Citalopram reduces aggregation of ATXN3 in a YAC transgenic mouse model of Machado-Joseph disease

Machado-Joseph disease, also known as spinocerebellar ataxia type 3, is a fatal polyglutamine disease with no disease-modifying treatment. The selective serotonin reuptake inhibitor citalopram was shown in nematode and mouse models to be a compelling repurposing candidate for Machado-Joseph disease therapeutics. We sought to confirm the efficacy of citalopram to decrease ATXN3 aggregation in an unrelated mouse model of Machado-Joseph disease. Four-week-old YACMJD84.2 mice and non-transgenic littermates were given citalopram 8 mg/kg in drinking water or water for 10 weeks. At the end of treatment, brains were collected for biochemical and pathological analyses. Brains of citalopram-treated YACMJD84.2 mice showed an approximate 50% decrease in the percentage of cells containing ATXN3-positive inclusions in the substantia nigra and three examined brainstem nuclei compared to controls. No differences in ATXN3 inclusion load were observed in deep cerebellar nuclei of mice. Citalopram effect on ATXN3 aggregate burden was corroborated by immunoblotting analysis. While lysates from the brainstem and cervical spinal cord of citalopram-treated mice showed a decrease in all soluble forms of ATXN3 and a trend toward reduction of insoluble ATXN3, no differences in ATXN3 levels were found between cerebella of citalopram-treated and vehicle-treated mice. Citalopram treatment altered levels of select components of the cellular protein homeostatic machinery that may be expected to enhance the capacity to refold and/or degrade mutant ATXN3. The results here obtained in a second independent mouse model of Machado-Joseph disease further support citalopram as a potential drug to be repurposed for this fatal disorder.This work was funded by Becky Babcox Research Fund/pilot research award G015617, University of Michigan to M.C.C. and NINDS/NIH R01NS038712 to H.L.P. The work performed at the University of Minho was funded by the European Regional Development Funds (FEDER), through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the project POCI-01-0145-FEDER-007038. This article was developed under the scope of the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Program (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the FEDER. This work was also supported by FCT and COMPETE through the projects [PTDC/SAU-GMG/112617/2009] (to P.M.) and [EXPL/BIM-MEC/ 0239/2012] (to A.T.C.); by FCT through the project [POCI-01-0145- FEDER-016818 (PTDC/NEU-NMC/3648/2014)] (to P.M.); by National Ataxia Foundation (to P.M. and to A.T.C.); and by Ataxia UK (to P.M.). S.D.S. and A.T.C. were supported by fellowships from FCT, SFRH/BD/ 78388/2011 and SFRH/BPD/102317/2014, respectively. FCT fellowships are co-financed by POPH, QREN, Governo da República Portuguesa and EU/FSE

Contrasting views on the role of mesenchymal stromal/stem cells in tumour growth : a systematic review of experimental design

The effect of mesenchymal stromal/stem cells (MSCs) on tumour growth remains controversial. Experimental evidence supports both an inhibitory and a stimulatory effect. We have assessed factors responsible for the contrasting effects of MSCs on tumour growth by doing a meta-analysis of existing literature between 2000 and May 2017. We assessed 183 original research articles comprising 338 experiments. We considered (a) in vivo and in vitro experiments, (b) whether in vivo studies were syngeneic or xenogeneic, and (c) if animals were immune competent or deficient. Furthermore, the sources and types of cancer cells and MSCs were considered together with modes of cancer induction and MSC administration. 56% of all 338 experiments reported that MSCs promote tumour growth. 78% and 79% of all experiments sourced human MSCs and cancer cells, respectively. MSCs were used in their naïve and engineered form in 86% and 14% of experiments, respectively, the latter to produce factors that could alter either their activity or that of the tumour. 53% of all experiments were conducted in vitro with 60% exposing cancer cells to MSCs via coculture. Of all in vivo experiments, 79% were xenogeneic and 63% were conducted in immune-competent animals. Tumour growth was inhibited in 80% of experiments that used umbilical cord-derived MSCs, whereas tumour growth was promoted in 64% and 57% of experiments that used bone marrow- and adipose tissue-derived MSCs, respectively. This contrasting effect of MSCs on tumour growth observed under different experimental conditions may reflect differences in experimental design. This analysis calls for careful consideration of experimental design given the large number of MSC clinical trials currently underway.The South African Medical Research Council in terms of the SAMRC’s Flagship Award Project SAMRC-RFA-UFSP-01-2013/STEM CELLS, the SAMRC Extramural Stem Cell Research and Therapy Unit, the National Research Foundation of South Africa (grant no. 86942), the National Health Laboratory Services Research Trust (grant no. 94453), the University of Pretoria Research Development Programme (A0Z778), the University of Pretoria Vice Chancellor’s Postdoctoral Fellowship and the Institute for Cellular and Molecular Medicine of the University of Pretoria.http://www.springer.comseries/5584hj2019ImmunologyOral Pathology and Oral Biolog

Interaktionen von Stammzellen und Tumorzellen unter Hypoxie

Einleitung: Die Interaktionen von Tumorzellen mit mesenchymalen Stammzellen (MSC) werden kontrovers diskutiert. Es werden v. a. proliferationsfördernde Eigenschaften von MSC auf Tumorzellen beschrieben. Untersuchungen zu derartigen Interaktionen finden üblicherweise unter Normoxie statt, obwohl innerhalb einer Tumorformation häufig hypoxische Bedingungen herrschen. Ziel dieser Arbeit war die Analyse der Interaktionen von MSC auf die Zelllinie FaDu unter Hypoxie. Methoden: MSC wurden bis zu 72 Stunden in Aerobiose und Anaerobiose kultiviert. Die so konditionierten Mediumüberstände wurden anschließend zur Kultivierung von FaDu-Zellen verwendet. Zielparameter waren die Morphologie, Vitalität, Proliferation und der Zellzyklus von MSC und FaDu-Zellen. Das durch MSC sezernierte Zytokinmuster wurde mit dem Dotblot-Assay bestimmt. Marker für die epithelial-mesenchymale Transition (EMT) wurden in der rt-PCR nachgewiesen.Ergebnisse: MSC zeigten unter Anaerobiose Zeichen von Autophagie sowie eine Proliferationshemmung. Vitalität und Proliferation von FaDu-Zellen waren bei Verwendung von Normoxie-MSC-Medium gesteigert, Hypoxie-Medium hatte keinen Einfluss auf das Wachstumsverhalten im Vergleich zur Kontrolle. Im Dotblot-Assay stellte sich IL-6 als ein Schlüsselzytokin dieser Interaktionen dar. Eine EMT von FaDu-Zellen findet unter Hypoxie nicht statt.Schlussfolgerungen: Die Interaktionen von Tumorzellen und MSC sind komplex und unterliegen verschiedenen Einflüssen. Unter Normoxie verhalten sich MSC gegenüber Tumorzellen deutlich unterschiedlich im Vergleich zur Hypoxie. Divergierende Aussagen in der Literatur können über derartige Phänomene erklärt werden. Weitere systematische Untersuchungen sind daher notwendig.Der Erstautor gibt keinen Interessenkonflikt an