data suggest that inhibition of the TGF beta type I receptor prevents BBB disruption under hypertensive conditions. These results emphasize the therapeutic potential of targeting TGF beta signaling as a novel treatment modality to protect the brain of hypertensive patients.
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    The effects of the methyl-beta-cyclodextrin and myriocin on blood-brain barrier integrity in septic rats
    (Wiley, 2019) Yılmaz, Canan Uğur; Orhan, Nurcan; Kotil, Tuğba; Arıcan, Nadir; N/A; Akcan, Uğur; Atış, Müge; Sarıkaya, Deniz; Ahıshalı, Bülent; Kaya, Mehmet; PhD Student; PhD Student; Undergraduate Student; Faculty Member; Faculty Member; Graduate School of Health Sciences; Graduate School of Health Sciences; School of Medicine; School of Medicine; School of Medicine; N/A; 346431; N/A; 9509; 10486
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    Mesenchymal stem cell derived extracellular vesicles enhance myelin plasticity in rhesus monkeys
    (2020) Go, Veronica; Zhao, Yuxin; Bowley, Bethany; Medalla, Maria; Rosene, Douglas; Buller, Benjamin; Moore, Tara; N/A; Sarıkaya, Deniz; Undergraduate Student; School of Medicine; N/A
    Cortical injury, such as injury from stroke, results in a cascade of events that includes cell death, inflammation and disruption of myelin. To date, there are no highly effective treatments for reducing the deficits that occur after injury. Recently, we have demonstrated that extracellular vesicles (EVs) harvested from rhesus monkey bone marrow derived cells when given 1 day and 14 days following injury facilitate recovery of function in aged rhesus monkeys within the first 3–5 weeks after cortical injury. Based on these findings and current proteomic literature of MSC-EVs, we hypothesized that MSC-EVs enhance myelin plasticity by limiting damage to oligodendrocytes and stimulating remyelination. To assess general myelin integrity after injury, we used Spectral Confocal Reflectance Microscopy (SCoRe) to image myelinated axons and found an increase in the density of myelinated axons in the EV group (p < 0.05). To assess whether the difference was due to reduced damage or remyelination, in sublesional white matter we assessed immunohistochemical labeling of Olig2, a general oligodendrocyte marker, and 8OHdG, a marker for DNA damage. We found reduced densities of Olig2 colocalized with 8OHdG in the EV group (p<0.05). As a marker of active demyelination and myelin debris clearance, we measured Myelin Basic Protein (MBP) concentrations in CSF and found a longitudinal reduction in the EV animals. To assess remyelination, we measured expression of MBP, a gene for myelination in mature oligodendrocytes, Myelin Regulatory Factor (MyRF), a gene for oligodendrocyte differentiation and maintenance, and Breast Carcinoma Amplified Sequence 1 (BCAS1), a gene for newly myelinating oligodendrocytes. Interestingly, we found a 4 fold increase in MyRF expression, and a 1.5 fold increase in MBP and BCAS1 in the EV animals relative to the vehicle control animals in perilesional brain tissue. Consistent with these gene expression differences associated with re-myelination, we found that the densities of newly-myelinating oligodendrocytes immune-labeled with BCAS1, as well as mature oligodendrocytes expressing CC1, exhibited a trend towards an increase in the EV group (p = 0.09). These results suggest that EV treatment reduces myelin damage, while also stimulating myelin repair. Finally, these results correlated with enhanced motor recovery, suggesting that EV-mediated white matter plasticity is a critical component for recovery after cortical injury.