TY - JOUR A1 - Wagenbrenner, Mike A1 - Poker, Konrad A1 - Heinz, Tizian A1 - Herrmann, Marietta A1 - Horas, Konstantin A1 - Ebert, Regina A1 - Mayer-Wagner, Susanne A1 - Holzapfel, Boris M. A1 - Rudert, Maximilian A1 - Steinert, Andre F. A1 - Weißenberger, Manuel T1 - Mesenchymal stromal cells (MSCs) isolated from various tissues of the human arthritic knee joint possess similar multipotent differentiation potential JF - Applied Sciences N2 - (1) Background: The mesenchymal stromal cells (MSCs) of different tissue origins are applied in cell-based chondrogenic regeneration. However, there is a lack of comparability determining the most suitable cell source for the tissue engineering (TE) of cartilage. The purpose of this study was to compare the in vitro chondrogenic potential of MSC-like cells from different tissue sources (bone marrow, meniscus, anterior cruciate ligament, synovial membrane, and the infrapatellar fat pad removed during total knee arthroplasty (TKA)) and define which cell source is best suited for cartilage regeneration. (2) Methods: MSC-like cells were isolated from five donors and expanded using adherent monolayer cultures. Differentiation was induced by culture media containing specific growth factors. Transforming growth factor (TGF)-ß1 was used as the growth factor for chondrogenic differentiation. Osteogenesis and adipogenesis were induced in monolayer cultures for 27 days, while pellet cell cultures were used for chondrogenesis for 21 days. Control cultures were maintained under the same conditions. After, the differentiation period samples were analyzed, using histological and immunohistochemical staining, as well as molecularbiological analysis by RT-PCR, to assess the expression of specific marker genes. (3) Results: Plastic-adherent growth and in vitro trilineage differentiation capacity of all isolated cells were proven. Flow cytometry revealed the clear co-expression of surface markers CD44, CD73, CD90, and CD105 on all isolated cells. Adipogenesis was validated through the formation of lipid droplets, while osteogenesis was proven by the formation of calcium deposits within differentiated cell cultures. The formation of proteoglycans was observed during chondrogenesis in pellet cultures, with immunohistochemical staining revealing an increased relative gene expression of collagen type II. RT-PCR proved an elevated expression of specific marker genes after successful differentiation, with no significant differences regarding different cell source of native tissue. (4) Conclusions: Irrespective of the cell source of native tissue, all MSC-like cells showed multipotent differentiation potential in vitro. The multipotent differentiation capacity did not differ significantly, and chondrogenic differentiation was proven in all pellet cultures. Therefore, cell suitability for cell-based cartilage therapies and tissue engineering is given for various tissue origins that are routinely removed during total knee arthroplasty (TKA). This study might provide essential information for the clinical tool of cell harvesting, leading to more flexibility in cell availability. KW - knee joint KW - MSCs KW - cellular origin KW - cartilage regeneration KW - tissue engineering KW - cell-based therapies KW - osteoarthritis Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262334 SN - 2076-3417 VL - 12 IS - 4 ER - TY - JOUR A1 - Herrmann, Thomas A1 - Karunakaran, Mohindar M. T1 - Butyrophilins: γδ T cell receptor ligands, immunomodulators and more JF - Frontiers in Immunology N2 - Butyrophilins (BTN) are relatives of the B7 family (e.g., CD80, PD-L1). They fulfill a wide range of functions including immunomodulation and bind to various receptors such as the γδ T cell receptor (γδTCR) and small molecules. One intensively studied molecule is BTN3A1, which binds via its cytoplasmic B30.2 domain, metabolites of isoprenoid synthesis, designated as phosphoantigen (PAg), The enrichment of PAgs in tumors or infected cells is sensed by Vγ9Vδ2 T cells, leading to the proliferation and execution of effector functions to remove these cells. This article discusses the contribution of BTNs, the related BTNL molecules and SKINT1 to the development, activation, and homeostasis of γδ T cells and their immunomodulatory potential, which makes them interesting targets for therapeutic intervention. KW - butyrophilin KW - immune therapy KW - T cell receptor KW - γδ T cell KW - BTN3A1 KW - BTN2A1 KW - phosphoantigen KW - tumor Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265944 SN - 1664-3224 VL - 13 ER - TY - JOUR A1 - Herrmann, Johannes A1 - Lotz, Christopher A1 - Karagiannidis, Christian A1 - Weber-Carstens, Steffen A1 - Kluge, Stefan A1 - Putensen, Christian A1 - Wehrfritz, Andreas A1 - Schmidt, Karsten A1 - Ellerkmann, Richard K. A1 - Oswald, Daniel A1 - Lotz, Gösta A1 - Zotzmann, Viviane A1 - Moerer, Onnen A1 - Kühn, Christian A1 - Kochanek, Matthias A1 - Muellenbach, Ralf A1 - Gaertner, Matthias A1 - Fichtner, Falk A1 - Brettner, Florian A1 - Findeisen, Michael A1 - Heim, Markus A1 - Lahmer, Tobias A1 - Rosenow, Felix A1 - Haake, Nils A1 - Lepper, Philipp M. A1 - Rosenberger, Peter A1 - Braune, Stephan A1 - Kohls, Mirjam A1 - Heuschmann, Peter A1 - Meybohm, Patrick T1 - Key characteristics impacting survival of COVID-19 extracorporeal membrane oxygenation JF - Critical Care N2 - Background Severe COVID-19 induced acute respiratory distress syndrome (ARDS) often requires extracorporeal membrane oxygenation (ECMO). Recent German health insurance data revealed low ICU survival rates. Patient characteristics and experience of the ECMO center may determine intensive care unit (ICU) survival. The current study aimed to identify factors affecting ICU survival of COVID-19 ECMO patients. Methods 673 COVID-19 ARDS ECMO patients treated in 26 centers between January 1st 2020 and March 22nd 2021 were included. Data on clinical characteristics, adjunct therapies, complications, and outcome were documented. Block wise logistic regression analysis was applied to identify variables associated with ICU-survival. Results Most patients were between 50 and 70 years of age. PaO\(_{2}\)/FiO\(_{2}\) ratio prior to ECMO was 72 mmHg (IQR: 58–99). ICU survival was 31.4%. Survival was significantly lower during the 2nd wave of the COVID-19 pandemic. A subgroup of 284 (42%) patients fulfilling modified EOLIA criteria had a higher survival (38%) (p = 0.0014, OR 0.64 (CI 0.41–0.99)). Survival differed between low, intermediate, and high-volume centers with 20%, 30%, and 38%, respectively (p = 0.0024). Treatment in high volume centers resulted in an odds ratio of 0.55 (CI 0.28–1.02) compared to low volume centers. Additional factors associated with survival were younger age, shorter time between intubation and ECMO initiation, BMI > 35 (compared to < 25), absence of renal replacement therapy or major bleeding/thromboembolic events. Conclusions Structural and patient-related factors, including age, comorbidities and ECMO case volume, determined the survival of COVID-19 ECMO. These factors combined with a more liberal ECMO indication during the 2nd wave may explain the reasonably overall low survival rate. Careful selection of patients and treatment in high volume ECMO centers was associated with higher odds of ICU survival. KW - Covid-19 KW - extracorporeal membrane oxygenation (ECMO) KW - intensive care unit Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-299686 VL - 26 IS - 1 ER - TY - JOUR A1 - Karunakaran, Mohindar M. A1 - Subramanian, Hariharan A1 - Jin, Yiming A1 - Mohammed, Fiyaz A1 - Kimmel, Brigitte A1 - Juraske, Claudia A1 - Starick, Lisa A1 - Nöhren, Anna A1 - Länder, Nora A1 - Willcox, Carrie R. A1 - Singh, Rohit A1 - Schamel, Wolfgang W. A1 - Nikolaev, Viacheslav O. A1 - Kunzmann, Volker A1 - Wiemer, Andrew J. A1 - Willcox, Benjamin E. A1 - Herrmann, Thomas T1 - A distinct topology of BTN3A IgV and B30.2 domains controlled by juxtamembrane regions favors optimal human γδ T cell phosphoantigen sensing JF - Nature Communications N2 - Butyrophilin (BTN)–3A and BTN2A1 molecules control the activation of human Vγ9Vδ2 T cells during T cell receptor (TCR)-mediated sensing of phosphoantigens (PAg) derived from microbes and tumors. However, the molecular rules governing PAg sensing remain largely unknown. Here, we establish three mechanistic principles of PAg-mediated γδ T cell activation. First, in humans, following PAg binding to the intracellular BTN3A1-B30.2 domain, Vγ9Vδ2 TCR triggering involves the extracellular V-domain of BTN3A2/BTN3A3. Moreover, the localization of both protein domains on different chains of the BTN3A homo-or heteromers is essential for efficient PAg-mediated activation. Second, the formation of BTN3A homo-or heteromers, which differ in intracellular trafficking and conformation, is controlled by molecular interactions between the juxtamembrane regions of the BTN3A chains. Finally, the ability of PAg not simply to bind BTN3A-B30.2, but to promote its subsequent interaction with the BTN2A1-B30.2 domain, is essential for T-cell activation. Defining these determinants of cooperation and the division of labor in BTN proteins improves our understanding of PAg sensing and elucidates a mode of action that may apply to other BTN family members. KW - gammadelta T cells KW - immunosurveillance Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-358179 VL - 14 ER - TY - JOUR A1 - Zeiner, Carsten A1 - Schröder, Malte A1 - Metzner, Selina A1 - Herrmann, Johannes A1 - Notz, Quirin A1 - Hottenrott, Sebastian A1 - Röder, Daniel A1 - Meybohm, Patrick A1 - Lepper, Philipp M. A1 - Lotz, Christopher T1 - High-dose methylprednisolone pulse therapy during refractory COVID-19 acute respiratory distress syndrome: a retrospective observational study JF - BMC Pulmonary Medicine N2 - Background Current COVID-19 guidelines recommend the early use of systemic corticoids for COVID-19 acute respiratory distress syndrome (ARDS). It remains unknown if high-dose methylprednisolone pulse therapy (MPT) ameliorates refractory COVID-19 ARDS after many days of mechanical ventilation or rapid deterioration with or without extracorporeal membrane oxygenation (ECMO). Methods This is a retrospective observational study. Consecutive patients with COVID-19 ARDS treated with a parenteral high-dose methylprednisolone pulse therapy at the intensive care units (ICU) of two University Hospitals between January 1st 2021 and November 30st 2022 were included. Clinical data collection was at ICU admission, start of MPT, 3-, 10- and 14-days post MPT. Results Thirty-seven patients (mean age 55 ± 12 years) were included in the study. MPT started at a mean of 17 ± 12 days after mechanical ventilation. Nineteen patients (54%) received ECMO support when commencing MPT. Mean paO2/FiO2 significantly improved 3- (p = 0.034) and 10 days (p = 0.0313) post MPT. The same applied to the necessary FiO2 10 days after MPT (p = 0.0240). There were no serious infectious complications. Twenty-four patients (65%) survived to ICU discharge, including 13 out of 20 (65%) needing ECMO support. Conclusions Late administration of high-dose MPT in a critical subset of refractory COVID-19 ARDS patients improved respiratory function and was associated with a higher-than-expected survival of 65%. These data suggest that high-dose MPT may be a viable salvage therapy in refractory COVID-19 ARDS. KW - corticoid KW - methylprednisolone KW - pulse therapy KW - SARS-CoV2 KW - ECMO KW - salvage therapy Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357231 VL - 23 ER - TY - JOUR A1 - Breun, Maria A1 - Flock, Katharina A1 - Feldheim, Jonas A1 - Nattmann, Anja A1 - Monoranu, Camelia M. A1 - Herrmann, Pia A1 - Ernestus, Ralf-Ingo A1 - Löhr, Mario A1 - Hagemann, Carsten A1 - Stein, Ulrike T1 - Metastasis associated in colorectal cancer 1 (MACC1) mRNA expression is enhanced in sporadic vestibular schwannoma and correlates to deafness JF - Cancers N2 - Vestibular schwannoma (VS) are benign cranial nerve sheath tumors of the vestibulocochlear nerve. Their incidence is mostly sporadic, but they can also be associated with NF2-related schwannomatosis (NF2), a hereditary tumor syndrome. Metastasis associated in colon cancer 1 (MACC1) is known to contribute to angiogenesis, cell growth, invasiveness, cell motility and metastasis of solid malignant cancers. In addition, MACC1 may be associated with nonsyndromic hearing impairment. Therefore, we evaluated whether MACC1 may be involved in the pathogenesis of VS. Sporadic VS, recurrent sporadic VS, NF2-associated VS, recurrent NF2-associated VS and healthy vestibular nerves were analyzed for MACC1 mRNA and protein expression by quantitative polymerase chain reaction and immunohistochemistry. MACC1 expression levels were correlated with the patients’ clinical course and symptoms. MACC1 mRNA expression was significantly higher in sporadic VS compared to NF2-associated VS (p < 0.001). The latter expressed similar MACC1 concentrations as healthy vestibular nerves. Recurrent tumors resembled the MACC1 expression of the primary tumors. MACC1 mRNA expression was significantly correlated with deafness in sporadic VS patients (p = 0.034). Therefore, MACC1 might be a new molecular marker involved in VS pathogenesis. KW - vestibular schwannoma KW - metastasis associated in colorectal cancer 1 (MACC1) KW - pathogenesis KW - deafness KW - NF2-related schwannomatosis (NF2) KW - mRNA expression Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-362543 SN - 2072-6694 VL - 15 IS - 16 ER -