Haematopoietic stem cells in perisinusoidal niches are protected from ageing.

With ageing, intrinsic haematopoietic stem cell (HSC) activity decreases, resulting in impaired tissue homeostasis, reduced engraftment following transplantation and increased susceptibility to diseases. However, whether ageing also affects the HSC niche, and thereby impairs its capacity to support HSC function, is still widely debated. Here, by using in-vivo long-term label-retention assays we demonstrate that aged label-retaining HSCs, which are, in old mice, the most quiescent HSC subpopulation with the highest regenerative capacity and cellular polarity, reside predominantly in perisinusoidal niches. Furthermore, we demonstrate that sinusoidal niches are uniquely preserved in shape, morphology and number on ageing. Finally, we show that myeloablative chemotherapy can selectively disrupt aged sinusoidal niches in the long term, which is linked to the lack of recovery of endothelial Jag2 at sinusoids. Overall, our data characterize the functional alterations of the aged HSC niche and unveil that perisinusoidal niches are uniquely preserved and thereby protect HSCs from ageing

An open chat with… Cecília Maria Arraiano

Professor Cecília Maria Arraiano directs a research group named ‘Control of Gene Expression’ at Instituto de Tecnologia Química e Biológica, Universidade NOVA de Lisboa, Oeiras, Portugal. She started her scientific journey at the University of Lisbon, where she graduated in Biology, before completing her PhD in Genetics as a Fulbright‐Hays Fellow at the University of Georgia, Athens, USA. After a postdoc in the USA, she returned to Lisbon to establish her own lab. She has authored close to 200 publications mainly in the field of RNA degradation mechanisms, with a focus on enzymes and RNA chaperones that mediate RNA decay in microorganisms. She has received several prizes and is an active member of prestigious organizations. Namely, she is an EMBO member, Fellow of the European Academy of Microbiology, Fellow of the American Academy of Microbiology, and member of the Portuguese Academy of Sciences. In addition, Prof Arraiano has chaired the FEBS Working Group on Women in Science from 2014 to 2022. In this fascinating interview, she discusses her research, her experience working in the USA and Portugal, and the importance of initiatives to support women in science

Continuous mitotic activity of primitive hematopoietic stem cells in adult mice

The proliferative activity of aging hematopoietic stem cells (HSCs) is controversially discussed. Inducible fluorescent histone 2B fusion protein (H2B-FP) transgenic mice are important tools for tracking the mitotic history of murine HSCs in label dilution experiments. A recent study proposed that primitive HSCs symmetrically divide only four times to then enter permanent quiescence. We observed that background fluorescence due to leaky H2B-FP expression, occurring in all H2B-FP transgenes independent of label induction, accumulated with age in HSCs with high repopulation potential. We argue that this background had been misinterpreted as stable retention of induced label. We found cell division–independent half-lives of H2B-FPs to be short, which had led to overestimation of HSC divisional activity. Our data do not support abrupt entry of HSCs into permanent quiescence or sudden loss of regeneration potential after four divisions, but show that primitive HSCs of adult mice continue to cycle rarely

Somatic mutation rates scale with lifespan across mammals.

The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans1-7. Comparative analyses can shed light on the diversity of mutagenesis across species, and on long-standing hypotheses about the evolution of somatic mutation rates and their role in cancer and ageing. Here we performed whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. We found that somatic mutagenesis was dominated by seemingly endogenous mutational processes in all species, including 5-methylcytosine deamination and oxidative damage. With some differences, mutational signatures in other species resembled those described in humans8, although the relative contribution of each signature varied across species. Notably, the somatic mutation rate per year varied greatly across species and exhibited a strong inverse relationship with species lifespan, with no other life-history trait studied showing a comparable association. Despite widely different life histories among the species we examined-including variation of around 30-fold in lifespan and around 40,000-fold in body mass-the somatic mutation burden at the end of lifespan varied only by a factor of around 3. These data unveil common mutational processes across mammals, and suggest that somatic mutation rates are evolutionarily constrained and may be a contributing factor in ageing

MPN patients harbor recurrent truncating mutations in transcription factor NF-E2

Item does not contain fulltextThe molecular etiology of myeloproliferative neoplasms (MPNs) remains incompletely understood, despite recent advances incurred through the discovery of several different mutations in MPN patients. We have recently described overexpression of the transcription factor NF-E2 in MPN patients and shown that elevated NF-E2 levels in vivo cause an MPN phenotype and predispose to leukemic transformation in transgenic mice. We report the presence of acquired insertion and deletion mutations in the NF-E2 gene in MPN patients. These result in truncated NF-E2 proteins that enhance wild-type (WT) NF-E2 function and cause erythrocytosis and thrombocytosis in a murine model. NF-E2 mutant cells acquire a proliferative advantage, witnessed by clonal dominance over WT NF-E2 cells in MPN patients. Our data underscore the role of increased NF-E2 activity in the pathophysiology of MPNs

Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer

Non-alcoholic fatty liver disease ranges from steatosis to non-alcoholic steatohepatitis (NASH), potentially progressing to cirrhosis and hepatocellular carcinoma (HCC). Here, we show that platelet number, platelet activation and platelet aggregation are increased in NASH but not in steatosis or insulin resistance. Antiplatelet therapy (APT; aspirin/clopidogrel, ticagrelor) but not nonsteroidal anti-inflammatory drug (NSAID) treatment with sulindac prevented NASH and subsequent HCC development. Intravital microscopy showed that liver colonization by platelets depended primarily on Kupffer cells at early and late stages of NASH, involving hyaluronan-CD44 binding. APT reduced intrahepatic platelet accumulation and the frequency of platelet-immune cell interaction, thereby limiting hepatic immune cell trafficking. Consequently, intrahepatic cytokine and chemokine release, macrovesicular steatosis and liver damage were attenuated. Platelet cargo, platelet adhesion and platelet activation but not platelet aggregation were identified as pivotal for NASH and subsequent hepatocarcinogenesis. In particular, platelet-derived GPIbα proved critical for development of NASH and subsequent HCC, independent of its reported cognate ligands vWF, P-selectin or Mac-1, offering a potential target against NASH.We thank D. Heide, J. Hetzer, R. Hillermann, C. Gropp, F. Muller, S. Prokosch, D. Kull, R. Dunkl, O. Seelbach, M. Bawohl, R. Maire, M. Bieri, C. Mittmann, H. HoncharovaBiletska, A. Fitsche, A. Adili, P. Munzer, T. Nussbaumer, F. Prutek, G. Dharmalingam and I. Singh for excellent technical assistance. We thank K. Nikolaou for the help with the human cohort recruitment and analysis. M. Malehmir was partially supported by grants from the University Zurich (Zurich Integrative Human Physiology (ZHIP) Sprint Fellowship) and from the Hartmann Muller Stiftung, Zurich. A.W. was supported by a grant from the Swiss National Science Foundation (320030_182764/1). M. Heikenwaelder was supported by an ERC Consolidator grant (HepatoMetaboPath), an EOS grant, SFBTR 209, SFBTR179, Research Foundation Flanders (FWO) under grant 30826052 (EOS Convention MODEL-IDI), Deutsche Krebshilfe projects 70113166 and 70113167, and the Helmholtz-Gemeinschaft, Zukunftsthema 'Immunology and Inflammation' (ZT-0027). This project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement 667273 and the DFG (SFB/TR 240 (project 374031971) to B.N. and D. S.), ERC Consolidator grant 'CholangioConcept' (to L.Z.), and the German Research Foundation (DFG): grants FOR2314, SFB685 and the Gottfried Wilhelm Leibniz Program (to L.Z.). Further funding was provided by the German Ministry for Education and Research (BMBF) (eMed/Multiscale HCC), the German Universities Excellence Initiative (third funding line: 'future concept'), the German Center for Translational Cancer Research (DKTK) and the German-Israeli Cooperation in Cancer Research (DKFZ-MOST) (to L.Z. and M. Heikenwaelder). D. I. was supported by an EMBO Long-term Fellowship. J.M.L. is supported by Asociacion Espanola Contra el Cancer (Accelerator award: HUNTER), Spanish National Health Institute (SAF2013-41027), Generalitat de Catalunya (SGR 1162 and AGAUR, SGR-1358), the Samuel Waxman Cancer Research Foundation, the US Department of Defense (CA150272P3), the European Commission Horizon 2020 Program (HEPCAR, proposal number 667273-2), and the National Cancer Institute (P30 CA196521). D. A. M. is supported by CRUK grant C18342/A23390 and MRC grant MR/K001949/1. M. P. is supported by the German Research Foundation (DFG). M. G., T. G. and D. R. was supported by grants from the German Research Foundation (KFO274 and SFB/TR240 (project 374031971)). D. J. W. received a Wellcome Trust Strategic Award (098565/Z/12/Z) and funding from the Medical Research Council (MC-A654-5QB40). C.L.W. was funded by CRUK project Cancer Research UK Programme Grant C18342/A23390. H. G. A. has been supported by the Deutsche Forschungsgemeinschaft (SFB-TR209 'Liver Cancer').S