Publications by authors named "Süleyman Ergün"

125 Publications

Anti-inflammatory activity of 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid in LPS-induced rat model.

Prostaglandins Other Lipid Mediat 2021 Apr 5;154:106549. Epub 2021 Apr 5.

Faculty of Pharmacy, Widya Mandala Catholic University Surabaya, Jalan Kalisari Selatan 1, Surabaya, 60237, East Java, Indonesia. Electronic address:

Introduction: Salicylic acid derivate is very popular for its activity to suppress pain, fever, and inflammation. One of its derivatives is acetylsalicylic acid (ASA) which has been reported repeatedly that, as a non-steroidal anti-inflammatory drug (NSAID), it has a cardioprotective effect. Although ASA has various advantages, several studies have reported that it may induce severe peptic ulcer disease. We recently synthesized a new compound derived from salicylic acid, namely 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid (3-CHCl) which still has the benefit of acetylsalicylic acid as an analgesic and antiplatelet, but lacks its harmful side effects (Caroline et al., 2019). In addition, in silico studies of 3-CHCl showed a higher affinity towards protein receptor cyclooxygenase-2 (COX-2; PDB: 5F1A) than ASA. We hypothesized that 3-CHCl inhibits the COX-2 activity which could presumably decrease the inflammatory responses. However, no knowledge is available on the anti-inflammatory response and molecular signaling of this new compound. Hence, in this study, we investigated the potential functional relevance of 3-CHCl in regulating the inflammatory response in lipopolysaccharide (LPS)-induced rats. The results of this study show that this compound could significantly reduce the inflammatory parameter in LPS-induced rats.

Material And Methods: Rats were induced with LPS of 0.5 mg/kg bw intravenously, prior oral administration with vehicle (3% Pulvis Gummi Arabicum / PGA), 500 mg/60 kg body weight (bw; rat dosage converted to human) of 3-CHCl and ASA. The inflammatory parameters such as changes in the temperature of septic shock, cardiac blood plasma concentrations of IL-1β and TNF-α (ELISA), blood inflammation parameters, white blood cell concentrations, and lung histopathology were observed. Meanwhile, the stability of 3-CHCl powder was evaluated.

Result: After the administration of 500 mg/60 kg bw of 3-CHCl (rat dosage converted to human) to LPS-induced rats, we observed a significant reduction of both TNF-α (5.70+/-1.04 × 10 pg/mL, p=<0.001) and IL-1β (2.32+/-0.28 × 10 pg/mL, p=<0.001) cardiac blood plasma concentrations. Besides, we found a reduction of white blood cell concentration and the severity of lung injury in the 3-CHCl group compared to the LPS-induced rat group. Additionally, this compound maintained the rat body temperature within normal limits during inflammation, preventing the rats to undergo septic shock, characterized by hypothermic (t = 120 min.) or hyperthermic (t = 360 min) conditions. Furthermore, 3-CHCl was found to be stable until 3 years at 25°C with a relative humidity of 75 ± 5%.

Conclusion: 3-CHCl compound inhibited inflammation in the LPS-induced inflammation response model in rats, hypothetically through binding to COX-2, and presumably inhibited LPS-induced NF-κβ signaling pathways. This study could be used as a preliminary hint to investigate the target molecular pathways of 3-CHCl as a novel and less toxic therapeutical agent in alleviating the COX-related inflammatory diseases, and most importantly to support the planning and development of clinical trial.
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http://dx.doi.org/10.1016/j.prostaglandins.2021.106549DOI Listing
April 2021

CXCL12-Abundant Reticular (CAR) Cells Direct Megakaryocyte Protrusions across the Bone Marrow Sinusoid Wall.

Cells 2021 Mar 24;10(4). Epub 2021 Mar 24.

Institute of Anatomy and Cell Biology, Julius-Maximilians-University Würzburg, 97070 Würzburg, Germany.

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.
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http://dx.doi.org/10.3390/cells10040722DOI Listing
March 2021

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).

Stem Cell Res 2021 Feb 18;53:102256. Epub 2021 Feb 18.

Comprehensive Heart Failure Center (CHFC), Department of Cardiovascular Genetics, University Clinics Würzburg, Würzburg, Germany; Department of Medicine I, University Clinics Würzburg, Würzburg, Germany. Electronic address:

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 (JMUi001-A). 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.
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http://dx.doi.org/10.1016/j.scr.2021.102256DOI Listing
February 2021

The Impact of Oxygen Availability and Multilineage Communication on Organoid Maturation.

Antioxid Redox Signal 2021 Feb 11. Epub 2021 Feb 11.

Institute of Anatomy and Cell Biology, Julius-Maximilians-University Würzburg, Würzburg, Germany.

An optimal supply with oxygen is of high importance during embryogenesis and a prerequisite for proper organ development. Different tissues require varying amounts of oxygen, and even within single organs, different phases of development go alongside with either physiological hypoxia or the need for sufficient oxygen supply. Human induced pluripotent stem cell-derived organoid models are state of the art cell culture platforms for the investigation of developmental processes, disease modeling, and drug testing. Organoids modeling the development of multiple tissues were developed within the past years. Until now, optimization of oxygen supply and its role during organoid growth, differentiation, and maturation have only rarely been addressed. Recent publications indicate that hypoxia-induced processes play an important role in three-dimensional tissue cultures, triggering multilineage communication between mesenchymal cells, the endothelium, as well as organotypic cells. Later in culture, a sufficient supply with oxygen is of high importance to allow larger organoid sizes. Moreover, cellular stress is reduced and tissue maturation is improved. Therefore, a functional blood vessel network is required. In this review, we will briefly summarize aspects of the role of oxygen during embryonic development and organogenesis, present an update on novel organoid models with a special focus on organoid vascularization, and discuss the importance of complex organoids involving parenchymal cells, mesenchymal cells, inflammatory cells, and functional blood vessels for the generation of mature and fully functional tissues .
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http://dx.doi.org/10.1089/ars.2020.8195DOI Listing
February 2021

Bone marrow-derived myeloid progenitors in the leptomeninges of adult mice.

Stem Cells 2021 Feb 11;39(2):227-239. Epub 2020 Dec 11.

Institute of Anatomy and Cell Biology, Julius Maximilian University of Würzburg, Würzburg, Germany.

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 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.
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http://dx.doi.org/10.1002/stem.3311DOI Listing
February 2021

Generation of Vascularized Neural Organoids by Co-culturing with Mesodermal Progenitor Cells.

STAR Protoc 2020 Jun 3;1(1):100041. Epub 2020 Jun 3.

Institute of Anatomy and Cell Biology, University of Würzburg, Koellikerstr.6, 97070 Würzburg, Germany.

Organoids are three-dimensional (3D) constructs generated in stem cell cultures and are thought to mimic tissue and organ development . However, until recently, they often exclusively recapitulated the development of the organ`s parenchyma without the major components of the organ stroma. Here, we describe a protocol to incorporate stromal components, first of all blood vessels, by co-culturing with induced pluripotent stem cell-derived mesodermal progenitor cells. For complete details on the use and execution of this protocol, please refer to Wörsdörfer et al. (2019).
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http://dx.doi.org/10.1016/j.xpro.2020.100041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580204PMC
June 2020

Pro-angiogenic effects of pregnancy-specific glycoproteins in endothelial and extravillous trophoblast cells.

Reproduction 2020 11;160(5):737-750

Department of Pathology, Uniformed Services University of Health Sciences, Bethesda, Maryland, USA.

We previously reported that binding to heparan sulfate (HS) is required for the ability of the placentally secreted pregnancy-specific glycoprotein 1 (PSG1) to induce endothelial tubulogenesis. PSG1 is composed of four immunoglobulin-like domains but which domains of the protein bind to HS remains unknown. To analyze the interaction of PSG1 with HS, we generated several recombinant proteins, including the individual domains, chimeric proteins between two PSG1 domains, and mutants. Using flow cytometric and surface plasmon resonance studies, we determined that the B2 domain of PSG1 binds to HS and that the positively charged amino acids encompassed between amino acids 43-59 are required for this interaction. Furthermore, we showed that the B2 domain of PSG1 is required for the increase in the formation of tubes by endothelial cells (EC) including a human endometrial EC line and two extravillous trophoblast (EVT) cell lines and for the pro-angiogenic activity of PSG1 observed in an aortic ring assay. PSG1 enhanced the migration of ECs while it increased the expression of matrix metalloproteinase-2 in EVTs, indicating that the pro-angiogenic effect of PSG1 on these two cell types may be mediated by different mechanisms. Despite differences in amino acid sequence, we observed that all human PSGs bound to HS proteoglycans and confirmed that at least two other members of the family, PSG6 and PSG9, induce tube formation. These findings contribute to a better understanding of the pro-angiogenic activity of human PSGs and strongly suggest conservation of this function among all PSG family members.
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http://dx.doi.org/10.1530/REP-20-0169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575825PMC
November 2020

Resident CD34-positive cells contribute to peri-endothelial cells and vascular morphogenesis in salivary gland after irradiation.

J Neural Transm (Vienna) 2020 11 6;127(11):1467-1479. Epub 2020 Oct 6.

Institute of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany.

Salivary gland (SG) hypofunction is a common post-radiotherapy complication. Besides the parenchymal damage after irradiation (IR), there are also effects on mesenchymal stem cells (MSCs) which were shown to contribute to regeneration and repair of damaged tissues by differentiating into stromal cell types or releasing vesicles and soluble factors supporting the healing processes. However, there are no adequate reports about their roles during SG damage and regeneration so far. Using an irradiated SG mouse model, we performed certain immunostainings on tissue sections of submandibular glands at different time points after IR. Immunostaining for CD31 revealed that already one day after IR, vascular impairment was induced at the level of capillaries. In addition, the expression of CD44-a marker of acinar cells-diminished gradually after IR and, by 20 weeks, almost disappeared. In contrast, the number of CD34-positive cells significantly increased 4 weeks after IR and some of the CD34-positive cells were found to reside within the adventitia of arteries and veins. Laser confocal microscopic analyses revealed an accumulation of CD34-positive cells within the area of damaged capillaries where they were in close contact to the CD31-positive endothelial cells. At 4 weeks after IR, a fraction of the CD34-positive cells underwent differentiation into α-SMA-positive cells, which suggests that they may contribute to regeneration of smooth muscle cells and/or pericytes covering the small vessels from the outside. In conclusion, SG-resident CD34-positive cells represent a population of progenitors that could contribute to new vessel formation and/or remodeling of the pre-existing vessels after IR and thus, might be an important player during SG tissue healing.
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http://dx.doi.org/10.1007/s00702-020-02256-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578140PMC
November 2020

3D cone-beam CT with a twin robotic x-ray system in elbow imaging: comparison of image quality to high-resolution multidetector CT.

Eur Radiol Exp 2020 09 8;4(1):52. Epub 2020 Sep 8.

Department of Diagnostic and Interventional Radiology, University Hospital Würzburg, Oberdürrbacher Straße 6, 97080, Würzburg, Germany.

Background: Elbow imaging is challenging with conventional multidetector computed tomography (MDCT), while cone-beam CT (CBCT) provides superior options. We compared intra-individually CBCT versus MDCT image quality in cadaveric elbows.

Methods: A twin robotic x-ray system with new CBCT mode and a high-resolution clinical MDCT were compared in 16 cadaveric elbows. Both systems were operated with a dedicated low-dose (LD) protocol (equivalent volume CT dose index [CTDI] = 3.3 mGy) and a regular clinical scan dose (RD) protocol (CTDI = 13.8 mGy). Image quality was evaluated by two radiologists (R1 and R2) on a seven-point Likert scale, and estimation of signal intensity in cancellous bone was conducted. Wilcoxon signed-rank tests and intraclass correlation coefficient (ICC) statistics were used.

Results: The CBCT prototype provided superior subjective image quality compared to MDCT scans (for RD, p ≤ 0.004; for LD, p ≤ 0.001). Image quality was rated very good or excellent in 100% of the cases by both readers for RD CBCT, 100% (R1) and 93.8% (R2) for LD CBCT, 62.6% and 43.8% for RD MDCT, and 0.0% and 0.0% for LD MDCT. Single-measure ICC was 0.95 (95% confidence interval 0.91-0.97; p < 0.001). Software-based assessment supported subjective findings with less "undecided" pixels in CBCT than dose-equivalent MDCT (p < 0.001). No significant difference was found between LD CBCT and RD MDCT.

Conclusions: In cadaveric elbow studies, the tested cone-beam CT prototype delivered superior image quality compared to high-end multidetector CT and showed a potential for considerable dose reduction.
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http://dx.doi.org/10.1186/s41747-020-00177-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477066PMC
September 2020

Evaluation of Ultra-High-Resolution Cone-Beam CT Prototype of Twin Robotic Radiography System for Cadaveric Wrist Imaging.

Acad Radiol 2020 Jul 9. Epub 2020 Jul 9.

Department of Diagnostic and Interventional Radiology, University Hospital Würzburg, Oberdürrbacher Straße 6, 97080 Würzburg, Germany.

Rationale And Objectives: Cone-beam CT (CBCT) applications possess potential for dose reduction in musculoskeletal imaging. This study evaluates the ultra-high-resolution CBCT prototype of a twin robotic X-ray system in wrist examinations compared to high-resolution multidetector CT (MDCT).

Materials And Methods: Sixteen wrists of body donors were examined with the CBCT scan mode and a 384 slice MDCT system. Radiation-equivalent low-dose (CTDI  = 3.3 mGy) and full-dose protocols (CTDI  = 13.8 mGy) were used for both systems. Two observers assessed image quality on a seven-point Likert scale. In addition, software-assisted quantification of signal intensity fractions in cancellous bone was performed. Fewer pixels with intermediate signal intensity were considered to indicate superior depiction of bone microarchitecture.

Results: Subjective image quality in CBCT was superior to dose equivalent MDCT with p ≤ 0.03 for full-dose and p < 0.001 for low-dose scans, respectively. Median Likert values were 7/7 (reader 1 / reader 2) in full-dose CBCT, 6/6 in full-dose MDCT, 5/6 in low-dose CBCT and 3/3 in low-dose MDCT. Intraclass correlation coefficient was 0.936 (95% confidence interval, 0.897-0.961; p < 0.001), indicating excellent reliability. Objective analysis displayed smaller fractions of "indecisive" pixels with intermediate signal intensity for full-dose CBCT (0.57 [interquartile range 0.13]) compared to full-dose MDCT (0.68 [0.21]), low-dose CBCT (0.72 [0.19]), and low-dose MDCT (0.80 [0.15]) studies. No significant difference was observed between low-dose CBCT and full-dose MDCT.

Conclusion: The new CBCT prototype provides superior image quality for trabecula and bone marrow in cadaveric wrist studies and enables dose reduction up to 75% compared to high-resolution MDCT.
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http://dx.doi.org/10.1016/j.acra.2020.06.018DOI Listing
July 2020

Generation of two patient-derived iPSC lines from siblings (LIBUCi001-A and LIBUCi002-A) and a genetically modified iPSC line (JMUi001-A-1) to mimic dilated cardiomyopathy with ataxia (DCMA) caused by a homozygous DNAJC19 mutation.

Stem Cell Res 2020 07 2;46:101856. Epub 2020 Jun 2.

Comprehensive Heart Failure Center (CHFC) and Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany; Libin Cardiovascular Institute of Alberta, Department of Cardiac Sciences, University of Calgary, Calgary, Canada. Electronic address:

Dilated cardiomyopathy with ataxia (DCMA) is an autosomal recessive disorder arising from mutations in DNAJC19. Two patient-derived dermal fibroblast cell lines of siblings with the same homozygous splice acceptor site mutation in DNAJC19 (NM_145261.4):c.130-1G>C were reprogrammed into induced pluripotent stem cell (iPSC) lines (LIBUCi001-A and LIBUCi002-A) using non-integrative Sendai virus. Additionally, a third DNAJC19tv (truncation variant) iPSC line (JMUi001-A-1) was generated by CRISPR/Cas9 in healthy control iPSCs (JMUi001-A). All three DCMA iPSC lines present normal karyotypes, high expression of pluripotency markers and the capacity to differentiate into cells of all three germ layers.
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http://dx.doi.org/10.1016/j.scr.2020.101856DOI Listing
July 2020

Influence of gender in monocrotaline and chronic hypoxia induced pulmonary hypertension in obese rats and mice.

Respir Res 2020 Jun 3;21(1):136. Epub 2020 Jun 3.

Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Aulweg 130, 35392, Giessen, Germany.

Background: Obesity and pulmonary hypertension (PH) share common characteristics, such as augmented inflammation and oxidative stress. However, the exact role of obesity in the pathology of PH is largely uninvestigated. Therefore, we have hypothesized that in the context of obesity the gender difference may have influence on development of PH in animal models of this disease.

Methods: Animal experiments were conducted in monocrotaline (MCT) and chronic hypoxia (HOX) models of PH. Lean and obese Zucker rats or B6 mice of both genders were used for MCT or HOX models, respectively. Echocardiography, hemodynamic measurements, histology and immuno-histochemistry were performed to analyze various parameters, such as right ventricular function and hypertrophy, hemodynamics, pulmonary vascular remodeling and lung inflammation.

Results: Both lean and obese male and female Zucker rats developed PH after a single MCT injection. However, negligible differences were seen between lean and obese male rats in terms of PH severity at the end stage of disease. Conversely, a more prominent and severe PH was observed in obese female rats compared to their lean counterparts. In contrast, HOX induced PH in lean and obese, male and female mice did not show any apparent differences.

Conclusion: Gender influences PH severity in obese MCT-injected rats. It is also an important factor associated with altered inflammation. However, further research is necessary to investigate and reveal the underlying mechanisms.
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http://dx.doi.org/10.1186/s12931-020-01394-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268383PMC
June 2020

Do not keep it simple: recent advances in the generation of complex organoids.

J Neural Transm (Vienna) 2020 11 8;127(11):1569-1577. Epub 2020 May 8.

Institute of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany.

3D cell culture models which closely resemble real human tissues are of high interest for disease modelling, drug screening as well as a deeper understanding of human developmental biology. Such structures are termed organoids. Within the last years, several human organoid models were described. These are usually stem cell derived, arise by self-organization, mimic mechanisms of normal tissue development, show typical organ morphogenesis and recapitulate at least some organ specific functions. Many tissues have been reproduced in vitro such as gut, liver, lung, kidney and brain. The resulting entities can be either derived from an adult stem cell population, or generated from pluripotent stem cells using a specific differentiation protocol. However, many organoid models only recapitulate the organs parenchyma but are devoid of stromal components such as blood vessels, connective tissue and inflammatory cells. Recent studies show that the incorporation of endothelial and mesenchymal cells into organoids improved their maturation and might be required to create fully functional micro-tissues, which will allow deeper insights into human embryogenesis as well as disease development and progression. In this review article, we will summarize and discuss recent works trying to incorporate stromal components into organoids, with a special focus on neural organoid models.
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http://dx.doi.org/10.1007/s00702-020-02198-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577912PMC
November 2020

Visualizing the Synaptic and Cellular Ultrastructure in Neurons Differentiated from Human Induced Neural Stem Cells-An Optimized Protocol.

Int J Mol Sci 2020 Mar 2;21(5). Epub 2020 Mar 2.

Institute of Anatomy and Cell Biology, University of Würzburg, 97070 Würzburg, Germany.

The size of the synaptic subcomponents falls below the limits of visible light microscopy. Despite new developments in advanced microscopy techniques, the resolution of transmission electron microscopy (TEM) remains unsurpassed. The requirements of tissue preservation are very high, and human post mortem material often does not offer adequate quality. However, new reprogramming techniques that generate human neurons in vitro provide samples that can easily fulfill these requirements. The objective of this study was to identify the culture technique with the best ultrastructural preservation in combination with the best embedding and contrasting technique for visualizing neuronal elements. Two induced neural stem cell lines derived from healthy control subjects underwent differentiation either adherent on glass coverslips, embedded in a droplet of highly concentrated Matrigel, or as a compact neurosphere. Afterward, they were fixed using a combination of glutaraldehyde (GA) and paraformaldehyde (PFA) followed by three approaches (standard stain, Ruthenium red stain, high contrast en-bloc stain) using different combinations of membrane enhancing and contrasting steps before ultrathin sectioning and imaging by TEM. The compact free-floating neurospheres exhibited the best ultrastructural preservation. High-contrast en-bloc stain offered particularly sharp staining of membrane structures and the highest quality visualization of neuronal structures. In conclusion, compact neurospheres growing under free-floating conditions in combination with a high contrast en-bloc staining protocol, offer the optimal preservation and contrast with a particular focus on visualizing membrane structures as required for analyzing synaptic structures.
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http://dx.doi.org/10.3390/ijms21051708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084184PMC
March 2020

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy.

Front Mol Biosci 2019 31;6:160. Epub 2020 Jan 31.

Department of Medicine, Institute of Anatomy and Cell Biology, Universität Würzburg, Würzburg, Germany.

Solid tumors are complex organ-like structures that consist not only of tumor cells but also of vasculature, extracellular matrix (ECM), stromal, and immune cells. Often, this tumor microenvironment (TME) comprises the larger part of the overall tumor mass. Like the other components of the TME, the ECM in solid tumors differs significantly from that in normal organs. Intratumoral signaling, transport mechanisms, metabolisms, oxygenation, and immunogenicity are strongly affected if not controlled by the ECM. Exerting this regulatory control, the ECM does not only influence malignancy and growth of the tumor but also its response toward therapy. Understanding the particularities of the ECM in solid tumor is necessary to develop approaches to interfere with its negative effect. In this review, we will also highlight the current understanding of the physical, cellular, and molecular mechanisms by which the pathological tumor ECM affects the efficiency of radio-, chemo-, and immunotherapy. Finally, we will discuss the various strategies to target and modify the tumor ECM and how they could be utilized to improve response to therapy.
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http://dx.doi.org/10.3389/fmolb.2019.00160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025524PMC
January 2020

CEACAM1 promotes vascular aging processes.

Aging (Albany NY) 2020 02 21;12(4):3121-3123. Epub 2020 Feb 21.

Institute of Anatomy and Cell Biology, Julius-Maximilians-University Würzburg, Würzburg, Germany.

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http://dx.doi.org/10.18632/aging.102868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066878PMC
February 2020

Twin Robotic X-Ray System for 3D Cone-Beam CT of the Wrist: An Evaluation of Image Quality and Radiation Dose.

AJR Am J Roentgenol 2020 02 4;214(2):422-427. Epub 2019 Dec 4.

Department of Diagnostic and Interventional Radiology, University Hospital Würzburg, Oberdürrbacherstr 6, 97080 Würzburg, Germany.

The purpose of this study was to assess image quality and radiation dose of a novel twin robotic x-ray system's 3D cone-beam CT (CBCT) function for the depiction of cadaveric wrists. Sixteen cadaveric wrists were scanned using dedicated low-dose and standard-dose CBCT protocols as well as clinical MDCT for comparison. Three readers assessed overall image quality, noise, and artifacts in bone and soft tissue on 5-point Likert scales. For radiation dose analysis, volume CT dose indexes (CTDI) were compared. Overall image quality of most studies was very good or excellent in MDCT (for readers 1, 2, and 3: 100%, 100%, and 88%, respectively), standard-dose CBCT (100%, 100%, and 94%), and low dose CBCT (100%, 94%, and 88%) with two readers favoring standard-dose CBCT over MDCT image quality (readers 1 and 2; ≤ 0.046). In soft tissue, standard-dose (readers 1, 2, and 3; ≤ 0.021) and low-dose (all ≤ 0.001) CBCT images had more noise than MDCT in all cases. Standard-dose (all ≤ 0.003) and low-dose (all < 0.001) CBCT images also displayed more artifacts. In osseous tissue, one reader observed more noise ( < 0.001) and artifacts ( = 0.020) for low-dose CBCT than for MDCT, whereas no difference was found between standard-dose CBCT and MDCT. Mean CTDI was significantly lower for standard-dose (5.2 ± 0.6 mGy; < 0.001) and low-dose CBCT (1.8 ± 0.2 mGy; < 0.001) than for clinical MDCT without automatic dose modulation (15.0 ± 0.0 mGy). The tested CBCT function delivers suitable image quality for clinical wrist imaging at significantly lower radiation levels than conventional MDCT. In combination with comfortable positioning options and the ability to perform additional radiographic and fluoroscopic examinations, the twin robotic x-ray system may hold the potential to be a one-stop shop device for trauma-associated wrist imaging.
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http://dx.doi.org/10.2214/AJR.19.21911DOI Listing
February 2020

Generation of complex human organoid models including vascular networks by incorporation of mesodermal progenitor cells.

Sci Rep 2019 10 30;9(1):15663. Epub 2019 Oct 30.

Institute of Anatomy and Cell Biology, Koellikerstraße 6, University of Würzburg, 97070, Würzburg, Germany.

Organoids derived from human pluripotent stem cells are interesting models to study mechanisms of morphogenesis and promising platforms for disease modeling and drug screening. However, they mostly remain incomplete as they lack stroma, tissue resident immune cells and in particular vasculature, which create important niches during development and disease. We propose, that the directed incorporation of mesodermal progenitor cells (MPCs) into organoids will overcome the aforementioned limitations. In order to demonstrate the feasibility of the method, we generated complex human tumor as well as neural organoids. We show that the formed blood vessels display a hierarchic organization and mural cells are assembled into the vessel wall. Moreover, we demonstrate a typical blood vessel ultrastructure including endothelial cell-cell junctions, a basement membrane as well as luminal caveolae and microvesicles. We observe a high plasticity in the endothelial network, which expands, while the organoids grow and is responsive to anti-angiogenic compounds and pro-angiogenic conditions such as hypoxia. We show that vessels within tumor organoids connect to host vessels following transplantation. Remarkably, MPCs also deliver Iba1 cells that infiltrate the neural tissue in a microglia-like manner.
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http://dx.doi.org/10.1038/s41598-019-52204-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821804PMC
October 2019

3D cone-beam CT of the ankle using a novel twin robotic X-ray system: Assessment of image quality and radiation dose.

Eur J Radiol 2019 Oct 7;119:108659. Epub 2019 Sep 7.

Department of Diagnostic and Interventional Radiology, University Hospital Würzburg, Würzburg, Germany.

Purpose: To evaluate image quality (IQ) and radiation dose in cone-beam computed tomography (CBCT) of the ankle using a novel twin robotic X-ray system.

Method: We examined 16 cadaveric ankles with standard-dose (FD) and low-dose (LD) protocols using the new system's CBCT mode. For comparison, we performed multi-slice CT imaging (MSCT) with a clinical protocol. Three radiologists assessed IQ, noise and artifacts in bone and soft tissue on a five-point Likert scale (1= poor IQ; strong noise or artifacts; 5= excellent IQ; minimal noise or artifacts). Volume CT dose indices (CTDI) were calculated for radiation dose comparison between CBCT and MSCT.

Results: Overall IQ was described as very good or excellent by reader 1/2/3 in 62.5/87.5/56.3% of LD, 87.5/87.5/81.3% of FD and 100/87.5/87.5% of MSCT studies. Readers agreed that IQ was better in MSCT than LD (R1/R2/R3; p ≤ 0.008), two also found advantages of MSCT over FD (R1/R3; p ≤ 0.034). Soft tissue noise and artifacts were stronger in FD (all p ≤ 0.002) and LD (all p ≤ 0.001). In bone, artifacts and noise were also more severe in LD (all p < 0.001) and FD (all p ≤ 0.003). CTDI for clinical MSCT scans without dose modulation (15.0 ± 0.0 mGy) were higher than for FD (5.3 ± 1.0 mGy) and LD studies (2.9 ± 0.6 mGy; both p < 0.001).

Conclusions: Despite MSCT providing better overall IQ than the twin robotic X-ray system's CBCT mode, both cone-beam protocols offer very good IQ in most studies and are suitable for clinical ankle imaging. Standard-dose and especially low-dose CBCT studies deliver up to five times less radiation dose than MSCT imaging.
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http://dx.doi.org/10.1016/j.ejrad.2019.108659DOI Listing
October 2019

Aging-related carcinoembryonic antigen-related cell adhesion molecule 1 signaling promotes vascular dysfunction.

Aging Cell 2019 12 6;18(6):e13025. Epub 2019 Aug 6.

Institute of Anatomy and Cell Biology, Julius-Maximilians-University Würzburg, Würzburg, Germany.

Aging is an independent risk factor for cardiovascular diseases and therefore of particular interest for the prevention of cardiovascular events. However, the mechanisms underlying vascular aging are not well understood. Since carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is crucially involved in vascular homeostasis, we sought to identify the role of CEACAM1 in vascular aging. Using human internal thoracic artery and murine aorta, we show that CEACAM1 is upregulated in the course of vascular aging. Further analyses demonstrated that TNF-α is CEACAM1-dependently upregulated in the aging vasculature. Vice versa, TNF-α induces CEACAM1 expression. This results in a feed-forward loop in the aging vasculature that maintains a chronic pro-inflammatory milieu. Furthermore, we demonstrate that age-associated vascular alterations, that is, increased oxidative stress and vascular fibrosis, due to increased medial collagen deposition crucially depend on the presence of CEACAM1. Additionally, age-dependent upregulation of vascular CEACAM1 expression contributes to endothelial barrier impairment, putatively via increased VEGF/VEGFR-2 signaling. Consequently, aging-related upregulation of vascular CEACAM1 expression results in endothelial dysfunction that may promote atherosclerotic plaque formation in the presence of additional risk factors. Our data suggest that CEACAM1 might represent an attractive target in order to delay physiological aging and therefore the transition to vascular disorders such as atherosclerosis.
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http://dx.doi.org/10.1111/acel.13025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826129PMC
December 2019

Versatile cell ablation tools and their applications to study loss of cell functions.

Cell Mol Life Sci 2019 Dec 29;76(23):4725-4743. Epub 2019 Jul 29.

Department of Neuroscience, Lewis Katz School of Medicine at Temple University, 3500 N Broad Street, Philadelphia, PA, 19140, USA.

Targeted cell ablation is a powerful approach for studying the role of specific cell populations in a variety of organotypic functions, including cell differentiation, and organ generation and regeneration. Emerging tools for permanently or conditionally ablating targeted cell populations and transiently inhibiting neuronal activities exhibit a diversity of application and utility. Each tool has distinct features, and none can be universally applied to study different cell types in various tissue compartments. Although these tools have been developed for over 30 years, they require additional improvement. Currently, there is no consensus on how to select the tools to answer the specific scientific questions of interest. Selecting the appropriate cell ablation technique to study the function of a targeted cell population is less straightforward than selecting the method to study a gene's functions. In this review, we discuss the features of the various tools for targeted cell ablation and provide recommendations for optimal application of specific approaches.
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http://dx.doi.org/10.1007/s00018-019-03243-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858955PMC
December 2019

The Best for the Most Important: Maintaining a Pristine Proteome in Stem and Progenitor Cells.

Stem Cells Int 2019 2;2019:1608787. Epub 2019 May 2.

Institute of Anatomy and Cell Biology, Julius-Maximilians Universität Würzburg, Koellikerstrasse 6, Würzburg, 97070 Bayern, Germany.

Pluripotent stem cells give rise to reproductively enabled offsprings by generating progressively lineage-restricted multipotent stem cells that would differentiate into lineage-committed stem and progenitor cells. These lineage-committed stem and progenitor cells give rise to all adult tissues and organs. Adult stem and progenitor cells are generated as part of the developmental program and play critical roles in tissue and organ maintenance and/or regeneration. The ability of pluripotent stem cells to self-renew, maintain pluripotency, and differentiate into a multicellular organism is highly dependent on sensing and integrating extracellular and extraorganismal cues. Proteins perform and integrate almost all cellular functions including signal transduction, regulation of gene expression, metabolism, and cell division and death. Therefore, maintenance of an appropriate mix of correctly folded proteins, a pristine proteome, is essential for proper stem cell function. The stem cells' proteome must be pristine because unfolded, misfolded, or otherwise damaged proteins would interfere with unlimited self-renewal, maintenance of pluripotency, differentiation into downstream lineages, and consequently with the development of properly functioning tissue and organs. Understanding how various stem cells generate and maintain a pristine proteome is therefore essential for exploiting their potential in regenerative medicine and possibly for the discovery of novel approaches for maintaining, propagating, and differentiating pluripotent, multipotent, and adult stem cells as well as induced pluripotent stem cells. In this review, we will summarize cellular networks used by various stem cells for generation and maintenance of a pristine proteome. We will also explore the coordination of these networks with one another and their integration with the gene regulatory and signaling networks.
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http://dx.doi.org/10.1155/2019/1608787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525796PMC
May 2019

Inhibition of platelet GPVI induces intratumor hemorrhage and increases efficacy of chemotherapy in mice.

Blood 2019 06 5;133(25):2696-2706. Epub 2019 Apr 5.

Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.

Maintenance of tumor vasculature integrity is indispensable for tumor growth and thus affects tumor progression. Previous studies have identified platelets as major regulators of tumor vascular integrity, as their depletion selectively rendered tumor vessels highly permeable and caused massive intratumoral hemorrhage. While these results established platelets as potential targets for antitumor therapy, their depletion is not a treatment option due to their essential role in hemostasis. Thus, a detailed understanding of how platelets safeguard vascular integrity in tumors is urgently demanded. Here, we show for the first time that functional inhibition of glycoprotein VI (GPVI) on the platelet surface with an antibody (JAQ1) F(ab) fragment rapidly induces tumor hemorrhage and diminishes tumor growth similar to complete platelet depletion while not inducing systemic bleeding complications. The intratumor bleeding and tumor growth arrest could be reverted by depletion of Ly6G cells, confirming them to be responsible for the induction of bleeding and necrosis within the tumor. In addition, JAQ1 F(ab)-mediated GPVI inhibition increased intratumoral accumulation of coadministered chemotherapeutic agents, such as Doxil and paclitaxel, thereby resulting in a profound antitumor effect. In summary, our findings identify platelet GPVI as a key regulator of vascular integrity specifically in growing tumors and could serve as a basis for the development of antitumor strategies based on the interference with platelet function.
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http://dx.doi.org/10.1182/blood.2018877043DOI Listing
June 2019

Recommendations of the working group of the Anatomische Gesellschaft on reduction of formaldehyde exposure in anatomical curricula and institutes.

Ann Anat 2019 Jan 25;221:179-185. Epub 2018 Oct 25.

Institute for Functional and Clinical Anatomy, University of Erlangen-Nürnberg, Erlangen, Germany. Electronic address:

The practice of human and veterinary medicine is based on the science of anatomy and dissection courses are still irreplaceable in the teaching of anatomy. Embalming is required to preserve body donors, for which process formaldehyde (FA) is the most frequently used and well characterized biocidal substance. Since January 2016, a new occupational exposure limit (OEL) for FA of 0.37mg/m issued by the European Committee on Hazardous Substances is obligatory since FA has been classified as a human 1B carcinogen. The anatomical institutes in the German-speaking region are called upon to consolidate efforts to reduce use of FA in anatomical curricula and body donations. As a result, the Anatomische Gesellschaft (AG) has formed a "Working Group for Reduction of Formaldehyde Exposure in Dissection Courses" tasked with discussion and recommendation of measures to reduce FA. Based on the assessment of the Working Group, the AG has issued an official opinion to the effect that, at this point in time, embalming of body donors without FA completely is not feasible. Therefore, a combination of approaches are to be used to reduce FA exposure, including technical and structural (architectural) adaptations, modification of protocols for fixation and preservation as well as organizational measures. One structural measure considered unavoidable is the integration of air supply and exhaust of individual dissecting tables into the ventilation system of the anatomy building. To embalm human body donors, intra-arterial perfusion fixation with up to 4% FA and a total fluid volume of 150mL/kg body weight will suffice. For animals where body weights and biology of bodies vary widely (i.e. special needs of fixation for ruminants, large animals as horses) perfusion fixation with up to 4% FA and a quantity of fixative solution of 10-15% of the body weight may be required. Preservation of body donors in storage (immersion) can be done with 40% ethanol or in a full bath preservation containing up to 2% FA. Corpse humidification in the dissecting room is possible with 2% phenoxyethanol, in each case without FA. In veterinary anatomy, microbiological burden is often higher and therefore might lead to a need of FA in long-time storage. Compliance with the current OEL in all institutes would appear to be feasible in combination with various organizational measures.
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http://dx.doi.org/10.1016/j.aanat.2018.10.007DOI Listing
January 2019

Restriction of drug transport by the tumor environment.

Histochem Cell Biol 2018 Dec 25;150(6):631-648. Epub 2018 Oct 25.

Institute of Anatomy and Cell Biology, Universität Würzburg, Koellikerstrasse 6, 97070, Würzburg, Germany.

As in the systemic treatment of any disease, it is crucial for anti-cancer drugs to reach their target at a sufficient that is a therapeutically effective dose. However, unlike normal organs, solid tumors have a tendency to be undersupplied and hypoxic. This not only leads to insufficient supply of oxygen and nutrients but also to inefficient transport of drugs into tumors. As a consequence, administered doses have to be raised, resulting in increased side effects and often premature termination of treatment. A better understanding of the mechanisms that hamper transport of drugs into tumors could lead to the development of auxiliary strategies aimed at increasing tumor drug delivery and accumulation and thereby improving the efficacy of anti-cancer drugs at our disposal. The tumor microenvironment (TME), i.e., its vasculature, stroma, extracellular matrix and immune environment affect the transport of drugs to the tumor and their distribution within the tumor tissue in various ways. In this review we will highlight the current research regarding the cellular and molecular mechanisms that remain as an obstacle towards an effective cancer therapy, and also focus on the various strategies to alter the TME to increase tumor drug exposure and thereby treatment efficacy.
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http://dx.doi.org/10.1007/s00418-018-1744-zDOI Listing
December 2018

Generation of Cardiomyocytes From Vascular Adventitia-Resident Stem Cells.

Circ Res 2018 08;123(6):686-699

From the Institute of Anatomy and Cell Biology II (S.R.M., P.W., J.B., O.S., N.W., L.R., K.L., G.E., C.K.K., F.E., V.P., S.K., S.E.).

Rationale: Regeneration of lost cardiomyocytes is a fundamental unresolved problem leading to heart failure. Despite several strategies developed from intensive studies performed in the past decades, endogenous regeneration of heart tissue is still limited and presents a big challenge that needs to be overcome to serve as a successful therapeutic option for myocardial infarction.

Objective: One of the essential prerequisites for cardiac regeneration is the identification of endogenous cardiomyocyte progenitors and their niche that can be targeted by new therapeutic approaches. In this context, we hypothesized that the vascular wall, which was shown to harbor different types of stem and progenitor cells, might serve as a source for cardiac progenitors.

Methods And Results: We describe generation of spontaneously beating mouse aortic wall-derived cardiomyocytes without any genetic manipulation. Using aortic wall-derived cells (AoCs) of WT (wild type), αMHC (α-myosin heavy chain), and Flk1 (fetal liver kinase 1)-reporter mice and magnetic bead-associated cell sorting sorting of Flk1 AoCs from GFP (green fluorescent protein) mice, we identified Flk1CD (cluster of differentiation) 34Sca-1 (stem cell antigen-1)-CD44 AoCs as the population that gives rise to aortic wall-derived cardiomyocytes. This AoC subpopulation delivered also endothelial cells and macrophages with a particular accumulation within the aortic wall-derived cardiomyocyte containing colonies. In vivo, cardiomyocyte differentiation capacity was studied by implantation of fluorescently labeled AoCs into chick embryonic heart. These cells acquired cardiomyocyte-like phenotype as shown by αSRA (α-sarcomeric actinin) expression. Furthermore, coronary adventitial Flk1 and CD34 cells proliferated, migrated into the myocardium after mouse myocardial infarction, and expressed Isl-1 (insulin gene enhancer protein-1) indicative of cardiovascular progenitor potential.

Conclusions: Our data suggest Flk1CD34 vascular adventitia-resident stem cells, including those of coronary adventitia, as a novel endogenous source for generating cardiomyocytes. This process is essentially supported by endothelial cells and macrophages. In summary, the therapeutic manipulation of coronary adventitia-resident cardiac stem and their supportive cells may open new avenues for promoting cardiac regeneration and repair after myocardial infarction and for preventing heart failure.
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http://dx.doi.org/10.1161/CIRCRESAHA.117.312526DOI Listing
August 2018

Longitudinal 18F-FDG PET imaging in a rat model of autoimmune myocarditis.

Eur Heart J Cardiovasc Imaging 2019 04;20(4):467-474

Department of Nuclear Medicine, University Hospital Würzburg, Oberdürrbacherstr. 6, Würzburg, Germany.

Aims: Although mortality rate is very high, diagnosis of acute myocarditis remains challenging with conventional tests. We aimed to elucidate the potential role of longitudinal 2-Deoxy-2-18F-fluoro-D-glucose (18F-FDG) positron emission tomography (PET) inflammation monitoring in a rat model of experimental autoimmune myocarditis.

Methods And Results: Autoimmune myocarditis was induced in Lewis rats by immunizing with porcine cardiac myosin emulsified in complete Freund's adjuvant. Time course of disease was assessed by longitudinal 18F-FDG PET imaging. A correlative analysis between in- and ex vivo18F-FDG signalling and macrophage infiltration using CD68 staining was conducted. Finally, immunohistochemistry analysis of the cell-adhesion markers CD34 and CD44 was performed at different disease stages determined by longitudinal 18F-FDG PET imaging. After immunization, myocarditis rats revealed a temporal increase in 18F-FDG uptake (peaked at week 3), which was followed by a rapid decline thereafter. Localization of CD68 positive cells was well correlated with in vivo18F-FDG PET signalling (R2 = 0.92) as well as with ex vivo18F-FDG autoradiography (R2 = 0.9, P < 0.001, respectively). CD44 positivity was primarily observed at tissue samples obtained at acute phase (i.e. at peak 18F-FDG uptake), while CD34-positive staining areas were predominantly identified in samples harvested at both sub-acute and chronic phases (i.e. at 18F-FDG decrease).

Conclusion: 18F-FDG PET imaging can provide non-invasive serial monitoring of cardiac inflammation in a rat model of acute myocarditis.
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http://dx.doi.org/10.1093/ehjci/jey119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429237PMC
April 2019

The role of connexins during early embryonic development: pluripotent stem cells, gene editing, and artificial embryonic tissues as tools to close the knowledge gap.

Histochem Cell Biol 2018 Oct 23;150(4):327-339. Epub 2018 Jul 23.

Institute of Anatomy and Cell Biology, University of Würzburg, Koellikerstr.6, 97070, Würzburg, Germany.

Since almost 4 decades, connexins have been discussed as important regulators of embryogenesis. Several different members of the gene family can be detected in the preimplantation embryo and during gastrulation. However, genetically engineered mice deficient for every connexin expressed during early development are available and even double-deficient mice were generated. Interestingly, all of these mice complete gastrulation without any abnormalities. This raises the question if the role of connexins has been overrated or if other gene family members compensate and mask their importance. To answer this question, embryos completely devoid of any gap junctional communication need to be investigated. This is challenging because a variety of connexin genes are co-expressed and some null mutations lead to a lethal phenotype. In addition, maternal connexin transcripts were described to persist until the blastocyst stage. In this review, we summarize the current knowledge about the role of connexins during preimplantation development and in embryonic stem cells. We propose that the use of pluripotent stem cells, trophoblast stem cells, as well as artificial embryo-like structures and organoid cultures in combination with multiplex CRISPR/Cas9-based genome editing provides a powerful platform to comprehensively readdress this issue and decipher the role of connexins during lineage decision, differentiation, and morphogenesis in a cell culture model for mouse and human development.
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http://dx.doi.org/10.1007/s00418-018-1697-2DOI Listing
October 2018

LOX-catalyzed collagen stabilization is a proximal cause for intrinsic resistance to chemotherapy.

Oncogene 2018 09 21;37(36):4921-4940. Epub 2018 May 21.

Institute of Anatomy and Cell Biology II, Universität Würzburg, Koellikerstrasse 6, 97070, Würzburg, Germany.

The potential of altering the tumor ECM to improve drug response remains fairly unexplored. To identify targets for modification of the ECM aiming to improve drug response and overcome resistance, we analyzed expression data sets from pre-treatment patient cohorts. Cross-evaluation identified a subset of chemoresistant tumors characterized by increased expression of collagens and collagen-stabilizing enzymes. We demonstrate that strong collagen expression and stabilization sets off a vicious circle of self-propagating hypoxia, malignant signaling, and aberrant angiogenesis that can be broken by an appropriate auxiliary intervention: Interfering with collagen stabilization by inhibition of lysyl oxidases significantly enhanced response to chemotherapy in various tumor models, even in metastatic disease. Inhibition of collagen stabilization by itself can reduce or enhance tumor growth depending on the tumor type. The mechanistical basis for this behavior is the dependence of the individual tumor on nutritional supply on one hand and on high tissue stiffness for FAK signaling on the other.
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http://dx.doi.org/10.1038/s41388-018-0320-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127085PMC
September 2018

Endothelial barrier function is differentially regulated by CEACAM1-mediated signaling.

FASEB J 2018 10 10;32(10):5612-5625. Epub 2018 May 10.

Institute of Anatomy and Cell Biology, Julius-Maximilians-University Würzburg, Würzburg, Germany.

Carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1) is known to be crucial to vasculogenesis and angiogenesis. Recently, CEACAM1 deficiency was shown to result in the formation of aortic plaque-like lesions, indicating a role for CEACAM1 in adult vessels as well. The underlying mechanisms remained largely elusive. Therefore, we aimed to elucidate the role of CEACAM1 in endothelial homeostasis. Here, we show that CEACAM1 deficiency causes subcellular eNOS redistribution in endothelial cells ( i.e., by eNOS depalmitoylation) and alters endothelial glycocalyx that confers antiadhesive properties to the endothelium ( i.e., by repression of glycocalyx-degrading enzymes). Accordingly, our analysis revealed an increased leukocyte-endothelial interaction in CEACAM1-deficient endothelium. In addition, CEACAM1 age dependently modulated basal and TNF-α-mediated endothelial barrier (EB) leakiness. In younger mice, CEACAM1 was protective for EB, whereas in aged mice it promoted EB leakiness. EB function depends on interendothelial adherence junctions formed by β-catenin/vascular endothelial-cadherin complexes. We show here that CEACAM1 influenced basal and TNF-α-mediated phosphorylation of β-catenin and caveolin-1, which are essential players in EB modulation. Both increased adhesiveness to leukocytes and EB modulation due to CEACAM1 deficiency may facilitate inflammatory cell transmigration into the vascular wall and subsequent plaque formation. Collectively, these results identify a crucial role for CEACAM1 in endothelial homeostasis of adult blood vessels.-Ghavampour, S., Kleefeldt, F., Bömmel, H., Volland, J., Paus, A., Horst, A., Pfeiffer, V., Hübner, S., Wagner, N., Rueckschloss, U., Ergün, S. Endothelial barrier function is differentially regulated by CEACAM1-mediated signaling.
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http://dx.doi.org/10.1096/fj.201800331RDOI Listing
October 2018