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Öğe Can Wharton jelly derived or adipose tissue derived mesenchymal stem cell can be a treatment option for duchenne muscular dystrophy? answers as transcriptomic aspect(2020) Sun, Eda; Karaöz, ErdalIntroduction: Mesenchymal stem cells (MSCs) are able to differentiate into several cell lineages including skeletal muscle. In addition to their differentiation capacities, they have the ability to transfer their content genomic information horizontally through their exosomes and fusion abilities, as we have shown in our previous clinic study on Duchenne Muscular Dystrophy (DMD) patients, dystrophin expression increased after MSC treatment. Therefore, this study aimed to compare the transcriptomic properties of Wharton's jelly derived (WJ-) MSC and Adipose tissue (AT-) derived MSC, which are the two most preferred sources in MSC treatments applied in DMD. Methods: Both MSC cell lines obtained from ATCC (PCS-500-010; PCS-500-011) were characterized by flow cytometry then WJ-MSC and AT-MSC cell lines were sequenced via RNA-SEQ. R language was used to obtain the differentially expressed genes (DEGs) and differentially expressed miRNAs, respectively. Additionally, in order to support the results of our study, a gene expression profile data set of DMD patients (GSE1004) were acquired from Gene Expression Omnibus (GEO) database. Results: Here, we demonstrated that activated WNT signaling and downregulated TGF-? pathways under the control of decreased mir-24 which are involved in myogenic differentiation are differentially expressed in WJ-MSC. We have shown that the expression of mir-199a-5p, which is known to increase in exosomes of DMD patients, is less in WJ-MSC. Additionally, we have shown activated PI3K/Akt pathway, which is controlling mitochondria transfer via Tunnelling Nanotube as a new perspective in cellular therapies in myodegenerative diseases, in WJ-MSC more than in AT-MSCs. Conclusion: Summing up, WJ-MSC, which we recommend as an appropriate source candidate due to its immune-regulation properties, stands forward as a preferable source in the cellular treatment of DMD patients due to its transcriptomic aspect.Öğe A case of non-progressive congenital myopathy: Efficacy and clinical outcomes of the wharton's jelly derived mesenchymal stem cell transplantation(Medical Sciences University of Teheran, 2022) Azeri, Rıza; Sun, Eda; Karaöz, ErdalNon-Progressive Congenital Myopathy is a disease characterized by muscle weakness, and unfortunately, there is no conventional treatment. In the last decade, regenerative medicine practices have become a rising value, and Mesenchymal Stem Cells (MSCs) have fascinating outcomes in regenerative medicine with their high regenerative capacities, their ability to regulate with paracrine secretions, and their immunological properties. Based on our experience in our previous clinical studies, Wharton's-Jelly-derived (WJ-)MSCs are the most suitable source for muscle diseases among all MSC sources. In this study, we evaluated the outcomes of 10 doses of WJ-MSC transplantation to the patient diagnosed with Non-Progressive Congenital Myopathy. A 17-year-old female with a SPEN-1 mutation, Non-Progressive Congenital Myopathy patient received 10 times as 1×10?/kg in the intra-arterial, intramuscular and intravenous administration of allogenic WJ-MSC. Before and after the treatment, the patient was followed-up with the upper extremity scale, Vignos lower extremity scale, muscle strength scale, functional independence measure, and evaluation of Serum creatine kinase (CK) levels. Improvement in both upper extremity scale and Vignos lower extremity scales, increasing in muscle strength, and decreasing in CK-level were detected. Although transplantation of WJ-MSC cannot treat any genetic-based diseases, they may benefit in alleviating clinical outcomes of disease. More importantly, WJ-MSC transplantation may offer a better quality of life by alleviating the symptoms of this rare disease with no treatment option that can be provided in conventional methods. © 2022 Tehran University of Medical Sciences. All rights reserved.Öğe Comparative analyses of immunosuppressive characteristics of bone-marrow, wharton's jelly, and adipose tissue-derived human mesenchymal stem cells(Galenos Yayincilik, 2017) Karaöz, Erdal; Demircan, Pınar Çetinalp; Erman, Gülay; Sun, Eda; Sarıboyacı, Ayla EkerObjective: Mesenchymal stem cells (MSCs), which possess immunosuppressive characteristics on induced T-cells, were shown to be applicable in prevention and treatment of graft-versus-host disease. However, knowledge of effective cell sources is still limited. In this study, MSCs from different human tissues, i.e. bone marrow (BM), Wharton's jelly (WJ), and adipose tissue, were isolated, and the immune suppression of stimulated T cells was analyzed comparatively. Materials and Methods: MSCs were co-cultured with phytohemagglutinin-induced T-cells with co-culture techniques with and without cell-to-cell contact. After co-culture for 24 and 96 h, the proliferation rate of T cells was estimated by carboxyfluorescein succinimidyl ester and apoptosis by annexin V/PI methods. Both T cells and MSCs were analyzed with respect to gene expressions by real-time polymerase chain reaction and their specific protein levels by ELISA. Results: The results showed that all three MSC lines significantly suppressed T-cell proliferation; BM-MSCs were most effective. Similarly, T-cell apoptosis was induced most strongly by BM-MSCs in indirect culture. In T cells, the genes in NFkB and tumor necrosis factor pathways were silenced and the caspase pathway was induced after co-culture. These results were confirmed with the measurement of protein levels, like transforming growth factor beta 1, IL-6, interferon-gamma, interleukin (IL)-2, and tumor necrosis factor-alpha. Additionally, IL-17A was detected in high levels in WJ-MSC co-cultures. We showed that IL-17A-producing Tregs are the key mediators in the treatment of graft-versus-host disease. Conclusion: BM-MSCs, which have been used in clinical applications for a while, showed the greatest immunosuppressive effect compared to other MSCs. However, a promising cell source could also be WJ, which is also effective in suppression with fewer ethical concerns. We described the molecular mechanism of WJ-MSCs in allogenic transplants for the first time.Öğe Comprehensive analysis of transcriptomic portrait of T-cell acute lymphoblastic leukemia by RNA sequencing(Pergamon-Elsevier Science Ltd, 2018) Sun, Eda; Ng, O. Hatırnaz; Erbilgin, Y.; Fırtına, S.; Sayitoğlu, M.Objective: T cell-acute lymphoblastic leukemia (T-ALL) is one of the most aggressive treatment-resistant types of leukemia, which has no specific prognostic marker for disease follow up. Objective: The aim of this study is to demonstrate the altered genes in T-ALL, WNT-specific analysis of exhibit abnormal activity in the T-ALL and identify the tissue-specific expressions of alternative splicing products by transcriptome sequencingÖğe Efficacy of stem cell therapy in ambulatory and nonambulatory children with Duchenne muscular dystrophy - Phase I-II(Dove Medical Press Ltd, 2018) Dai, Alper; Başpınar, Osman; Yeşilyurt, Ahmet; Sun, Eda; Aydemir, Çiğdem İnci; Öztel, Olga Nehir; Karaöz, ErdalPurpose: Duchenne muscular dystrophy (DMD) is an X-linked recessive pediatric disorder that ultimately leads to progressive muscle degeneration. It has been known that cell-based therapies were used to promote muscle regeneration. The main purpose of this study was to investigate the effects of allogeneic Wharton jelly-derived mesenchymal stem cells therapy in Duchenne muscular dystrophy. Patients and methods: Four ambulatory and five nonambulatory male patients were assessed as having acceptance criteria. Gene expression and immunohistochemical analysis were performed for dystrophin gene expression. The fluorescent in situ hybridization method was used for detection of chimerism and donor-recipient compatibility. Complement dependent lymphocyto-toxic crossmatch test and detection of panel reactive antigen were performed. All patients were treated with 2 x 10(6) cells/kg dose of allogeneic Wharton jelly-derived mesenchymal stem cells via intra-arterial and intramuscular administration. Stability was maintained in patient follow-up tests, which are respiratory capacity tests, cardiac measurements, and muscle strength tests. Results: The vastus intermedius muscle was observed in one patient with MRI. Chimerism was detected by fluorescent in situ hybridization and mean gene expression was increased to 3.3-fold. An increase in muscle strength measurements and pulmonary function tests was detected. Additionally, we observed two of nine patients with positive panel reactive antigen result. Conclusion: All our procedures are well tolerated, and we have not seen any application-related complications so far. Our main purpose of this study was to investigate the effects of allogeneic mesenchymal stem cell therapy and determine its suitability and safety as a form of treatment in this untreatable disorder.Öğe Genomic and proteomic monitoring of stem cell-derived exosomes(HUMANA PRESS INC, 2019) Karaöz, Erdal; Sun, EdaThe mesenchymal stem cell (MSC) transplantations are increasing day by day in clinical therapies. Recent studies have described that the treatment activities of MSCs are mediated by paracrine factors secreted. These paracrine factors are spread through messenger clouds as exosomes secreted from MSCs, which are also involved in the cellular communication via transferring their mRNA, miRNA, and protein contents horizontally. With the understanding of this mechanism, cell-free therapies have begun to create a new path in MSC based therapies as a cell-free treatment. It is important to understand how much the mRNA, miRNA, and protein contents of the MSCs and their secreted exosomes are overlapping. Additionally, the content of these exosomes must be determined in order to both define their efficacy and to be able to select their most suitable sources. Therefore, in this chapter, we have described different transcriptomic and proteomic methods for displaying the contents of the exosomes.Öğe Lösemi modelinde tüm Genom RNA dizileme analiz algoritması geliştirilmesi(DergiPark, 2020) Sun, Eda; Sayitoğlu, MügeAmaç: RNA Dizileme teknolojisi gen anlatım farklılıkları ve kodlayan bölgedeki varyasyonlar, kodlama yapmayan küçük RNAların anlatımları ve gen füzyonlarının belirlenmesi ile bu farklılıkların nedenlerini sunabilmektedir. Ancak bu kadar enformatik bilgiler sunabilen bu teknolojinin analizlerinin yapılması ve yorumlanması oldukça zorludur. T- hücreli akut lenfoblastik lösemi (T-ALL) de prognostik öneme sahip ve hastalığın takibinde kullanılabilecek güvenilir bir genetik belirteç bulunmamakla birlikte, doğrudan tedavi protokolünü ve tedavide yararlanılacak yeni hedef proteinleri belirlemede esas olacak moleküler alt yapı ve sınıflandırma da bilinmemektedir. Gereç ve Yöntem: Biz de bu çalışmamızda, T-ALL gibi karmaşık bir genomik arka plana sahip lösemi hücrelerinde RNA-dizileme için en uygun enformatik iş akış algoritmasını oluşturmayı amaçladık. Bu çalışmada RNA dizileme ile Jurkat ve Molt 4 hücre hatları dizilenmiştir. Doğrulama ve karşılaştırma amacıyla açık veri bankalarından elde edilen sağlıklı timosit alt grupları ve T-ALL hasta (n=12) örnekleri (GSE48173) kullanılmıştır. Bulgular: Açık erişimli veri araçları ile gerçekleştirdiğimiz enformatik analizlerde doku spesifik alternatif kırpılma ürünlerinin kantitatif tayinini, spesifik gen varyasyonlarını ve global gen anlatım düzeylerini başarılı bir şekilde tespit ettik ve T-ALL hasta verisinde aynı yaklaşımları kullanarak doğrulama yaptık. Sonuç: Çalışmamızın sonucunda lösemi hastalarının veri analizinde kullanılabilecek uygun araçlar ve algoritma belirlenmiştir.Öğe Mesenchymal stem cell-derived exosomes do not promote the proliferation of cancer cells in vitro(2019) Karaöz, Erdal; Sun, Eda; Subaşı Demir, CansuNowadays, the use of Mesenchymal stem cells (MSCs) in clinical therapies have an increased acceleration, while it constitutes two sides of yin-yang with its ameliorating effects in regenerative medicine and promoting effects in carcinogenesis. It has been shown that the treatment activities of MSCs are mediated by paracrine factors secreted. These paracrine factors are transmitting via exosomes secreted from MSCs. With the understanding of this mechanism, cell-free therapies have begun to create a new path in MSC based therapies. At this point, two sides of the yin-yang have once again become controversial. In addition, there are conflicting study results in the literature. Due to this contradiction, we have designed this study to demonstrate the role of MSCs in the carcinogenesis process and we investigated the proliferation effect of MSC-derived exosomes on cancer cell lines. Two parallel experimental setups were established, as an experimental group, the four-different epithelial cancer cell lines and Wharton's Jelly (WJ)-MSC derived exosomes were directly co-cultured with in 6 different concentrations and simultaneously in the control group cells were cultured respectively. PKH-26 labelling was performed for detection of exosome locations in co-cultures. Each group were evaluated by WST-1 and xCelligence assays for proliferation and confirmed with PCNA staining. The results were analysed with paired t-test and Newman-Keuls comparison. The relative comparison demonstrated a significant increase in the rate of proliferation only in exosome co-cultures with WJ-MSCs and it was supported by PCNA staining. Cancer cell lines in co-cultures have not shown any significant increase neither in proliferation assays nor in PCNA staining. MSCs regulate their secretions according to the microenvironment, they have more dominant regenerative feature rather than triggering cancer proliferation.Öğe Mesenchymal stem cells for the treatment of covid-19: why and when they should be used?(Nova Science Publishers, 2021) Darıcı, Hakan; Sun, Eda; Koyuncu Irmak, Duygu; Karaöz, ErdalCOVID-19 is a pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which caused deaths of more than 300.000 people around the world within the first few months of 2020. SARS-CoV-2 uses ACE2 receptors to infect respiratory system cells and may cause pneumonia and severe lung damage. The virus can also spread other organs rapidly via ACE2 expressing endothelial cells and cause coagulopathy, and further damage to the organs. Another and probably more harmful effect of the virus is the overreaction of the immune system leading to hyperinflammation causing multiple organ failure and death. Therefore COVID-19 can be considered as a viral infection causing auto-immune disorders. Currently, no vaccine or effective pharmacological treatment established for the disease. On the other hand, Mesenchymal Stem Cells (MSCs) possess anti-inflammatory and immune-regulatory effects along with their regenerative abilities. In this article, we thoroughly evaluate the COVID-19 pandemic and the damage mechanisms on the cellular level which can be ameliorated with the cellular therapies. We also gathered previous and ongoing stem cell clinical trial data from diseases with similar symptoms. All these accumulated data and current clinical trial results indicate that the cellular therapies could be the most effective treatment option for COVID-19 patients to ameliorate the damaged tissues and save lives.Öğe Mesenchymal stem cells for the treatment of covid-19: why and when they should be used?(Nova Science Publishers, 2020) Darıcı, Hakan; Sun, Eda; Irmak, Duygu Koyuncu; Karaöz, ErdalCOVID-19 is a pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which caused deaths of more than 300.000 people around the world within the first few months of 2020. SARS-CoV-2 uses ACE2 receptors to infect respiratory system cells and may cause pneumonia and severe lung damage. The virus can also spread other organs rapidly via ACE2 expressing endothelial cells and cause coagulopathy, and further damage to the organs. Another and probably more harmful effect of the virus is the overreaction of the immune system leading to hyperinflammation causing multiple organ failure and death. Therefore COVID-19 can be considered as a viral infection causing auto-immune disorders. Currently, no vaccine or effective pharmacological treatment established for the disease. On the other hand, Mesenchymal Stem Cells (MSCs) possess anti- inflammatory and immune-regulatory effects along with their regenerative abilities. In this article, we thoroughly evaluate the COVID-19 pandemic and the damage mechanisms on the cellular level which can be ameliorated with the cellular therapies. We also gathered previous and ongoing stem cell clinical trial data from diseases with similar symptoms. All these accumulated data and current clinical trial results indicate that the cellular therapies could be the most effective treatment option for COVID-19 patients to ameliorate the damaged tissues and save lives.Öğe Safety and efficacy of the stem cell transplantation in friedreich's ataxia: a report of three cases(IJPHY PUBLISHERS, 2021) Azeri, Rıza; Irmak, Duygu Koyuncu; Sun, Eda; Karaöz, ErdalBackground: Friedreich's ataxia is a progressive degenerative disorder caused by deficiency of the frataxin protein. Expanded GAA repeats in intron 1 of the FXN gene lead to its heterochromatinization and transcriptional silencing. Strategies being trialed to treat Friedreich's ataxia include drugs that improve mitochondrial function and reduce oxidative injury. It has been shown that mesenchymal stem cell (MSC)-derived factors can restore cellular homeostasis and function to frataxin deficient cells. Case Summary: Here, we report three FRDA cases treated with four consecutive allogeneic transplantations of umbilical cord-derived MSCs with 30 days interval, upon per patient regulatory approvals for advanced cellular therapy. Outcome Measures: The cases were followed up after the treatment in means of the therapeutic effect of the cellular treatment by attenuating the neurological findings and gene expression parameters. Conclusions: Closely followed promising safety and efficacy outcomes demonstrated that the MSC treatment for FRDA might positively affect the clinical results caused by the defect in this genetic-based disease.
