TY - JOUR A1 - Schlecht, Anja A1 - Thien, Adrian A1 - Wolf, Julian A1 - Prinz, Gabriele A1 - Agostini, Hansjürgen A1 - Schlunck, Günther A1 - Wieghofer, Peter A1 - Boneva, Stefaniya A1 - Lange, Clemens T1 - Immunosenescence in choroidal neovascularization (CNV) — Transcriptional profiling of naïve and CNV-associated retinal myeloid cells during aging JF - International Journal of Molecular Sciences N2 - Immunosenescence is considered a possible factor in the development of age-related macular degeneration and choroidal neovascularization (CNV). However, age-related changes of myeloid cells (MCs), such as microglia and macrophages, in the healthy retina or during CNV formation are ill-defined. In this study, Cx3cr1-positive MCs were isolated by fluorescence-activated cell sorting from six-week (young) and two-year-old (old) Cx3cr1\(^{GFP/+}\) mice, both during physiological aging and laser-induced CNV development. High-throughput RNA-sequencing was performed to define the age-dependent transcriptional differences in MCs during physiological aging and CNV development, complemented by immunohistochemical characterization and the quantification of MCs, as well as CNV size measurements. These analyses revealed that myeloid cells change their transcriptional profile during both aging and CNV development. In the steady state, senescent MCs demonstrated an upregulation of factors contributing to cell proliferation and chemotaxis, such as Cxcl13 and Cxcl14, as well as the downregulation of microglial signature genes. During CNV formation, aged myeloid cells revealed a significant upregulation of angiogenic factors such as Arg1 and Lrg1 concomitant with significantly enlarged CNV and an increased accumulation of MCs in aged mice in comparison to young mice. Future studies need to clarify whether this observation is an epiphenomenon or a causal relationship to determine the role of immunosenescence in CNV formation. KW - age-related macular degeneration (AMD) KW - choroidal neovascularization (CNV) KW - aging KW - immunosenescence KW - microglia KW - myeloid cells KW - RNA-sequencing Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284342 SN - 1422-0067 VL - 22 IS - 24 ER - TY - JOUR A1 - Rajendran, Ranjithkumar A1 - Rajendran, Vinothkumar A1 - Giraldo-Velasquez, Mario A1 - Megalofonou, Fevronia-Foivi A1 - Gurski, Fynn A1 - Stadelmann, Christine A1 - Karnati, Srikanth A1 - Berghoff, Martin T1 - Oligodendrocyte-specific deletion of FGFR1 reduces cerebellar inflammation and neurodegeneration in MOG\(_{35-55}\)-induced EAE JF - International Journal of Molecular Sciences N2 - Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS). MS commonly affects the cerebellum causing acute and chronic symptoms. Cerebellar signs significantly contribute to clinical disability, and symptoms such as tremor, ataxia, and dysarthria are difficult to treat. Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies such as MS. In autopsy tissue from patients with MS, increased expression of FGF1, FGF2, FGF9, and FGFR1 was found in lesion areas. Recent research using mouse models has focused on regions such as the spinal cord, and data on the expression of FGF/FGFR in the cerebellum are not available. In recent EAE studies, we detected that oligodendrocyte-specific deletion of FGFRs results in a milder disease course, less cellular infiltrates, and reduced neurodegeneration in the spinal cord. The objective of this study was to characterize the role of FGFR1 in oligodendrocytes in the cerebellum. Conditional deletion of FGFR1 in oligodendrocytes (Fgfr1\(^{ind−/−}\) was achieved by tamoxifen application, EAE was induced using the MOG\(_{35-55}\) peptide. The cerebellum was analyzed by histology, immunohistochemistry, and western blot. At day 62 p.i., Fgfr1\(^{ind−/−}\) mice showed less myelin and axonal degeneration compared to FGFR1-competent mice. Infiltration of CD3(+) T cells, Mac3(+) cells, B220(+) B cells and IgG(+) plasma cells in cerebellar white matter lesions (WML) was less in Fgfr1\(^{ind−/−}\)mice. There were no effects on the number of OPC or mature oligodendrocytes in white matter lesion (WML). Expression of FGF2 and FGF9 associated with less myelin and axonal degeneration, and of the pro-inflammatory cytokines IL-1β, IL-6, and CD200 was downregulated in Fgfr1\(^{ind−/−}\) mice. The FGF/FGFR signaling protein pAkt, BDNF, and TrkB were increased in Fgfr1\(^{ind−/−}\) mice. These data suggest that cell-specific deletion of FGFR1 in oligodendrocytes has anti-inflammatory and neuroprotective effects in the cerebellum in the EAE disease model of MS. KW - FGFR1 KW - oligodendrocytes KW - demyelination KW - inflammation KW - cerebellum KW - EAE KW - MS Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284296 SN - 1422-0067 VL - 22 IS - 17 ER - TY - JOUR A1 - Rajendran, Ranjithkumar A1 - Böttiger, Gregor A1 - Dentzien, Niklas A1 - Rajendran, Vinothkumar A1 - Sharifi, Bischand A1 - Ergün, Süleyman A1 - Stadelmann, Christine A1 - Karnati, Srikanth A1 - Berghoff, Martin T1 - Effects of FGFR tyrosine kinase inhibition in OLN-93 oligodendrocytes JF - Cells N2 - Fibroblast growth factor (FGF) signaling is involved in the pathogenesis of multiple sclerosis (MS). Data from neuropathology studies suggest that FGF signaling contributes to the failure of remyelination in MS. In MOG\(_{35–55}\)-induced EAE, oligodendrocyte-specific deletion of FGFR1 and FGFR2 resulted in a less severe disease course, reduced inflammation, myelin and axon degeneration and changed FGF/FGFR and BDNF/TrkB signaling. Since signaling cascades in oligodendrocytes could not be investigated in the EAE studies, we here aimed to characterize FGFR-dependent oligodendrocyte-specific signaling in vitro. FGFR inhibition was achieved by application of the multi-kinase-inhibitor dovitinib and the FGFR1/2/3-inhibitor AZD4547. Both substances are potent inhibitors of FGF signaling; they are effective in experimental tumor models and patients with malignancies. Effects of FGFR inhibition in oligodendrocytes were studied by immunofluorescence microscopy, protein and gene analyses. Application of the tyrosine kinase inhibitors reduced FGFR1, phosphorylated ERK and Akt expression, and it enhanced BDNF and TrkB expression. Furthermore, the myelin proteins CNPase and PLP were upregulated by FGFR inhibition. In summary, inhibition of FGFR signaling in oligodendrocytes can be achieved by application of tyrosine kinase inhibitors. Decreased phosphorylation of ERK and Akt is associated with an upregulation of BDNF/TrkB signaling, which may be responsible for the increased production of myelin proteins. Furthermore, these data suggest that application of FGFR inhibitors may have the potential to promote remyelination in the CNS. KW - multiple sclerosis KW - oligodendrocytes KW - dovitinib KW - AZD4547 KW - FGFR signaling KW - myelin Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239600 SN - 2073-4409 VL - 10 IS - 6 ER - TY - JOUR A1 - Rajendran, Ranjithkumar A1 - Böttiger, Gregor A1 - Stadelmann, Christine A1 - Karnati, Srikanth A1 - Berghoff, Martin T1 - FGF/FGFR pathways in multiple sclerosis and in its disease models JF - Cells N2 - Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS) affecting more than two million people worldwide. In MS, oligodendrocytes and myelin sheaths are destroyed by autoimmune-mediated inflammation, while remyelination is impaired. Recent investigations of post-mortem tissue suggest that Fibroblast growth factor (FGF) signaling may regulate inflammation and myelination in MS. FGF2 expression seems to correlate positively with macrophages/microglia and negatively with myelination; FGF1 was suggested to promote remyelination. In myelin oligodendrocyte glycoprotein (MOG)\(_{35–55}\)-induced experimental autoimmune encephalomyelitis (EAE), systemic deletion of FGF2 suggested that FGF2 may promote remyelination. Specific deletion of FGF receptors (FGFRs) in oligodendrocytes in this EAE model resulted in a decrease of lymphocyte and macrophage/microglia infiltration as well as myelin and axon degeneration. These effects were mediated by ERK/Akt phosphorylation, a brain-derived neurotrophic factor, and downregulation of inhibitors of remyelination. In the first part of this review, the most important pharmacotherapeutic principles for MS will be illustrated, and then we will review recent advances made on FGF signaling in MS. Thus, we will suggest application of FGFR inhibitors, which are currently used in Phase II and III cancer trials, as a therapeutic option to reduce inflammation and induce remyelination in EAE and eventually MS. KW - FGF KW - FGFR KW - multiple sclerosis KW - EAE KW - ERK KW - Akt KW - BDNF KW - LINGO-1 KW - SEMA3A Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236594 SN - 2073-4409 VL - 10 IS - 4 ER - TY - JOUR A1 - Luetkens, Karsten Sebastian A1 - Ergün, Süleyman A1 - Huflage, Henner A1 - Kunz, Andreas Steven A1 - Gietzen, Carsten Herbert A1 - Conrads, Nora A1 - Pennig, Lenhard A1 - Goertz, Lukas A1 - Bley, Thorsten Alexander A1 - Gassenmaier, Tobias A1 - Grunz, Jan-Peter T1 - Dose reduction potential in cone-beam CT imaging of upper extremity joints with a twin robotic x-ray system JF - Scientific Reports N2 - Cone-beam computed tomography is a powerful tool for 3D imaging of the appendicular skeleton, facilitating detailed visualization of bone microarchitecture. This study evaluated various combinations of acquisition and reconstruction parameters for the cone-beam CT mode of a twin robotic x-ray system in cadaveric wrist and elbow scans, aiming to define the best possible trade-off between image quality and radiation dose. Images were acquired with different combinations of tube voltage and tube current–time product, resulting in five scan protocols with varying volume CT dose indices: full-dose (FD; 17.4 mGy), low-dose (LD; 4.5 mGy), ultra-low-dose (ULD; 1.15 mGy), modulated low-dose (mLD; 0.6 mGy) and modulated ultra-low-dose (mULD; 0.29 mGy). Each set of projection data was reconstructed with three convolution kernels (very sharp [Ur77], sharp [Br69], intermediate [Br62]). Five radiologists subjectively assessed the image quality of cortical bone, cancellous bone and soft tissue using seven-point scales. Irrespective of the reconstruction kernel, overall image quality of every FD, LD and ULD scan was deemed suitable for diagnostic use in contrast to mLD (very sharp/sharp/intermediate: 60/55/70%) and mULD (0/3/5%). Superior depiction of cortical and cancellous bone was achieved in FD\(_{Ur77}\) and LD\(_{Ur77}\) examinations (p < 0.001) with LD\(_{Ur77}\) scans also providing favorable bone visualization compared to FD\(_{Br69}\) and FD\(_{Br62}\) (p < 0.001). Fleiss’ kappa was 0.618 (0.594–0.641; p < 0.001), indicating substantial interrater reliability. In this study, we demonstrate that considerable dose reduction can be realized while maintaining diagnostic image quality in upper extremity joint scans with the cone-beam CT mode of a twin robotic x-ray system. Application of sharper convolution kernels for image reconstruction facilitates superior display of bone microarchitecture. KW - medical research KW - preclinical research Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270429 VL - 11 IS - 1 ER - TY - JOUR A1 - Jordan, Martin C. A1 - Jäckle, Veronika A1 - Scheidt, Sebastian A1 - Gilbert, Fabian A1 - Hölscher-Doht, Stefanie A1 - Ergün, Süleyman A1 - Meffert, Rainer H. A1 - Heintel, Timo M. T1 - Trans-obturator cable fixation of open book pelvic injuries JF - Scientific Reports N2 - Operative treatment of ruptured pubic symphysis by plating is often accompanied by complications. Trans-obturator cable fixation might be a more reliable technique; however, have not yet been tested for stabilization of ruptured pubic symphysis. This study compares symphyseal trans-obturator cable fixation versus plating through biomechanical testing and evaluates safety in a cadaver experiment. APC type II injuries were generated in synthetic pelvic models and subsequently separated into three different groups. The anterior pelvic ring was fixed using a four-hole steel plate in Group A, a stainless steel cable in Group B, and a titan band in Group C. Biomechanical testing was conducted by a single-leg-stance model using a material testing machine under physiological load levels. A cadaver study was carried out to analyze the trans-obturator surgical approach. Peak-to-peak displacement, total displacement, plastic deformation and stiffness revealed a tendency for higher stability for trans-obturator cable/band fixation but no statistical difference to plating was detected. The cadaver study revealed a safe zone for cable passage with sufficient distance to the obturator canal. Trans-obturator cable fixation has the potential to become an alternative for symphyseal fixation with less complications. KW - anatomy KW - medical research Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-261212 VL - 11 IS - 1 ER - TY - JOUR A1 - Meyer, Malin Tordis A1 - Watermann, Christoph A1 - Dreyer, Thomas A1 - Ergün, Süleyman A1 - Karnati, Srikanth T1 - 2021 update on diagnostic markers and translocation in salivary gland tumors JF - International Journal of Molecular Sciences N2 - Salivary gland tumors are a rare tumor entity within malignant tumors of all tissues. The most common are malignant mucoepidermoid carcinoma, adenoid cystic carcinoma, and acinic cell carcinoma. Pleomorphic adenoma is the most recurrent form of benign salivary gland tumor. Due to their low incidence rates and complex histological patterns, they are difficult to diagnose accurately. Malignant tumors of the salivary glands are challenging in terms of differentiation because of their variability in histochemistry and translocations. Therefore, the primary goal of the study was to review the current literature to identify the recent developments in histochemical diagnostics and translocations for differentiating salivary gland tumors. KW - salivary gland tumors KW - epithelial salivary gland KW - adenoid cystic carcinoma (ACC) KW - pleomorphic adenoma KW - mucoepidermoid carcinoma KW - diagnostic markers Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-261057 SN - 1422-0067 VL - 22 IS - 13 ER - TY - JOUR A1 - Meyer, Malin Tordis A1 - Watermann, Christoph A1 - Dreyer, Thomas A1 - Wagner, Steffen A1 - Wittekindt, Claus A1 - Klussmann, Jens Peter A1 - Ergün, Süleyman A1 - Baumgart-Vogt, Eveline A1 - Karnati, Srikanth T1 - Differential expression of peroxisomal proteins in distinct types of parotid gland tumors JF - International Journal of Molecular Sciences N2 - Salivary gland cancers are rare but aggressive tumors that have poor prognosis and lack effective cure. Of those, parotid tumors constitute the majority. Functioning as metabolic machinery contributing to cellular redox balance, peroxisomes have emerged as crucial players in tumorigenesis. Studies on murine and human cells have examined the role of peroxisomes in carcinogenesis with conflicting results. These studies either examined the consequences of altered peroxisomal proliferators or compared their expression in healthy and neoplastic tissues. None, however, examined such differences exclusively in human parotid tissue or extended comparison to peroxisomal proteins and their associated gene expressions. Therefore, we examined differences in peroxisomal dynamics in parotid tumors of different morphologies. Using immunofluorescence and quantitative PCR, we compared the expression levels of key peroxisomal enzymes and proliferators in healthy and neoplastic parotid tissue samples. Three parotid tumor subtypes were examined: pleomorphic adenoma, mucoepidermoid carcinoma and acinic cell carcinoma. We observed higher expression of peroxisomal matrix proteins in neoplastic samples with exceptional down regulation of certain enzymes; however, the degree of expression varied between tumor subtypes. Our findings confirm previous experimental results on other organ tissues and suggest peroxisomes as possible therapeutic targets or markers in all or certain subtypes of parotid neoplasms. KW - peroxisomes KW - parotid gland KW - salivary KW - tumors KW - pleomorphic adenoma KW - mucoepidermoid carcinoma KW - acinic cell carcinoma KW - differential expression KW - immunohistochemistry KW - mRNA Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-261047 SN - 1422-0067 VL - 22 IS - 15 ER - TY - JOUR A1 - Bielmeier, Christina B. A1 - Roth, Saskia A1 - Schmitt, Sabrina I. A1 - Boneva, Stefaniya K. A1 - Schlecht, Anja A1 - Vallon, Mario A1 - Tamm, Ernst R. A1 - Ergün, Süleyman A1 - Neueder, Andreas A1 - Braunger, Barbara M. T1 - Transcriptional profiling identifies upregulation of neuroprotective pathways in retinitis pigmentosa JF - International Journal of Molecular Sciences N2 - Hereditary retinal degenerations like retinitis pigmentosa (RP) are among the leading causes of blindness in younger patients. To enable in vivo investigation of cellular and molecular mechanisms responsible for photoreceptor cell death and to allow testing of therapeutic strategies that could prevent retinal degeneration, animal models have been created. In this study, we deeply characterized the transcriptional profile of mice carrying the transgene rhodopsin V20G/P23H/P27L (VPP), which is a model for autosomal dominant RP. We examined the degree of photoreceptor degeneration and studied the impact of the VPP transgene-induced retinal degeneration on the transcriptome level of the retina using next generation RNA sequencing (RNASeq) analyses followed by weighted correlation network analysis (WGCNA). We furthermore identified cellular subpopulations responsible for some of the observed dysregulations using in situ hybridizations, immunofluorescence staining, and 3D reconstruction. Using RNASeq analysis, we identified 9256 dysregulated genes and six significantly associated gene modules in the subsequently performed WGCNA. Gene ontology enrichment showed, among others, dysregulation of genes involved in TGF-β regulated extracellular matrix organization, the (ocular) immune system/response, and cellular homeostasis. Moreover, heatmaps confirmed clustering of significantly dysregulated genes coding for components of the TGF-β, G-protein activated, and VEGF signaling pathway. 3D reconstructions of immunostained/in situ hybridized sections revealed retinal neurons and Müller cells as the major cellular population expressing representative components of these signaling pathways. The predominant effect of VPP-induced photoreceptor degeneration pointed towards induction of neuroinflammation and the upregulation of neuroprotective pathways like TGF-β, G-protein activated, and VEGF signaling. Thus, modulation of these processes and signaling pathways might represent new therapeutic options to delay the degeneration of photoreceptors in diseases like RP. KW - retinitis pigmentosa KW - VPP mouse model KW - in-situ hybridization KW - neurodegeneration KW - neuroinflammation KW - extracellular matrix disorganisation KW - neuroprotective pathways Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260769 SN - 1422-0067 VL - 22 IS - 12 ER - TY - JOUR A1 - Janz, Anna A1 - Zink, Miriam A1 - Cirnu, Alexandra A1 - Hartleb, Annika A1 - Albrecht, Christina A1 - Rost, Simone A1 - Klopocki, Eva A1 - Günther, Katharina A1 - Edenhofer, Frank A1 - Ergün, Süleyman A1 - Gerull, Brenda T1 - CRISPR/Cas9-edited PKP2 knock-out (JMUi001-A-2) and DSG2 knock-out (JMUi001-A-3) iPSC lines as an isogenic human model system for arrhythmogenic cardiomyopathy (ACM) JF - Stem Cell Research N2 - Arrhythmogenic cardiomyopathy (ACM) is characterized by fibro-fatty replacement of the myocardium, heart failure and life-threatening ventricular arrhythmias. Causal mutations were identified in genes encoding for proteins of the desmosomes, predominantly plakophilin-2 (PKP2) and desmoglein-2 (DSG2). We generated gene-edited knock-out iPSC lines for PKP2 (JMUi001-A-2) and DSG2 (JMUi001-A-3) using the CRISPR/Cas9 system in a healthy control iPSC background (JMUi001A). Stem cell-like morphology, robust expression of pluripotency markers, embryoid body formation and normal karyotypes confirmed the generation of high quality iPSCs to provide a novel isogenic human in vitro model system mimicking ACM when differentiated into cardiomyocytes. KW - mutations Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259846 VL - 53 ER - TY - JOUR A1 - Liu, Fengming A1 - Han, Kun A1 - Blair, Robert A1 - Kenst, Kornelia A1 - Qin, Zhongnan A1 - Upcin, Berin A1 - Wörsdörfer, Philipp A1 - Midkiff, Cecily C. A1 - Mudd, Joseph A1 - Belyaeva, Elizaveta A1 - Milligan, Nicholas S. A1 - Rorison, Tyler D. A1 - Wagner, Nicole A1 - Bodem, Jochen A1 - Dölken, Lars A1 - Aktas, Bertal H. A1 - Vander Heide, Richard S. A1 - Yin, Xiao-Ming A1 - Kolls, Jay K. A1 - Roy, Chad J. A1 - Rappaport, Jay A1 - Ergün, Süleyman A1 - Qin, Xuebin T1 - SARS-CoV-2 Infects Endothelial Cells In Vivo and In Vitro JF - Frontiers in Cellular and Infection Microbiology N2 - SARS-CoV-2 infection can cause fatal inflammatory lung pathology, including thrombosis and increased pulmonary vascular permeability leading to edema and hemorrhage. In addition to the lung, cytokine storm-induced inflammatory cascade also affects other organs. SARS-CoV-2 infection-related vascular inflammation is characterized by endotheliopathy in the lung and other organs. Whether SARS-CoV-2 causes endotheliopathy by directly infecting endothelial cells is not known and is the focus of the present study. We observed 1) the co-localization of SARS-CoV-2 with the endothelial cell marker CD31 in the lungs of SARS-CoV-2-infected mice expressing hACE2 in the lung by intranasal delivery of adenovirus 5-hACE2 (Ad5-hACE2 mice) and non-human primates at both the protein and RNA levels, and 2) SARS-CoV-2 proteins in endothelial cells by immunogold labeling and electron microscopic analysis. We also detected the co-localization of SARS-CoV-2 with CD31 in autopsied lung tissue obtained from patients who died from severe COVID-19. Comparative analysis of RNA sequencing data of the lungs of infected Ad5-hACE2 and Ad5-empty (control) mice revealed upregulated KRAS signaling pathway, a well-known pathway for cellular activation and dysfunction. Further, we showed that SARS-CoV-2 directly infects mature mouse aortic endothelial cells (AoECs) that were activated by performing an aortic sprouting assay prior to exposure to SARS-CoV-2. This was demonstrated by co-localization of SARS-CoV-2 and CD34 by immunostaining and detection of viral particles in electron microscopic studies. Moreover, the activated AoECs became positive for ACE-2 but not quiescent AoECs. Together, our results indicate that in addition to pneumocytes, SARS-CoV-2 also directly infects mature vascular endothelial cells in vivo and ex vivo, which may contribute to cardiovascular complications in SARS-CoV-2 infection, including multipleorgan failure. KW - endothelial cell infection KW - animal models KW - SARS-CoV-2 KW - aorta ring KW - hACE2 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241948 SN - 2235-2988 VL - 11 ER - TY - JOUR A1 - Karnati, Srikanth A1 - Seimetz, Michael A1 - Kleefeldt, Florian A1 - Sonawane, Avinash A1 - Madhusudhan, Thati A1 - Bachhuka, Akash A1 - Kosanovic, Djuro A1 - Weissmann, Norbert A1 - Krüger, Karsten A1 - Ergün, Süleyman T1 - Chronic Obstructive Pulmonary Disease and the Cardiovascular System: Vascular Repair and Regeneration as a Therapeutic Target JF - Frontiers in Cardiovascular Medicine N2 - Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide and encompasses chronic bronchitis and emphysema. It has been shown that vascular wall remodeling and pulmonary hypertension (PH) can occur not only in patients with COPD but also in smokers with normal lung function, suggesting a causal role for vascular alterations in the development of emphysema. Mechanistically, abnormalities in the vasculature, such as inflammation, endothelial dysfunction, imbalances in cellular apoptosis/proliferation, and increased oxidative/nitrosative stress promote development of PH, cor pulmonale, and most probably pulmonary emphysema. Hypoxemia in the pulmonary chamber modulates the activation of key transcription factors and signaling cascades, which propagates inflammation and infiltration of neutrophils, resulting in vascular remodeling. Endothelial progenitor cells have angiogenesis capabilities, resulting in transdifferentiation of the smooth muscle cells via aberrant activation of several cytokines, growth factors, and chemokines. The vascular endothelium influences the balance between vaso-constriction and -dilation in the heart. Targeting key players affecting the vasculature might help in the development of new treatment strategies for both PH and COPD. The present review aims to summarize current knowledge about vascular alterations and production of reactive oxygen species in COPD. The present review emphasizes on the importance of the vasculature for the usually parenchyma-focused view of the pathobiology of COPD. KW - COPD KW - emphysema KW - pulmonary hypertension KW - hypoxia KW - oxidative stress Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235631 SN - 2297-055X VL - 8 ER - TY - JOUR A1 - Dogan, Leyla A1 - Scheuring, Ruben A1 - Wagner, Nicole A1 - Ueda, Yuichiro A1 - Schmidt, Sven A1 - Wörsdörfer, Philipp A1 - Groll, Jürgen A1 - Ergün, Süleyman T1 - Human iPSC-derived mesodermal progenitor cells preserve their vasculogenesis potential after extrusion and form hierarchically organized blood vessels JF - Biofabrication N2 - Post-fabrication formation of a proper vasculature remains an unresolved challenge in bioprinting. Established strategies focus on the supply of the fabricated structure with nutrients and oxygen and either rely on the mere formation of a channel system using fugitive inks or additionally use mature endothelial cells and/or peri-endothelial cells such as smooth muscle cells for the formation of blood vessels in vitro. Functional vessels, however, exhibit a hierarchical organization and multilayered wall structure that is important for their function. Human induced pluripotent stem cell-derived mesodermal progenitor cells (hiMPCs) have been shown to possess the capacity to form blood vessels in vitro, but have so far not been assessed for their applicability in bioprinting processes. Here, we demonstrate that hiMPCs, after formulation into an alginate/collagen type I bioink and subsequent extrusion, retain their ability to give rise to the formation of complex vessels that display a hierarchical network in a process that mimics the embryonic steps of vessel formation during vasculogenesis. Histological evaluations at different time points of extrusion revealed the initial formation of spheres, followed by lumen formation and further structural maturation as evidenced by building a multilayered vessel wall and a vascular network. These findings are supported by immunostainings for endothelial and peri-endothelial cell markers as well as electron microscopic analyses at the ultrastructural level. Moreover, endothelial cells in capillary-like vessel structures deposited a basement membrane-like matrix at the basal side between the vessel wall and the alginate-collagen matrix. After transplantation of the printed constructs into the chicken chorioallantoic membrane (CAM) the printed vessels connected to the CAM blood vessels and get perfused in vivo. These results evidence the applicability and great potential of hiMPCs for the bioprinting of vascular structures mimicking the basic morphogenetic steps of de novo vessel formation during embryogenesis. KW - vascular biofabrication KW - human iPSC-derived mesodermal cells (hiMPCs) KW - extrusion of hiMPC-containing bioinks alginate + collagen type I KW - multilayered vessel wall with intimate, media and adventitia KW - vascular network and hierarchical organized vessels KW - electron microscopy KW - serial block face EM Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-254046 VL - 13 IS - 4 ER - TY - JOUR A1 - Schlecht, Anja A1 - Vallon, Mario A1 - Wagner, Nicole A1 - Ergün, Süleyman A1 - Braunger, Barbara M. T1 - TGFβ-Neurotrophin Interactions in Heart, Retina, and Brain JF - Biomolecules N2 - Ischemic insults to the heart and brain, i.e., myocardial and cerebral infarction, respectively, are amongst the leading causes of death worldwide. While there are therapeutic options to allow reperfusion of ischemic myocardial and brain tissue by reopening obstructed vessels, mitigating primary tissue damage, post-infarction inflammation and tissue remodeling can lead to secondary tissue damage. Similarly, ischemia in retinal tissue is the driving force in the progression of neovascular eye diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD), which eventually lead to functional blindness, if left untreated. Intriguingly, the easily observable retinal blood vessels can be used as a window to the heart and brain to allow judgement of microvascular damages in diseases such as diabetes or hypertension. The complex neuronal and endocrine interactions between heart, retina and brain have also been appreciated in myocardial infarction, ischemic stroke, and retinal diseases. To describe the intimate relationship between the individual tissues, we use the terms heart-brain and brain-retina axis in this review and focus on the role of transforming growth factor β (TGFβ) and neurotrophins in regulation of these axes under physiologic and pathologic conditions. Moreover, we particularly discuss their roles in inflammation and repair following ischemic/neovascular insults. As there is evidence that TGFβ signaling has the potential to regulate expression of neurotrophins, it is tempting to speculate, and is discussed here, that cross-talk between TGFβ and neurotrophin signaling protects cells from harmful and/or damaging events in the heart, retina, and brain. KW - heart-brain axis KW - brain-retina axis KW - neurotrophins KW - TGFβ signaling KW - myocardial infarction KW - diabetic retinopathy KW - age-related macular degeneration KW - ischemic stroke Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246159 SN - 2218-273X VL - 11 IS - 9 ER - TY - JOUR A1 - Kamali, Salar A1 - Rajendran, Ranjithkumar A1 - Stadelmann, Christine A1 - Karnati, Srikanth A1 - Rajendran, Vinothkumar A1 - Giraldo‐Velasquez, Mario A1 - Berghoff, Martin T1 - Oligodendrocyte‐specific deletion of FGFR2 ameliorates MOG\(_{35-55}\)‐induced EAE through ERK and Akt signalling JF - Brain Pathology N2 - Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies including multiple sclerosis (MS). In our recent study, oligodendrocyte‐specific deletion of FGFR1 resulted in a milder disease course, less inflammation, reduced myelin and axon damage in EAE. The objective of this study was to elucidate the role of oligodendroglial FGFR2 in MOG\(_{35-55}\)‐induced EAE. Oligodendrocyte‐specific knockout of FGFR2 (Fgfr2\(^{ind-/-}\)) was achieved by application of tamoxifen; EAE was induced using the MOG\(_{35-55}\) peptide. EAE symptoms were monitored over 62 days. Spinal cord tissue was analysed by histology, immunohistochemistry and western blot. Fgfr2\(^{ind-/-}\) mice revealed a milder disease course, less myelin damage and enhanced axonal density. The number of oligodendrocytes was not affected in demyelinated areas. However, protein expression of FGFR2, FGF2 and FGF9 was downregulated in Fgfr2\(^{ind-/-}\) mice. FGF/FGFR dependent signalling proteins were differentially regulated; pAkt was upregulated and pERK was downregulated in Fgfr2\(^{ind-/-}\) mice. The number of CD3(+) T cells, Mac3(+) cells and B220(+) B cells was less in demyelinated lesions of Fgfr2\(^{ind-/-}\) mice. Furthermore, expression of IL‐1β, TNF‐α and CD200 was less in Fgfr2\(^{ind-/-}\) mice than controls. Fgfr2ind−/− mice showed an upregulation of PLP and downregulation of the remyelination inhibitors SEMA3A and TGF‐β expression. These data suggest that cell‐specific deletion of FGFR2 in oligodendrocytes has anti‐inflammatory and neuroprotective effects accompanied by changes in FGF/FGFR dependent signalling, inflammatory cytokines and expression of remyelination inhibitors. Thus, FGFRs in oligodendrocytes may represent potential targets for the treatment of inflammatory and demyelinating diseases including MS. KW - experimental autoimmune encephalomyelitis KW - FGF/FGFR signalling KW - multiple sclerosis KW - oligodendrocytes Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224354 VL - 31 SP - 297 EP - 311 ER - TY - JOUR A1 - Koeniger, Tobias A1 - Bell, Luisa A1 - Mifka, Anika A1 - Enders, Michael A1 - Hautmann, Valentin A1 - Mekala, Subba Rao A1 - Kirchner, Philipp A1 - Ekici, Arif B. A1 - Schulz, Christian A1 - Wörsdörfer, Philipp A1 - Mencl, Stine A1 - Kleinschnitz, Christoph A1 - Ergün, Süleyman A1 - Kuerten, Stefanie T1 - Bone marrow‐derived myeloid progenitors in the leptomeninges of adult mice JF - Stem Cells N2 - Although the bone marrow contains most hematopoietic activity during adulthood, hematopoietic stem and progenitor cells can be recovered from various extramedullary sites. Cells with hematopoietic progenitor properties have even been reported in the adult brain under steady‐state conditions, but their nature and localization remain insufficiently defined. Here, we describe a heterogeneous population of myeloid progenitors in the leptomeninges of adult C57BL/6 mice. This cell pool included common myeloid, granulocyte/macrophage, and megakaryocyte/erythrocyte progenitors. Accordingly, it gave rise to all major myelo‐erythroid lineages in clonogenic culture assays. Brain‐associated progenitors persisted after tissue perfusion and were partially inaccessible to intravenous antibodies, suggesting their localization behind continuous blood vessel endothelium such as the blood‐arachnoid barrier. Flt3\(^{Cre}\) lineage tracing and bone marrow transplantation showed that the precursors were derived from adult hematopoietic stem cells and were most likely continuously replaced via cell trafficking. Importantly, their occurrence was tied to the immunologic state of the central nervous system (CNS) and was diminished in the context of neuroinflammation and ischemic stroke. Our findings confirm the presence of myeloid progenitors at the meningeal border of the brain and lay the foundation to unravel their possible functions in CNS surveillance and local immune cell production. KW - hematopoietic KW - meninges KW - mouse KW - myeloid KW - progenitor Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224452 VL - 39 IS - 2 SP - 227 EP - 239 ER - TY - JOUR A1 - Horder, Hannes A1 - Guaza Lasheras, Mar A1 - Grummel, Nadine A1 - Nadernezhad, Ali A1 - Herbig, Johannes A1 - Ergün, Süleyman A1 - Teßmar, Jörg A1 - Groll, Jürgen A1 - Fabry, Ben A1 - Bauer-Kreisel, Petra A1 - Blunk, Torsten T1 - Bioprinting and differentiation of adipose-derived stromal cell spheroids for a 3D breast cancer-adipose tissue model JF - Cells N2 - Biofabrication, including printing technologies, has emerged as a powerful approach to the design of disease models, such as in cancer research. In breast cancer, adipose tissue has been acknowledged as an important part of the tumor microenvironment favoring tumor progression. Therefore, in this study, a 3D-printed breast cancer model for facilitating investigations into cancer cell-adipocyte interaction was developed. First, we focused on the printability of human adipose-derived stromal cell (ASC) spheroids in an extrusion-based bioprinting setup and the adipogenic differentiation within printed spheroids into adipose microtissues. The printing process was optimized in terms of spheroid viability and homogeneous spheroid distribution in a hyaluronic acid-based bioink. Adipogenic differentiation after printing was demonstrated by lipid accumulation, expression of adipogenic marker genes, and an adipogenic ECM profile. Subsequently, a breast cancer cell (MDA-MB-231) compartment was printed onto the adipose tissue constructs. After nine days of co-culture, we observed a cancer cell-induced reduction of the lipid content and a remodeling of the ECM within the adipose tissues, with increased fibronectin, collagen I and collagen VI expression. Together, our data demonstrate that 3D-printed breast cancer-adipose tissue models can recapitulate important aspects of the complex cell–cell and cell–matrix interplay within the tumor-stroma microenvironment KW - adipose-derived stromal cells KW - adipose tissue KW - bioprinting KW - breast cancer model KW - extracellular matrix KW - hyaluronic acid KW - spheroids Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236496 VL - 10 IS - 4 ER - TY - JOUR A1 - Wagner, Nicole A1 - Mott, Kristina A1 - Upcin, Berin A1 - Stegner, David A1 - Schulze, Harald A1 - Ergün, Süleyman T1 - CXCL12-abundant reticular (CAR) cells direct megakaryocyte protrusions across the bone marrow sinusoid wall JF - Cells N2 - Megakaryocytes (MKs) release platelets into the lumen of bone marrow (BM) sinusoids while remaining to reside within the BM. The morphogenetic events of this complex process are still not fully understood. We combined confocal laser scanning microscopy with transmission and serial block-face scanning electron microscopy followed by 3D-reconstruction on mouse BM tissue sections. These analyses revealed that MKs in close vicinity to BM sinusoid (BMS) wall first induce the lateral retraction of CXCL12-abundant reticular (CAR) cells (CAR), followed by basal lamina (BL) degradation enabling direct MK-sinusoidal endothelial cells (SECs) interaction. Subsequently, an endothelial engulfment starts that contains a large MK protrusion. Then, MK protrusions penetrate the SEC, transmigrate into the BMS lumen and form proplatelets that are in direct contact to the SEC surface. Furthermore, such processes are induced on several sites, as observed by 3D reconstructions. Our data demonstrate that MKs in interaction with CAR-cells actively induce BMS wall alterations, including CAR-cell retraction, BL degradation, and SEC engulfment containing a large MK protrusion. This results in SEC penetration enabling the migration of MK protrusion into the BMS lumen where proplatelets that are adherent to the luminal SEC surface are formed and contribute to platelet release into the blood circulation. KW - megakaryocytes KW - microvasculature KW - CXCL12-abundant reticular (CAR)-cells Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234180 SN - 2073-4409 VL - 10 IS - 4 ER - TY - JOUR A1 - Upcin, Berin A1 - Henke, Erik A1 - Kleefeldt, Florian A1 - Hoffmann, Helene A1 - Rosenwald, Andreas A1 - Irmak-Sav, Ster A1 - Aktas, Huseyin Bertal A1 - Rückschloß, Uwe A1 - Ergün, Süleyman T1 - Contribution of adventitia-derived stem and progenitor cells to new vessel formation in tumors JF - Cells N2 - Blocking tumor vascularization has not yet come to fruition to the extent it was hoped for, as angiogenesis inhibitors have shown only partial success in the clinic. We hypothesized that under- appreciated vascular wall-resident stem and progenitor cells (VW-SPCs) might be involved in tumor vascularization and influence effectiveness of anti-angiogenic therapy. Indeed, in patient samples, we observed that vascular adventitia-resident CD34\(^+\) VW-SPCs are recruited to tumors in situ from co-opted vessels. To elucidate this in detail, we established an ex vivo model using concomitant embedding of multi-cellular tumor spheroids (MCTS) and mouse aortic rings (ARs) into collagen gels, similar to the so-called aortic ring assay (ARA). Moreover, ARA was modified by removing the ARs’ adventitia that harbors VW-SPCs. Thus, this model enabled distinguishing the contribution of VW-SPCs from that of mature endothelial cells (ECs) to new vessel formation. Our results show that the formation of capillary-like sprouts is considerably delayed, and their number and network formation were significantly reduced by removing the adventitia. Substituting iPSC-derived neural spheroids for MCTS resulted in distinct sprouting patterns that were also strongly influenced by the presence or absence of VW-SPCs, also underlying the involvement of these cells in non-pathological vascularization. Our data suggest that more comprehensive approaches are needed in order to block all of the mechanisms contributing to tumor vascularization. KW - vascularization model KW - tumor spheroids KW - vascular wall stem and progenitor cells KW - aortic adventitia KW - vasculogenesis KW - tumor-vessel wall-interface model Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242577 VL - 10 IS - 7 ER - TY - JOUR A1 - Dunkel, Franz G. T1 - Sieben neue Arten aus dem Schweizer Ranunculus auricomus-Komplex T1 - Seven new species from the Swiss Ranunculus auricomus Complex JF - Forum Geobotanicum N2 - Die Arten des Schweizer Ranunculus-auricomus-Komplexes sind nur zu einem Teil bekannt. Zur vollständigeren Erfassung des Komplexes wurden Exkursionen in die südwestliche und östliche Schweiz unternommen. Es wurden sieben neue Arten entdeckt, die hier beschrieben und abgebildet sind. Ihre Taxonomie und Gefährdung wird diskutiert. R. chalarocarpus W. Koch ex Dunkel ist bereits bei Koch provisorisch erwähnt, R. clavicornis Dunkel wird nun gültig beschrieben. Beide Arten sind aufgrund ihres Vorkommens in Auwäldern und feuchten Laubwäldern stark gefährdet, R. clavicornis sogar fast ausgestorben. Der neu beschriebene R. thurgoviae kommt im Osten der Schweiz vor (Kanton Thurgau). Die bislang bekannte Verbreitung von R. allobrogorum Dunkel, R. crenulatus Dunkel, R. genevensis Dunkel und R. lineatus ist fast vollständig auf den Kanton Genf beschränkt. Die Arten des Ranunculus auricomus-Komplexes sind ein sensibler Indikator für Veränderungen der Vegetation und Umwelt und sollten diesbezüglich deutlich mehr Gewicht bekommen. N2 - The Swiss Ranunculus auricomus complex is still not completely known. To get a rather complete overview of the complex, field investigations of the south-western and eastern parts of Switzerland were undertaken and revealed seven new species of the spectrum. They are described, depicted, and their taxonomy and vulnerability discussed. One species has already been provisionally mentioned by Walo Koch: R. chalarocarpus W. Koch ex Dunkel, another one is named by an illegitimate name and now called R. clavicornis Dunkel. Both occur in alluvial forests or humid broad-leaved forests on the Central plateau and, therefore, are threatened due to desiccation and eutrophication of their habitat. The newly described R. thurgoviae Dunkel occurs in the eastern Swiss canton Thurgau. The other newly described species R. allobrogorum Dunkel, R. crenulatus Dunkel, R. genevensis Dunkel, and R. lineatus Dunkel are restricted to the area of Geneva. Species of the Ranunculus auricomus complex are a sensitive indicator of environment changes and for conservation strategies should gain more importance. KW - Apomixis KW - new species KW - Ranunculus auricomus KW - Switzerland KW - Ranunculus Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-243782 UR - http://www.forum-geobotanicum.net/articles/vol_10-2021/dunkel-ranunculus_auricomus/FG---dunkel-ranunculus_2021.pdf SN - 1867-9315 VL - 10 ER -