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Dive into the research topics where Jadranka Macas is active.

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Featured researches published by Jadranka Macas.


The Journal of Neuroscience | 2006

Increased generation of neuronal progenitors after ischemic injury in the aged adult human forebrain.

Jadranka Macas; Christian Nern; Karl H. Plate; Stefan Momma

The adult human brain retains the capacity to generate new neurons in the hippocampal formation (Eriksson et al., 1998) and neuronal progenitor cells (NPCs) in the forebrain (Bernier et al., 2000), but to what extent it is capable of reacting to injuries, such as ischemia, is not known. We analyzed postmortem tissue from normal and pathological human brain tissue (n = 54) to study the cellular response to ischemic injury in the forebrain. We observed that cells expressing the NPC marker polysialylated neural adhesion cell molecule (PSA-NCAM) are continuously generated in the adult human subventricular zone (SVZ) and migrate along the olfactory tracts. These cells were not organized in migrating chains as in the adult rodent rostral migratory stream, and their number was lower in the olfactory tracts of brains from old (56–81 years of age) compared with young (29 + 36 years of age) individuals. Moreover, we show that in brains of patients of advanced age (60–87 years of age), ischemia led to an elevated number of Ki-67-positive cells in the ipsilateral SVZ without concomitant apoptotic cell death. Additionally, ischemia led to an increased number of PSA-NCAM-positive NPCs close to the lateral ventricular walls, compared with brains of comparable age without obvious neuropathologic changes. These results suggest that the adult human brain retains a capacity to respond to ischemic injuries and that this capacity is maintained even in old age.


Journal of Experimental Medicine | 2012

Endothelial Wnt/β-catenin signaling inhibits glioma angiogenesis and normalizes tumor blood vessels by inducing PDGF-B expression

Marco Reis; Cathrin J. Czupalla; Nicole Ziegler; Kavi Devraj; Jenny Zinke; Sascha Seidel; Rosario Heck; Sonja Thom; Jadranka Macas; Ernesto Bockamp; Marcus Fruttiger; Makoto M. Taketo; Stefanie Dimmeler; Karl H. Plate; Stefan Liebner

Wnt modulates glioma vascularization by regulating PDGF-B expression.


The Journal of Neuroscience | 2009

Fusion of Hematopoietic Cells with Purkinje Neurons Does Not Lead to Stable Heterokaryon Formation under Noninvasive Conditions

Christian Nern; Ines Wolff; Jadranka Macas; Josefine von Randow; Christian Scharenberg; Josef Priller; Stefan Momma

Transplanted hematopoietic cells have previously been shown to contribute to cells of other tissues by cell fusion. We wanted to elucidate whether this phenomenon of cell fusion also occurs under physiological conditions. Using a transgenic mouse reporter system to irreversibly label cells of the hematopoietic lineage, we were able to test their contribution to other tissues in the absence of any additional and potentially confounding factors such as irradiation or chemoablation. We found genetically marked, fused Purkinje neurons as well as hepatocytes in numbers comparable to previous bone marrow transplantation studies. The number of fused Purkinje neurons increased after intrathecal administration of bacterial lipopolysaccharide, suggesting that cell fusion can be induced by inflammation. In contrast to previous studies, however, genetically labeled Purkinje neurons never contained more than one nucleus, and we found only a single cell containing two Y-chromosomes in a male mouse. Consistent with results from the mouse model and unlike human bone marrow transplant recipients, postmortem adult human cerebelli of nontransplanted individuals were devoid of binucleated or polyploid Purkinje neurons. Therefore, our data suggests that fusion of hematopoietic cells with Purkinje neurons is only transient and does not lead to stable heterokaryon formation under noninvasive conditions.


Acta Neuropathologica | 2016

Angiopoietin-2-induced blood-brain barrier compromise and increased stroke size are rescued by VE-PTP-dependent restoration of Tie2 signaling.

Stefanie Gurnik; Kavi Devraj; Jadranka Macas; Maiko Yamaji; Julia Starke; Alexander Scholz; Kathleen Sommer; Mariangela Di Tacchio; Rajkumar Vutukuri; Heike Beck; Michel Mittelbronn; Christian Foerch; Waltraud Pfeilschifter; Stefan Liebner; Kevin G. Peters; Karl H. Plate; Yvonne Reiss

The homeostasis of the central nervous system is maintained by the blood–brain barrier (BBB). Angiopoietins (Ang-1/Ang-2) act as antagonizing molecules to regulate angiogenesis, vascular stability, vascular permeability and lymphatic integrity. However, the precise role of angiopoietin/Tie2 signaling at the BBB remains unclear. We investigated the influence of Ang-2 on BBB permeability in wild-type and gain-of-function (GOF) mice and demonstrated an increase in permeability by Ang-2, both in vitro and in vivo. Expression analysis of brain endothelial cells from Ang-2 GOF mice showed a downregulation of tight/adherens junction molecules and increased caveolin-1, a vesicular permeability-related molecule. Immunohistochemistry revealed reduced pericyte coverage in Ang-2 GOF mice that was supported by electron microscopy analyses, which demonstrated defective intra-endothelial junctions with increased vesicles and decreased/disrupted glycocalyx. These results demonstrate that Ang-2 mediates permeability via paracellular and transcellular routes. In patients suffering from stroke, a cerebrovascular disorder associated with BBB disruption, Ang-2 levels were upregulated. In mice, Ang-2 GOF resulted in increased infarct sizes and vessel permeability upon experimental stroke, implicating a role of Ang-2 in stroke pathophysiology. Increased permeability and stroke size were rescued by activation of Tie2 signaling using a vascular endothelial protein tyrosine phosphatase inhibitor and were independent of VE-cadherin phosphorylation. We thus identified Ang-2 as an endothelial cell-derived regulator of BBB permeability. We postulate that novel therapeutics targeting Tie2 signaling could be of potential use for opening the BBB for increased CNS drug delivery or tighten it in neurological disorders associated with cerebrovascular leakage and brain edema.


Stem Cells | 2014

Generation of Neuronal Progenitor Cells in Response to Tumors in the Human Brain

Jadranka Macas; Min–Chi Ku; Christian Nern; Yuanzhi Xu; Helmut Bühler; Marc Remke; Michael Synowitz; Kea Franz; Volker Seifert; Karl H. Plate; Helmut Kettenmann; Rainer Glass; Stefan Momma

Data from transgenic mouse models show that neuronal progenitor cells (NPCs) migrate toward experimental brain tumors and modulate the course of pathology. However, the pathways whereby NPCs are attracted to CNS neoplasms are not fully understood and it is unexplored if NPCs migrate toward brain tumors (high‐grade astrocytomas) in humans. We analyzed the tumor‐parenchyma interface of neurosurgical resections for the presence of (NPCs) and distinguished these physiological cells from the tumor mass. We observed that polysialic acid neural cell adhesion molecule‐positive NPCs accumulate at the border of high‐grade astrocytomas and display a marker profile consistent with immature migratory NPCs. Importantly, these high‐grade astrocytoma‐associated NPCs did not carry genetic aberrations that are indicative of the tumor. Additionally, we observed NPCs accumulating in CNS metastases. These metastatic tumors are distinguished from neural cells by defined sets of markers. Transplanting murine glioma cells embedded in a cell‐impermeable hollow fiber capsule into the brains of nestin‐gfp reporter mice showed that diffusible factors are sufficient to induce a neurogenic reaction. In vitro, vascular endothelial growth factor (VEGF) secreted from glioma cells increases the migratory and proliferative behavior of adult human brain‐derived neural stem and progenitor cells via stimulation of VEGF receptor‐2 (VEGFR‐2). In vivo, inhibiting VEGFR‐2 signaling with a function‐blocking antibody led to a reduction in NPC migration toward tumors. Overall, our data reveal a mechanism by which NPCs are attracted to CNS tumors and suggest that NPCs accumulate in human high‐grade astrocytomas. Stem Cells 2014;32:244–257


Journal of Cerebral Blood Flow and Metabolism | 2017

Nucleoside diphosphate kinase B regulates angiogenic responses in the endothelium via caveolae formation and c-Src-mediated caveolin-1 phosphorylation.

Shalini Gross; Kavi Devraj; Yuxi Feng; Jadranka Macas; Stefan Liebner; Thomas Wieland

Nucleoside diphosphate kinase B (NDPK-B) is an enzyme required for nucleoside triphosphate homeostasis, which has been shown to interact with caveolin-1 (Cav-1). In endothelial cells (ECs), NDPK-B contributes to the regulation of angiogenesis and adherens junction (AJ) integrity. We therefore investigated whether an interaction of NDPK-B with Cav-1 in ECs is required for this regulation and the involvement of VEGF signaling herein. We report that simultaneous depletion of NDPK-B/Cav-1 in HUVECs synergistically impaired sprouting angiogenesis. NDPK-B depletion alone impaired caveolae formation, VEGF-induced phosphorylation of c-Src/Cav-1 but not of ERK1/2/AKT/eNOS. In vivo, Cav-1−/− mice showed impaired retinal vascularization at postnatal-day five, whereas NDPK-B−/− mice did not. Primary mouse brain ECs (MBMECs) from NDPK-B−/− mice showed no change in caveolae content and transendothelial-electrical resistance upon VEGF stimulation. Interestingly, NDPK-B−/− MBMECs displayed an accumulation of intracellular vesicles and increased Cav-1 levels. Dextran tracer analysis showed increased vascular permeability in the brain of NDPK-B−/− mice compared to wild type. In conclusion, our data indicate that NDPK-B is required for the correct localization of Cav-1 at the plasma membrane and the formation of caveolae. The genetic ablation of NDPK-B could partially be compensated by an increased Cav-1 content, which restored caveolae formation and some endothelial functions.


Oncotarget | 2018

Rhodocetin-αβ selectively breaks the endothelial barrier of the tumor vasculature in HT1080 fibrosarcoma and A431 epidermoid carcinoma tumor models

Stephan Niland; Dorde Komljenovic; Jadranka Macas; Thilo Bracht; Tobias Bäuerle; Stefan Liebner; Johannes A. Eble

The tumor vasculature differs from normal blood vessels in morphology, composition and stability. Here, we describe a novel tumor vessel-disrupting mechanism. In an HT1080/mouse xenograft tumor model rhodocetin-αβ was highly effective in disrupting the tumor endothelial barrier. Mechanistically, rhodocetin-αβ triggered MET signaling via neuropilin-1. As both neuropilin-1 and MET were only lumen-exposed in a subset of abnormal tumor vessels, but not in normal vessels, the prime target of rhodocetin-αβ were these abnormal tumor vessels. Consequently, cells lining such tumor vessels became increasingly motile which compromised the vessel wall tightness. After this initial leakage, rhodocetin-αβ could leave the bloodstream and reach the as yet inaccessible neuropilin-1 on the basolateral side of endothelial cells and thus disrupt nearby vessels. Due to the specific neuropilin-1/MET co-distribution on cells lining such abnormal tumor vessels in contrast to normal endothelial cells, rhodocetin-αβ formed the necessary trimeric signaling complex of rhodocetin-αβ-MET-neuropilin-1 only in these abnormal tumor vessels. This selective attack of tumor vessels, sparing endothelial cell-lined vessels of normal tissues, suggests that the neuropilin-1-MET signaling axis may be a promising drugable target for anti-tumor therapy, and that rhodocetin-αβ may serve as a lead structure to develop novel anti-tumor drugs that target such vessels.


Journal of Neuroimmunology | 2014

Extracellular vesicle-mediated transfer of genetic information between the hematopoietic system and the brain in response to inflammation

Kirsten Ridder; Sascha Keller; Maria Dams; Anne-Kathleen Rupp; Jessica Schlaudraff; Domenico Del Turco; Julia Starmann; Jadranka Macas; Darja Karpova; Kavi Devraij; Candan Depboylu; Britta Landfried; Bernd Arnold; Karl H. Plate; Günter U. Höglinger; Holger Sültmann; Peter Altevogt; Stefan Momma

(IL-6) and interleukin 10 (IL-10). Microglia are CNS-resident myeloid lineage cells that exhibit a range of activated phenotypes depending on signals present in their local environment. Microglia can cause oligodendroglial and neuronal damage via secretion of soluble factors, but have also been shown to improve remyelination in some toxininduced demyelination models. In this study, we investigated the antiinflammatory effects of DMF and MMF in primary human microglia isolated from 14 to 18 week-old fetal CNS tissue. These results were compared with responses in primary cultures of monocyte-derived macrophages. Following lipopolysaccharide (LPS) stimulation, enzymelinked immunosorbance assays (ELISA) were used to detect TNF, IL-6, and IL-10 in the culture supernatants. DMF dose-dependently suppressed secretion of TNF, IL-6, and IL-10 from microglia, but MMF did not. Macrophages exhibited robust cytokine responses to LPS that were not attenuated by DMF or MMF treatment. DMF inhibited expression of miR-155, a known inhibitor of suppressor of cytokine secretion 1 (SOCS1) in microglia, as assessed by quantitative polymerase chain reaction (qPCR). Our studies indicate that DMF inhibition of inflammatory propertiesmay bemyeloid sub-type specific and involves regulation of miR-155 expression.


Experimental Hematology | 2017

The role of Wnt/b-catenin-signalling for cell fate decision in megakaryopoiesis of the haematopoietic system

Burak Hasan Yalcin; Jadranka Macas; Eliza Wiercinska; Patrick N. Harter; Malak Fawaz; Ilaria Ghiro; Ralf H. Adams; Marcus Fruttiger; Jörn Lausen; Michael A. Rieger; Karl H. Plate; Halvard Bonig; Stefan Liebner


Neuro-oncology | 2014

P17.87ENDOGENOUS NEURAL PRECURSOR CELLS ACCUMULATE AT METASTATIC BRAIN TUMORS AND TROPISM OF PRECURSOR CELLS IS INDUCED BY TUMOR-RELEASED VEGF-A

Michael Synowitz; Jadranka Macas; Helmut Kettenmann; Rainer Glass; Stefan Momma

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Karl H. Plate

Goethe University Frankfurt

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Stefan Liebner

Goethe University Frankfurt

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Stefan Momma

Goethe University Frankfurt

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Kavi Devraj

Goethe University Frankfurt

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Christian Nern

Goethe University Frankfurt

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Helmut Kettenmann

Max Delbrück Center for Molecular Medicine

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Marco Reis

Goethe University Frankfurt

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