mTert induction in p21-positive cells counteracts capillary rarefaction and pulmonary emphysema

Lung diseases develop when telomeres shorten beyond a critical point. We constructed a mouse model in which the catalytic subunit of telomerase (mTert), or its catalytically inactive form (mTert), is expressed from the p21 locus. Expression of either TERT or TERT reduces global p21 levels in the lungs of aged mice, highlighting TERT non-canonical function. However, only TERT reduces accumulation of very short telomeres, oxidative damage, endothelial cell (ECs) senescence and senile emphysema in aged mice. Single-cell analysis of the lung reveals that p21 (and hence TERT) is expressed mainly in the capillary ECs. We report that a fraction of capillary ECs marked by CD34 and endowed with proliferative capacity declines drastically with age, and this is counteracted by TERT but not TERT. Consistently, only TERT counteracts decline of capillary density. Natural aging effects are confirmed using the experimental model of emphysema induced by VEGFR2 inhibition and chronic hypoxia. We conclude that catalytically active TERT prevents exhaustion of the putative CD34 + EC progenitors with age, thus protecting against capillary vessel loss and pulmonary emphysema.Work in VG’s Lab is supported by “La Ligue Contre le Cancer”, Equipe Labellisée, The Canceropole PACA (Projet Emergent), the “Institut National du Cancer” (INCA), PLBIO 2019, and the cross-cutting Inserm program on aging (AGEMED). SA’s Lab is supported by grants from the Inserm, Ministère de la Recherche, Agence Nationale pour la Recherche (ANR), Institut National du Cancer (INCA), and Fondation pour la Recherche Médicale (FRM), et la Fondation ARC. AL-V’s lab is supported by INCa (PLBIO2019) and La Ligue contre le cancer-Paris (RS21/75-24). SC-A is a recipient of a European CO-FUND PhD fellowship from Institut Curie (European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 666003). IF’s lab was funded by grants from the Spanish Ministry of Science and Innovation (PID2019-110339RB-I00) and the Comunidad de Madrid (S2017/BMD-3875). EG’s lab was supported by the Fondation ARC (Program ARC), and the cross-cutting Inserm program on aging (AGEMED). CIPHE is supported by PHENOMIN (French National Infrastructure for mouse Phenogenomics; ANR10-INBS-07)

MTM1-mediated production of phosphatidylinositol 5-phosphate fuels the formation of podosome-like protrusions regulating myoblast fusion

International audienceMyogenesis is a multistep process that requires a spatiotemporal regulation of cell events resulting finally in myoblast fusion into multinucleated myotubes. Most major insights into the mechanisms underlying fusion seem to be conserved from insects to mammals and include the formation of podosome-like protrusions (PLPs) that exert a driving force toward the founder cell. However, the machinery that governs this process remains poorly understood. In this study, we demonstrate that MTM1 is the main enzyme responsible for the production of phosphatidylinositol 5-phosphate, which in turn fuels PI5P 4-kinase α to produce a minor and functional pool of phosphatidylinositol 4,5-bisphosphate that concentrates in PLPs containing the scaffolding protein Tks5, Dynamin-2, and the fusogenic protein Myomaker. Collectively, our data reveal a functional crosstalk between a PI-phosphatase and a PI-kinase in the regulation of PLP formation

Endothelial DLL4 Is an Adipose Depot–Specific Fasting Sensor Regulating Fatty Acid Fluxes

International audienceBackground: Adaptation of fat depots to change in fuel availability is critical for metabolic flexibility and cardiometabolic health. The mechanisms responsible for fat depot-specific lipid sensing and shuttling remain elusive. Adipose tissue microvascular endothelial cells (AT-EC) regulates bidirectional fatty acid fluxes depending on fed or fasted state. How AT-EC sense and adapt to metabolic changes according to AT location remains to be established. Methods: We combined transcriptional analysis of native human AT-EC together with in vitro approaches in primary human AT-EC and in vivo and ex vivo studies of mice under fed and fasted conditions. Results: Transcriptional large-scale analysis of human AT-EC isolated from gluteofemoral and abdominal subcutaneous AT revealed that the endothelium exhibits a fat depot–specific signature associated with lipid handling and Notch signaling enrichment. We uncovered a functional link between metabolic status and endothelial DLL4 (delta-like canonical notch ligand 4), which decreases with fasting. DLL4 regulates fatty acid uptake through nontranscriptional modulation of macropinocytosis-dependent long chain fatty acid uptake. Importantly, the changes in DLL4 expression, in response to energy transition state, is impaired under obesogenic conditions, an early alteration coinciding with a defect in systemic fatty acid fluxes adaptation and a resistance to weight loss. Conclusions: DLL4 is a major actor in the adaptive mechanisms of AT-EC to regulate lipid fluxes. It likely contributes to fat depot-dependent metabolism in response to energy transition states. AT-EC alteration with obesity may favor metabolic inflexibility and the development of cardiometabolic disorders

Advancing tools for human early lifecourse exposome research and translation (ATHLETE): Project overview

Early life stages are vulnerable to environmental hazards and present important windows of opportunity for lifelong disease prevention. This makes early life a relevant starting point for exposome studies. The Advancing Tools for Human Early Lifecourse Exposome Research and Translation (ATHLETE) project aims to develop a toolbox of exposome tools and a Europe-wide exposome cohort that will be used to systematically quantify the effects of a wide range of community- and individual-level environmental risk factors on mental, cardiometabolic, and respiratory health outcomes and associated biological pathways, longitudinally from early pregnancy through to adolescence. Exposome tool and data development include as follows: (1) a findable, accessible, interoperable, reusable (FAIR) data infrastructure for early life exposome cohort data, including 16 prospective birth cohorts in 11 European countries; (2) targeted and nontargeted approaches to measure a wide range of environmental exposures (urban, chemical, physical, behavioral, social); (3) advanced statistical and toxicological strategies to analyze complex multidimensional exposome data; (4) estimation of associations between the exposome and early organ development, health trajectories, and biological (metagenomic, metabolomic, epigenetic, aging, and stress) pathways; (5) intervention strategies to improve early life urban and chemical exposomes, co-produced with local communities; and (6) child health impacts and associated costs related to the exposome. Data, tools, and results will be assembled in an openly accessible toolbox, which will provide great opportunities for researchers, policymakers, and other stakeholders, beyond the duration of the project. ATHLETE's results will help to better understand and prevent health damage from environmental exposures and their mixtures from the earliest parts of the life course onward.ISGlobal acknowledges support from the Spanish Ministry of Science, Innovation and Universities through the “Centro de Excelencia Severo Ochoa 2019–2023” Program (CEX2018-000806-S) and support from the Generalitat de Catalunya through the Centres de Recerca de Catalunya Program. We acknowledge collaboration with European projects, specifically: Human Early Life Exposome (HELIX) (FP7 grant agreement number 308333), LifeCycle (H2020 grant agreement number 733206), and Connecting Europe and Canada in personalized health (EUCAN-Connect) (H2020 Grant Agreement number 824989). The Born in Bradford (BiB) cohort is only possible because of the enthusiasm and commitment of the Children and Parents in BiB. We are grateful to all the participants, health professionals, and researchers who have made BiB happen. The BiB cohort is only possible because of the enthusiasm and commitment of the children and parents in BiB. We are grateful to all the participants, health professionals, schools, and researchers who have made BiB happen. BiB has received funding from the Wellcome Trust (101597), a joint grant from the UK Medical Research Council and UK Economic and Social Science Research Council (MR/N024391/1), a British Heart Foundation Clinical Study grant (CS/16/4/32482). The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. We are grateful to all the participating families in Norway who take part in this ongoing cohort study. The Danish National Birth Cohort was established with a significant grant from the Danish National Research Foundation. Additional support was obtained from the Danish Regional Committees, the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Health Foundation, and other minor grants. The Danish National Birth Cohort Biobank has been supported by the Novo Nordisk Foundation and the Lundbeck Foundation. Follow-up of mothers and children have been supported by the Danish Medical Research Council (SSVF 0646, 271-08-0839/06-066023, O602-01042B, 0602-02738B); the Lundbeck Foundation (195/04, R100-A9193); The Innovation Fund Denmark 0603-00294B (09-067124); the Nordea Foundation (02-2013-2014); Aarhus Ideas (AU R9-A959-13-S804); University of Copenhagen Strategic Grant (IFSV 2012); and the Danish Council for Independent Research (DFF—4183-00594 and DFF—4183-00152). The general design of the Generation R Study is made possible by financial support from the Erasmus MC, University Medical Center, Rotterdam, Erasmus University Rotterdam, Netherlands Organization for Health Research and Development (ZonMw), Netherlands Organisation for Scientific Research (NWO), Ministry of Health, Welfare and Sport, and Ministry of Youth and Families. This project received funding from the European Union’s Horizon 2020 research and innovation programme (LIFECYCLE, grant agreement number 733206, 2016; EUCAN-Connect grant agreement number 824989; ATHLETE, grant agreement number 874583). We gratefully acknowledge the contribution of participants, research collaborators, general practitioners, hospitals, midwives, and pharmacies in Rotterdam. The INfancia y Medio Ambiente cohort (INMA) Sababell study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; PI041436; PI081151 incl. Fondo Europeo de Desarollo Regional (FEDER) funds; PI12/01890 incl. FEDER funds; CP13/00054 incl. FEDER funds; PI15/00118 incl. FEDER funds; CP16/00128 incl. FEDER funds; PI16/00118 incl. FEDER funds; PI16/00261 incl. FEDER funds; PI17/01340 incl. FEDER funds, PI18/00547 incl. FEDER funds, PI20/01695 incl. FEDER funds), Centro de Investigación Biomédica en Red - Epidemiología y Salud Pública (CIBERESP), Generalitat de Catalunya-Comissió Interdepartamental de Recerca i Innovació Tecnològia 1999SGR 00241, Generalitat de Catalunya-Agencia de Gestión de Ayudas Universitarias y de Investigación (2009 SGR 501, 2014 SGR 822), Fundació La Marató de TV3 (090430), Spanish Ministry of Economy and Competitiveness (SAF2012-32991 incl. FEDER funds), Agence Nationale de Securite Sanitaire de l’Alimentation de l’Environnement et du Travail (1262C0010; EST-2016 RF-21, EST-19 RF-04), and the European Commission (261357, 308333, 603794 and 634453). The INMA Valencia study was supported by grants from Instituto de Salud Carlos III (FIS-FEDER: 13/2032, 13/1944, 14/00891, 16/1288, 17/00663, and 19/1338; Miguel Servet-FSE: CP15/0025 and MSII16/00051, 00051, and MSII20/0006), Alicia Koplowitz Foundation 2017, Generalitat Valenciana (AICO/2020/285), and Spanish Association Against Cancer (AECC) “Seed Ideas” 2019 (IDEAS19098LOPE). INMA Gipuzkoa was funded by grants from Instituto de Salud Carlos III (FIS-PI06/0867, FIS-PI09/00090, FIS-PI13/02187, and FIS-PI18/01142 incl. FEDER funds), CIBERESP, Department of Health of the Basque Government (2005111093, 2009111069, 2013111089, and 2015111065), and the Provincial Government of Gipuzkoa (DFG06/002, DFG08/001, and DFG15/221) and annual agreements with the municipalities of the study area (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain). The Sepages cohort would like to thank the Grenoble University Hospital (CHU-GA) biobank (bb-0033-00069). We thank the Sepages Study group (E. Eyriey, P. Hoffmann, E. Hullo, J. Lepeule, C. Llerena, S. Lyon-Caen, X. Morin, A. Morlot, C. Philippat, I. Pin, J. Quentin, V. Siroux, R. Slama) and the participants of the Suivi de l’Exposition à la Pollution Atmosphérique durant la Grossesse et Effets sur la Santé (SEPAGES) study. We acknowledge support from Auvergne-Rhône-Alpes Région, Soutien aux coopérations universitaires et scientifiques internationales fund to support collaborations between Catalunya and Auvergne-Rhône-Alpes. SEPAGES cohort was supported by the European Research Council (consolidator grant N 311765-E-DOHaD, Principal Investigator [PI], R. Slama), by French National Research Agency (ANR), the ANR (Pregnancy, Air Pollution, Epigenetics and Respiratory health project ANR-12-PDOC-0029-01, PI, J. Lepeule; A Longitudinal Analysis of Effects of Early Life Exposure to Phenols on Health in Humans project, 14-CE21-0007-01, PI, R. Slama; Gut Microbiota in early childhood and Maternal Environmental exposures project, PI, R. Slama; Prenatal Exposure to Tobacco smoking and Air Pollution and Effects on offspring respiratory and neurodevelopmental outcomes ANR 18-CE36-005, PI, J. Lepeule). The Central European Longitudinal Study of Pregnacy and Childhood: The Next Generation (TNG) cohort is supported by the RECETOX research infrastructure (the Ministry of Education, Youth and Sports of the Czech Republic: LM2018121) and the CETOCOEN EXCELLENCE Teaming 2 project of European Union (EU) Horizon 2020 (857560) and the MEYS of the Czech Republic (02.1.01/0.0/0.0/18_ 046/0015975). The Barcelona Life Study Cohort has received funding from European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under grant agreement number (785994) (Prenatal exposure to urban air pollution and pre and post-natal brain development project) and from the Health Effects Institute (HEI) under Agreement number 4959-RFPA15-1/18-1 (FRONTIER project). Genotyping in the HELIX study was supported by project PI17/01225 (Instituto de Salud Carlos III, co-funded by European Union [European Regional Development Fund], “A way to make Europe”) and the Centro Nacional de Genotipado-CEGEN (PRB2-ISCIII). The Nascita e Infanzia: gli Effetti dell’Ambiente cohort was partially funded by the Compagnia SanPaolo Foundation and the Piedmont Region. The Piccolipiù project was funded by the Italian National Center for Disease Prevention and Control (National Centre for Disease Prevention and Control grants years 2010 and 2014) and by the Italian Ministry of Health (art 12 and 12 bis D.lgs 502/92). The Perturbateurs Endocriniens: Étude Longitudinale sur les Anomalies de la Grossesse, l’Infertilité et l’Enfance study is supported by National Institute of Health and Medical Research and has received multiple funds from the ANR, the French Agency for Food, Environmental and Occupational Health and Safety (ANSES), the Fondation de France, the National Institute for Public Health Surveillance (InVS), the French, Ministry of Labor, the French Ministry of Health, and the French Ministry of Ecology. DataSHIELD is funded under a group of projects that underpin a program of development and application of secure methods for co-analysis, data sharing, and visualization in the Population Health Sciences Institute at Newcastle University (United Kingdom). These include: the “Connected Health Cities project” (North East and North Cumbria) funded by the UK Department of Health (RES/0150/7943/202); the “EUCanConnect project” (European Commission H2020 Flagship Collaboration with Canada); the “58FORWARDS project” (Fostering new Opportunities for Researchers via Wider Access to Research Data and Samples) funded jointly by the Wellcome Trust and the Medical Research Council (108439/Z/15/Z); and the “METADAC project” (Managing Ethico-social, Technical and Administrative issues in Data ACcess) funded jointly by the Medical Research Council, the Wellcome Trust, and the Economic and Social Research Council (MR/N01104X/1 and MR/N01104X/2). We acknowledge the Molecular Genetics Information System team, including Fleur Kelpin, Tommy de Boer, Mariska Slofstra, Connor Stroomberg, Jelmer Veen, Jeroen van Veen, Fernanda de Andrade, Marije van der Geest, Dieuwke Roelofs-Prins, Dennis Hendriksen, Bart Charbon, Joeri van der Velde, Max Postema, Erik Schaberg, Christiaan Hilbrands, Alexander Kellmann, and Luuk Dijkhuis

Rapid screening of COVID-19 patients using white blood cell scattergrams, a study on 381 patients

International audienceComplementary tools are warranted to increase the sensitivity of the initial testing for COVID-19. We identified a specific ‘sandglass’ aspect on the white blood cell scattergram of COVID-19 patients reflecting the presence of circulating plasmacytoid lymphocytes. Patients were dichotomized as COVID-19-positive or -negative based on reverse transcriptase polymerase chain reaction (RT-PCR) and chest computed tomography (CT) scan results. Sensitivity and specificity of the ‘sandglass’ aspect were 85·9% and 83·5% respectively. The positive predictive value was 94·3%. Our findings provide a non-invasive and simple tool to quickly categorize symptomatic patients as either COVID-19-probable or -improbable especially when RT-PCR and/or chest CT are not rapidly available

Telomerase Prevents Emphysema in Old Mice by Sustaining Subpopulations of Endothelial and AT2 Cells

Abstract Accumulation of senescent cells has been causally linked to the development of age-related pathologies. Here, we characterized a new mouse model (p21 +/Tert ) whose telomerase (TERT) is expressed from the p21 promoter that can be activated in response to telomere dysfunction. Lung parenchyma from p21 +/Tert old mice accumulated fewer senescent cells with age and this correlated with a reduction in age-related alveolar space enlargement, a feature of pulmonary emphysema. This protection against emphysema depends on TERT catalytic activity and is associated with increased proliferation of pulmonary endothelial cells (EC) and capillary density. Single-cell RNA sequencing of lung cells revealed that TERT expression was associated with the enrichment of ECs expressing genes involved in vessel regeneration and in AT2 cells overexpressing S/G2M markers. These findings indicate that p21-promoter-dependent expression of catalytically active telomerase prevents emphysema by sustaining the proliferation of subclasses of EC and AT2 cells

Induction of telomerase in p21-positive cells counteracts capillaries rarefaction in aging mice lung

ABSTRACT Telomerase is required for long-term cell proliferation and linked to stem cells. This is evident in the lung where short telomeres are associated with lung dysfunction. We constructed a mouse model in which the telomerase ( Tert ) is expressed from the p21 Cdkn1a promoter. We found that this peculiar Tert expression curb age-related emphysema and pulmonary perivascular fibrosis in old mice. In old mice lungs, such Tert expression preferentially occurs in endothelial cells where it reduces the number of senescent endothelial cells. Remarkably, we report that Tert counteracts the age-related decline in capillary density. This was associated with an increased number of Cd34+ cells identified as a subclass of capillary cells with proliferative capacity. Expression of catalytically inactive Tert neither prevents the decline of capillary density in old mice nor protects against age-related emphysema and fibrosis. These findings reveal that telomerase decreases age-decline of pulmonary functions by sustaining microvasculature regeneration and outgrowth