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Article Citation - WoS: 36Citation - Scopus: 43The Effect of Boron-Containing Nano-Hydroxyapatite on Bone Cells(Humana Press inc, 2020) Gizer, Merve; Kose, Sevil; Karaosmanoglu, Beren; Taskiran, Ekim Z.; Berkkan, Aysel; Timucin, Muharrem; Korkusuz, PetekMetabolic diseases or injuries damage bone structure and self-renewal capacity. Trace elements and hydroxyapatite crystals are important in the development of biomaterials to support the renewal of bone extracellular matrix. In this study, it was assumed that the boron-loaded nanometer-sized hydroxyapatite composite supports the construction of extracellular matrix by controlled boron release in order to prevent its toxic effect. In this context, boron release from nanometer-sized hydroxyapatite was calculated by ICP-MS as in large proportion within 1 h and continuing release was provided at a constant low dose. The effect of the boron-containing nanometer-sized hydroxyapatite composite on the proliferation of SaOS-2 osteoblasts and human bone marrow-derived mesenchymal stem cells was evaluated by WST-1 and compared with the effects of nano-hydroxyapatite and boric acid. Boron increased proliferation of mesenchymal stem cells at high doses and exhibited different effects on osteoblastic cell proliferation. Boron-containing nano-hydroxyapatite composites increased osteogenic differentiation of mesenchymal stem cells by increasing alkaline phosphatase activity, when compared to nano-hydroxyapatite composite and boric acid. The molecular mechanism of effective dose of boron-containing hydroxyapatite has been assessed by transcriptomic analysis and shown to affect genes involved in Wnt, TGF-beta, and response to stress signaling pathways when compared to nano-hydroxyapatite composite and boric acid. Finally, a safe osteoconductive dose range of boron-containing nano-hydroxyapatite composites for local repair of bone injuries and the molecular effect profile in the effective dose should be determined by further studies to validation of the regenerative therapeutic effect window.Article Citation - WoS: 1Citation - Scopus: 1Topical Intranasal Insulin Enhances Healing of Nasal Mucosa: an Experimental Animal Study(Sage Publications inc, 2023) Kulekci, Cagri; Ozer, Serdar; Onen, Selin; Korkusuz, Petek; Yilmaz, TanerObjective Aim of this study was to evaluate the effect of topical intranasal insulin on healing of nasal mucosa in a rat model. Methods Forty-eight Wistar rats, weighing between 250 and 300 g and aged 10-12 weeks were used and randomized into two equal groups. 1.9 mm curette was introduced through the left nostril and 1.9 mm mucosa from the left nasal septum was curetted. Postoperatively, animals in the control group received 1 mL of physiologic saline, 3 times a day in a nasal irrigation fashion. Animals in the experimental group received 1 mL of 5 IU/mL regular insulin in saline solution. Subjects were sacrificed after 5, 10, and 15 days and macroscopic and histomorphometric evaluations were performed. Results There were no mucosal synechiae and septal perforation macroscopically. Histological examination revealed that the defect size reduction was 21% in the saline group versus 56% in the insulin group on the fifth day (p = 0.006). There was 62% defect reduction in the saline group versus 79% in the insulin group on the 10th day (p = 0.034). On the 15th day, only 67% of saline group animals had complete defect closure, whereas 100% of animals treated with insulin had complete closure (92% vs 100% mucosal defect reduction, p = 0.036). Both edema and inflammation were less in the insulin group on 15th day (p = 0.006; p = 0.023, respectively). Conclusion The results from this study support the safety and efficacy of topical insulin on wound healing in the literature. This study could guide further experimental studies that examine human sinonasal wound healing.Book Part Citation - WoS: 13Citation - Scopus: 14Neurological Regulation of the Bone Marrow Niche(Springer international Publishing Ag, 2020) Aerts-Kaya, Fatima; Ulum, Baris; Mammadova, Aynura; Kose, Sevil; Aydin, Gozde; Korkusuz, Petek; Uckan-Cetinkaya, DuyguThe bone marrow (BM) hematopoietic niche is the microenvironment where in the adult hematopoietic stem and progenitor cells (HSPCs) are maintained and regulated. This regulation is tightly controlled through direct cell-cell interactions with mesenchymal stromal stem (MSCs) and reticular cells, adipocytes, osteoblasts and endothelial cells, through binding to extracellular matrix molecules and through signaling by cytokines and hematopoietic growth factors. These interactions provide a healthy environment and secure the maintenance of the HSPC pool, their proliferation, differentiation and migration. Recent studies have shown that innervation of the BM and interactions with the peripheral sympathetic neural system are important for maintenance of the hematopoietic niche, through direct interactions with HSCPs or via interactions with other cells of the HSPC microenvironment. Signaling through adrenergic receptors (ARs), opioid receptors (ORs), endocannabinoid receptors (CRs) on HSPCs and MSCs has been shown to play an important role in HSPC homeostasis and mobilization. In addition, a wide range of neuropeptides and neurotransmitters, such as Neuropeptide Y (NPY), Substance P (SP) and Tachykinins, as well as neurotrophins and neuropoietic growth factors have been shown to be involved in regulation of the hematopoietic niche. Here, a comprehensive overview is given of their role and interactions with important cells in the hematopoietic niche, including HSPCs and MSCs, and their effect on HSPC maintenance, regulation and mobilization.Article Citation - WoS: 16Citation - Scopus: 19A Pumpless Monolayer Microfluidic Device Based on Mesenchymal Stem Cell-Conditioned Medium Promotes Neonatal Mouse in Vitro Spermatogenesis(Bmc, 2023) Onen, Selin; Atik, Ali Can; Gizer, Merve; Kose, Sevil; Yaman, Onder; Kulah, Haluk; Korkusuz, PetekBackgroundChildhood cancer treatment-induced gonadotoxicity causes permanent infertility/sub-infertility in nearly half of males. The current clinical and experimental approaches are limited to cryopreservation of prepubertal testicular strips and in vitro spermatogenesis which are inadequate to achieve the expanded spermatogonial stem/progenitor cells and spermatogenesis in vitro. Recently, we reported the supportive effect of bone marrow-derived mesenchymal cell co-culture which is inadequate after 14 days of culture in static conditions in prepubertal mouse testis due to lack of microvascular flow and diffusion. Therefore, we generated a novel, pumpless, single polydimethylsiloxane-layered testis-on-chip platform providing a continuous and stabilized microfluidic flow and real-time cellular paracrine contribution of allogeneic bone marrow-derived mesenchymal stem cells.MethodsWe aimed to evaluate the efficacy of this new setup in terms of self-renewal of stem/progenitor cells, spermatogenesis and structural and functional maturation of seminiferous tubules in vitro by measuring the number of undifferentiated and differentiating spermatogonia, spermatocytes, spermatids and tubular growth by histochemical, immunohistochemical, flow cytometric and chromatographic techniques.ResultsBone marrow-derived mesenchymal stem cell-based testis-on-chip platform supported the maintenance of SALL4(+) and PLZF(+) spermatogonial stem/progenitor cells, for 42 days. The new setup improved in vitro spermatogenesis in terms of c-Kit(+) differentiating spermatogonia, VASA(+) total germ cells, the meiotic cells including spermatocytes and spermatids and testicular maturation by increasing testosterone concentration and improved tubular growth for 42 days in comparison with hanging drop and non-mesenchymal stem cell control.ConclusionsFuture fertility preservation for male pediatric cancer survivors depends on the protection/expansion of spermatogonial stem/progenitor cell pool and induction of in vitro spermatogenesis. Our findings demonstrate that a novel bone marrow-derived mesenchymal stem cell-based microfluidic testis-on-chip device supporting the maintenance of stem cells and spermatogenesis in prepubertal mice in vitro. This new, cell therapy-based microfluidic platform may contribute to a safe, precision-based cell and tissue banking protocols for prepubertal fertility restoration in future.Article ACPA Prevents Lung Fibroblast-to Transformation by Reprogramming the Tumor Microenvironment through NSCLC-Derived Exosomes(Nature Portfolio, 2025) Boyacioglu, Ozge; Kalali, Berfin Deniz; Recber, Tuba; Gelen-Gungor, Dilek; Nemutlu, Emirhan; Eroglu, Ipek; Korkusuz, Petek; Kilic, NedretNon-small cell lung cancer (NSCLC) accounts for most lung cancer cases. Current treatments often cause systemic side effects or lead to drug resistance, prompting the development of new therapies targeting tumors and related cells simultaneously. Cancer-associated fibroblasts (CAFs) are crucial stromal cells within the tumor microenvironment (TME), making them potential targets for therapy. Previously, we found that the CB1 receptor agonist ACPA has anti-tumor effects on NSCLC, inhibiting pathways such as Akt/PI3K, JNK, glycolysis, the citric acid cycle, and the urea cycle both in vitro and in vivo. We hypothesize that ACPA could enhance therapy by inhibiting the transformation of lung fibroblasts into CAFs via exosomes. Control and ACPA-treated NSCLC cell exosomes exhibited similar size, PDI, ZP, and high expression of CD9, CD63, and CD81. ACPA-treated exosomes showed reduced levels of miR-21 and miR-23. These exosomes decreased fibroblast viability within 12 h by disrupting pentose phosphate, lipid, and amino acid metabolism, and by lowering PDPN, alpha-SMA, and FAP expressions. This research highlights ACPA as a promising chemotherapeutic agent, capable of improving NSCLC treatment and reprogramming the TME with more targeted therapies.Article Citation - WoS: 1Citation - Scopus: 2Cannabinoid Receptor Ligands Modulate Fibrosis and Inflammation in Idiopathic Pulmonary Fibrosis: a Preliminary Study(Tubitak Scientific & Technological Research Council Turkey, 2024) Kose, Sevil; Onen, Selin; Gizer, Merve; Boduroglu, Esin; Gonullu, Ugur; Korkusuz, PetekBackground/aim: No specific pharmacological treatment regimen for idiopathic pulmonary fibrosis (IPF) exists. Therefore, new antiinflammatory therapeutic strategies are needed. Cannabinoids (CBs), known for their inflammation-modulating and antifibrotic effects, may be potential medication candidates for treating IPF. We aim to evaluate the inflammation-modulating and antifibrotic effects of CB receptor (CBR) agonists and antagonists in lipopolysaccharide-stimulated normal human lung fibroblast, epithelial cells, IPF fibroblast cells, and monocytes. Materials and methods: We detected CBRs in normal human lung fibroblasts (LL24) and IPF fibroblast cells (LL29), epithelial cells (A549) and monocytes (THP-1) by flow cytometry. We determined TGF-(31, IL-8, and TNF-alpha inflammatory cytokines in the LL24, LL29, A549, and THP-1 cell culture supernatants on days 1 and 5 by ELISA. We evaluated the cell viability in LL24, LL29, and A549 cells on days 1, 3, and 5 spectrophotometrically and detected collagen Type I (ColI) production in the LL24 and LL29 cell culture supernatants on days 1, 3, and 5 by ELISA. Results: LL24, LL29, A549, and THP-1 cells exhibited CB1 (CB1R) and CB2 (CB2R) receptors. CB1R and CB2R agonists WIN55,2122 and JWH015 inhibited fibroblastic and epithelial cell proliferation on day 5. TGF-(31 and TNF-alpha release increased, while IL-8 release decreased in LL24, LL29, A549, and THP-1 cells in response to the administration of WIN55,212-2 and JWH015 at a 10-2 mM concentration. CB1R and CB2R antagonists AM251 and AM630 did not block agonistic responses, suggesting a nonclassical CBRmediated pathway. CB2R agonist JWH015 decreased ColI expression in IPF lung fibroblasts LL29 on day 3. Conclusion: These results suggest that CB signaling regulates the progression of pulmonary inflammation and fibrosis via CBR activation. This may offer a potential pharmacological tool for developing antifibrosis therapies.Article Citation - WoS: 3Citation - Scopus: 3Detection of spermatogonial stem/progenitor cells in prepubertal mouse testis with deep learning(Springer/plenum Publishers, 2023) Kahveci, Burak; Onen, Selin; Akal, Fuat; Korkusuz, PetekPurposeRapid and easy detection of spermatogonial stem/progenitor cells (SSPCs) is crucial for clinicians dealing with male infertility caused by prepubertal testicular damage. Deep learning (DL) methods may offer visual tools for tracking SSPCs on testicular strips of prepubertal animal models. The purpose of this study is to detect and count the seminiferous tubules and SSPCs in newborn mouse testis sections using a DL method.MethodsTesticular sections of the C57BL/6-type newborn mice were obtained and enumerated. Odd-numbered sections were stained with hematoxylin and eosin (H&E), and even-numbered sections were immune labeled (IL) with SSPC specific marker, SALL4. Seminiferous tubule and SSPC datasets were created using odd-numbered sections. SALL4-labeled sections were used as positive control. The YOLO object detection model based on DL was used to detect seminiferous tubules and stem cells.ResultsTest scores of the DL model in seminiferous tubules were obtained as 0.98 mAP, 0.93 precision, 0.96 recall, and 0.94 f1-score. The SSPC test scores were obtained as 0.88 mAP, 0.80 precision, 0.93 recall, and 0.82 f1-score.ConclusionSeminiferous tubules and SSPCs on prepubertal testicles were detected with a high sensitivity by preventing human-induced errors. Thus, the first step was taken for a system that automates the detection and counting process of these cells in the infertility clinic.Article Citation - WoS: 9Citation - Scopus: 11Human Laryngeal Squamous Cell Carcinoma Cell Line Release of Endogenous Anandamide and 2-Arachidonoylglycerol, and Their Antiproliferative Effect Via Exogenous Supplementation: an in Vitro Study(Springer, 2022) Onay, Ovsen; Kose, Sevil; Suslu, Nilda; Korkusuz, Petek; Nemutlu, Emirhan; Aydin, Canset; Hosal, SefikThe level of the major endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are altered in several types of carcinomas, and are known to regulate tumor growth. Thusly, this study hypothesized that the HEp-2 human laryngeal squamous cell carcinoma (LSCC) cell line releases AEA and 2-AG, and aimed to determine if their exogenous supplementation has an anti-proliferative effect in vitro. In this in vitro observational study a commercial human LSCC cell line (HEp-2) was used to test for endogenous AEA and 2-AG release via liquid chromatography-tandem mass spectrometry (LC-MS/MS). The anti-proliferative effect of AEA and 2-AG supplementation was evaluated via WST-1 proliferation assay. It was observed that the HEp-2 LSCC cell line released AEA and 2-AG; the median quantity of AEA released was 15.69 ng mL(-1) (range: 14.55-15.95 ng mL(-1)) and the median quantity of 2-AG released was 2.72 ng (-1) (range: 2.67-2.74 ng mL(-1)). Additionally, both AEA and 2-AG exhibited an anti-proliferative effect. The anti-proliferative effect of 2-AG was stronger than that of AEA. These findings suggest that AEA might function via a CB1 receptor-independent pathway and that 2-AG might function via a CB2-dependent pathway. The present findings show that the HEp-2 LSCC cell line releases the major endocannabinoids AEA and 2-AG, and that their supplementation inhibits tumor cell proliferation in vitro. Thus, cannabinoid ligands might represent novel drug candidates for laryngeal cancers, although functional in vivo studies are required in order to validate their potency.Article Citation - WoS: 5Citation - Scopus: 6Clinic-Oriented Injectable Smart Material for the Treatment of Diabetic Wounds: Coordinating the Release of Gm-Csf and Vegf(Elsevier, 2024) Kinali, Hurmet; Kalaycioglu, Gokce Dicle; Boyacioglu, Ozge; Korkusuz, Petek; Aydogan, Nihal; Vargel, IbrahimChronic wounds are often caused by diabetes and present a challenging clinical problem due to vascular problems leading to ischemia. This inhibits proper wound healing by delaying inflammatory responses and angiogenesis. To address this problem, we have developed injectable particle-loaded hydrogels which sequentially release Granulocyte-macrophage- colony-stimulating-factor (GM-CSF) and Vascular endothelial growth factor (VEGF) encapsulated in polycaprolactone-lecithin-geleol mono-diglyceride hybrid particles. GM-CSF promotes inflammation, while VEGF facilitates angiogenesis. The hybrid particles (200 -1000 nm) designed within the scope of the study can encapsulate the model proteins Bovine Serum Albumin 65 +/- 5 % and Lysozyme 77 +/- 10 % and can release stably for 21 days. In vivo tests and histological findings revealed that in the hydrogels containing GM-CSF/VEGF-loaded hybrid particles, wound depth decreased, inflammation phase increased, and fibrotic scar tissue decreased, while mature granulation tissue was formed on day 10. These findings confirm that the hybrid particles first initiate the inflammation phase by delivering GM-CSF, followed by VEGF, increasing the number of vascularization and thus increasing the healing rate of wounds. We emphasize the importance of multi-component and sequential release in wound healing and propose a unifying therapeutic strategy to sequentially deliver ligands targeting wound healing stages, which is very important in the treatment of the diabetic wounds.Article Citation - WoS: 23Citation - Scopus: 26Mesenchymal Stem Cells Promote Spermatogonial Stem/Progenitor Cell Pool and Spermatogenesis in Neonatal Mice in Vitro(Nature Portfolio, 2022) Onen, Selin; Kose, Sevil; Yersal, Nilgun; Korkusuz, PetekPrepubertal cancer treatment leads to irreversible infertility in half of the male patients. Current in vitro spermatogenesis protocols and cryopreservation techniques are inadequate to expand spermatogonial stem/progenitor cells (SSPC) from testicles. Bone marrow derived mesenchymal stem cells (BM-MSC) bearing a close resemblance to Sertoli cells, improved spermatogenesis in animal models. We asked if a co-culture setup supported by syngeneic BM-MSC that contributes to the air-liquid interphase (ALI) could lead to survival, expansion and differentiation of SSPCs in vitro. We generated an ALI platform able to provide a real-time cellular paracrine contribution consisting of syngeneic BM-MSCs to neonatal C57BL/6 mice testes. We aimed to evaluate the efficacy of this culture system on SSPC pool expansion and spermatogenesis throughout a complete spermatogenic cycle by measuring the number of total germ cells (GC), the undifferentiated and differentiating spermatogonia, the spermatocytes and the spermatids. Furthermore, we evaluated the testicular cell cycle phases, the tubular and luminal areas using histochemical, immunohistochemical and flow cytometric techniques. Cultures in present of BM-MSCs displayed survival of ID4(+) spermatogonial stem cells (SSC), expansion of SALL4(+) and OCT4(+) SSPCs, VASA(+) total GCs and Ki67(+) proliferative cells at 42 days and an increased number of SCP3(+) spermatocytes and Acrosin(+) spermatids at 28 days. BM-MSCs increased the percentage of mitotic cells within the G2-M phase of the total testicular cell cycle increased for 7 days, preserved the cell viability for 42 days and induced testicular maturation by enlargement of the tubular and luminal area for 42 days in comparison to the control. The percentage of PLZF(+) SSPCs increased within the first 28 days of culture, after which the pool started to get smaller while the number of spermatocytes and spermatids increased simultaneously. Our findings established the efficacy of syngeneic BM-MSCs on the survival and expansion of the SSPC pool and differentiation of spermatogonia to round spermatids during in vitro culture of prepubertal mice testes for 42 days. This method may be helpful in providing alternative cures for male fertility by supporting in vitro differentiated spermatids that can be used for round spermatid injection (ROSI) to female oocyte in animal models. These findings can be further exploited for personalized cellular therapy strategies to cure male infertility of prepubertal cancer survivors in clinics.
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