Biology subjects

Mass, E.

Publications and source records attributed to Mass, E..

15 recordsLinked to original sources

bioRxiv2026

Ferroptosis is a Physiologic Vulnerability of Iron-Recycling Macrophages

Iron deficiency anemia affects one-third of the global human population. Paradoxically, the daily iron required to fuel the production red blood cell (RBC) and prevent anemia is provided through its recycling from senescent RBC. This is achieved by splenic red pulp macrophages (RPM) that extract iron from the heme groups of hemoglobin (Hb). How these professional erythrophagocytic macrophages prevent intracellular iron flux from inducing cell death via ferroptosis is unknown. Here we show that SPI-C, the master transcriptional regulator of the erythrophagocytic lineage, orchestrates two redundant anti-ferroptosis pathways. One supports glutathione synthesis, via NF-E2-related factor 2 (NRF2), and the other relies on bilirubin production by biliverdin reductase A (BVRA). Genetic ablation of both pathways, but not either alone, sensitizes erythrophagocytic macrophages to ferroptosis, depletes RPM and increases the severity of iron deficiency anemia in mice. These findings reveal a central physiologic role of ferroptosis in the control of macrophage function, iron homeostasis and iron-deficiency anemia. HighlightsO_LISPI-C enforces the antioxidant metabolic program of RPM. C_LIO_LISPI-C controls bilirubin production by biliverdin reductase A. C_LIO_LIBilirubin protects erythrophagocytic macrophages from ferroptosis. C_LIO_LIFerroptosis protection supports iron-recycling macrophages and limit iron deficiency anemia. C_LI

immunology↗

bioRxiv2026

Macrophage renewal in the small intestine governs early-life control of streptococci

Group B Streptococcus (GBS) is both a common intestinal colonizer that is transmitted intergenerationally, and a primary cause of neonatal sepsis worldwide. However, the innate immune mechanisms that restrict the pathogen at the intestinal barrier early in life remain poorly understood. Using an enteral GBS-colonization model in infant mice, we found that lamina-propria (LP) macrophages controlled both GBS-colonization densities and invasion in an age-dependent fashion. LP macrophages turnover and differentiation were strongly impacted by topology. In the small intestine, monocytes infiltration of the LP occurred from birth on in response to perinatally acquired microbiota, whereas in the colon it was driven by the weaning reaction. Moreover, macrophages of the small intestine mounted a robust, MyD88-dependent inflammatory response to GBS, while those of the colon remained largely unaffected. Together, these findings demonstrate that region-specific macrophage dynamics early in life critically influence host-pathogen-interactions during GBS-colonization.

immunology↗

bioRxiv2025

Kupffer cells control neonatal hepatic metabolism via Igf1 signaling

During perinatal development, liver metabolism is tightly regulated to ensure energy supply for the newborn. Before birth, glycogen is stored in hepatocytes and later metabolized to glucose, meeting the energy demands of the neonate. Shortly after birth, lipogenesis begins, driven by the transcriptional activation of enzymes involved in fatty acid oxidation. These processes are thought to be largely regulated by systemic insulin and glucagon levels. However, the role of liver-derived local factors in neonatal hepatocyte metabolism remains unexplored. Kupffer cells (KCs), the livers resident macrophages, colonize the fetal liver early in embryogenesis and support liver metabolism in adulthood. Yet, whether KCs influence neonatal hepatocyte metabolism is unknown. Here, using conditional knockout mouse models targeting macrophages, we demonstrate that yolk sac-derived KCs play a critical role in hepatocyte glycogen storage and function by regulating the tricarboxylic acid (TCA) cycle - a role that monocyte-derived KC-like cells cannot substitute. Newborn pups lacking yolk sac-derived KCs mobilize glycogen more rapidly, a process regulated by insulin-like growth factor 1 (Igf1) production. Our findings reveal that macrophages are a major source of Igf1 at birth and that local Igf1 production by KCs is essential for balanced hepatocyte metabolism.

developmental biology↗

bioRxiv2024

CD226+ adipose tissue macrophages arise from MDP-derived monocytes and regulate lipid metabolism.

Macrophages are innate immune cells present in all tissues, in which they participate in immune responses and maintenance of tissue homeostasis. They develop either from embryonic precursors or from circulating monocytes, and their origin impacts their functions. We previously observed robust recruitment of monocytes to brown adipose tissue in which they could differentiation into two distinct macrophage subsets identifiable by CD206 or CD226 expression. In the present study, we investigated monocyte differentiation pathways in brown adipose tissue and the function of monocyte-derived macrophages. Fate mapping analysis revealed a low contribution of GMP- and a high contribution of MDP-derived monocytes to the CD226high macrophage subset. Importantly, adoptive transfer experiments demonstrate that MDP- but not GMP-derived monocytes are pre-conditioned to give rise to CD226high macrophages. We found that MDP-derived CD226high macrophages were also present in other tissues including peritoneal cavity, adrenal glands and all adipose depots. CD226high macrophages were regulated by both GM-CSF and CSF1R. Genetic depletion of CD226high macrophages caused increased BAT and plasma triglyceride content. We thus identify CD226high MDP-derived macrophages as a new myeloid cell type conserved across tissues and tied to lipid metabolism homeostasis.

immunology↗

bioRxiv2024

cOmicsArt - a customizable Omics Analysis and reporting tool

MotivationThe availability of bulk-omic data is steadily increasing, necessitating collaborative efforts between experimental and computational researchers. While software tools with graphical user interfaces (GUIs) enable rapid and interactive data assessment, they are limited to pre-implemented methods, often requiring transitions to custom code for further adjustments. However, most available tools lack GUI-independent reproducibility such as direct integration with R, resulting in very limited support for transition. ResultsWe introduce the customizable Omics Analysis and reporting tool - cOmicsArt. cOmicsArt aims to enhance collaboration through integration of GUI-based analysis with R. The GUI allows researchers to perform user-friendly exploratory and statistical analyses with interactive visualizations and automatic documentation. Downloadable R scripts and results ensure reproducibility and seamless integration with R, supporting both novice and experienced programmers by enabling easy customizations and serving as a foundation for more advanced analyses. This versatility also allows for usage in educational settings guiding students from GUI-based analysis to R Code. AvailabilitycOmicsArt is freely available at https://shiny.iaas.uni-bonn.de/cOmicsArt/ User documentation is available at https://icb-dcm.github.io/cOmicsArt/ Source code is available on GitHub https://github.com/ICB-DCM/cOmicsArt A docker image can be retrieved from https://hub.docker.com/r/pauljonasjost/comicsart/tags A snapshot upon publication can be found on Zenodo: https://zenodo.org/records/13740904 A screen recording of cOmicsArt is available at: https://www.youtube.com/watch?v=pTGjtIYQOakp Contactjan.hasenauer@uni-bonn.de Supplementary informationSupplementary data are available online.

bioinformatics↗

bioRxiv2024

Disease-associated microglia and activation of CD8+ T cells precede neuronal cell loss in a model of hereditary spastic paraplegia

In central nervous system (CNS) diseases characterized by late-onset neurodegeneration, the interplay between innate and adaptive immune responses remains poorly understood. This knowledge gap is amplified by the prolonged nature of these diseases, complicating the delineation of brain-resident and infiltrating cells. Here, we conducted a comprehensive profiling of innate and adaptive immune cells across various CNS regions in a murine model of spastic paraplegia 15 (SPG15), a complicated form of hereditary spastic paraplegia (HSP). Using fate-mapping of bone marrow-derived cells via genetic labeling, we identified microgliosis and microglial MHC-II upregulation accompanied by infiltration and local expansion of T cells in the CNS of Spg15-/- mice. Single-cell analysis revealed an increase of disease-associated microglia (DAM) and clonal expansion of effector CD8+ T cells across CNS regions occurring prior to neuronal loss. Analysis of potential cell-cell communication pathways suggested bidirectional interactions between DAM and effector CD8+ T cells potentially contributing to disease progression in Spg15-/- mice. In summary, we identified a shift in microglial phenotypes associated with recruitment and clonal expansion of T cells as a new characteristic of Spg15-driven neuropathology. Targeting activated microglia, CD8+ T cells and their communication represent promising avenues to prevent the loss of neuronal function in HSP.

immunology↗

bioRxiv2024

Identification of a mesodermal progenitor for the pro-definitive angio-hematopoietic lineage

Mammalian hematopoietic cells arise from mesodermal progenitors in a close developmental relationship with endothelium, and along three distinct cell lineages known as primitive, pro-definitive, and definitive hematopoiesis. However, the developmental hierarchy between mesodermal progenitors, endothelium, and blood cell lineages is incompletely understood. We report here the identification in mouse gastrula and human (h)iPSC cultures of a population of CXCR4+ primitive streak stage mesodermal progenitors that give rise to yolk sac endothelium, blood islands, yolk sac hematopoiesis, and resident macrophages, corresponding to the pro-definitive lineage. Strikingy, this progenitor does not give rise to primitive erythropoiesis or to caudal endothelium and definitive hematopoiesis. Interestingly however, the pro-definitive progenitor population also gives rise to rostral endothelium that persists in adults. Finally, pro-definitive progenitor-derived endothelium is the first and main source of macrophages in embryo and hiPSC cultures, both directly and via previously described multipotent Erythro-Myeloid Progenitors. The identification and isolation of this mesodermal progenitor defines a revised pro-definitive angio-hematopoietic lineage and provides a framework for resident macrophage and endothelial differentiation relevant to disease pathophysiology and their manipulation for therapeutic purposes. One sentence summaryIdentification in gastrulating embryo and hiPSC cultures of a mesodermal progenitor for yolk sac and rostral endothelial cells, early macrophages, and Erythro-Myeloid Progenitors characterize pro-definitive hematopoiesis and provide a revised framework for early angio-hematopoietic development. Graphical abstractSchematic represents the progeny of angio-hematopoietic progenitors at the posterior primitive streak. Developmental timing of CXCR4 expression distinguishes i) CXCR4- primitive hematopoiesis, ii) Early CXCR4+ angio-hematopoietic progenitors (EXAP) (purple) which express CXCR4 between E6.5 and E7.5 and give rise to rostral vessels and resident macrophages through YS hemogenic endothelium, and iii) late CXCR4+ intraembryonic angio-hematopoietic progenitors (blue) which acquire expression of CXCR4 around E8 and give rise to definitive hematopoiesis through an intraembryonic hemogenic endothelium. Abbreviations: E (Mouse Embryonic Day); YS (Yolk Sac); Hemog. (Hemogenic); Endo. (Endothelium); Defi. (Definitive). O_FIG O_LINKSMALLFIG WIDTH=165 HEIGHT=200 SRC="FIGDIR/small/609533v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@afb5fdorg.highwire.dtl.DTLVardef@1d4f772org.highwire.dtl.DTLVardef@c173d9org.highwire.dtl.DTLVardef@9cc17d_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Dysregulation of gene expression during gastrulation results in impaired primitive erythropoiesis and vascular development in Trim71-KO embryos

The transition of an embryo from gastrulation to organogenesis requires precisely coordinated changes in gene expression. The RNA-binding protein Trim71 is essential for embryonic survival, but its exact role in mammalian development in vivo remains poorly defined. Here we show that murine Trim71-KO embryos appear normal until embryonic day (E)8.5 but display severe defects in primitive erythropoiesis, yolk sac vasculature and heart function during the onset of organogenesis at E9.5 and E10.5. This led to an impaired vascular translocation of yolk sac-derived macrophage progenitors to the embryo head, independent of Trim71 expression in erythro-myeloid progenitors. The cardiovascular and erythropoiesis defects explain the embryonic lethality upon global Trim71-KO. Targeting Trim71 in hematoendothelial progenitors did not induce strong developmental defects, indicating an earlier developmental origin of these phenotypes in Trim71-KO embryos. ScRNA-seq of E7.5 Trim71-KO embryos revealed that transcriptomic changes arise already at gastrulation, showing a strong upregulation of the transcription factor Eomes. We identify Eomes as a direct target of Trim71-mediated mRNA repression via the NHL domain, demonstrating a functional link of Trim71 to a key regulator of mesodermal development. Taken together, our data suggest that Trim71-dependent control of gene expression at gastrulation establishes a framework for proper development during organogenesis.

developmental biology↗

bioRxiv2024

From Planning Stage To FAIR Data: A Practical Metadatasheet For Biomedical Scientists

Datasets consist of measurement data and metadata. Metadata provides context, essential for understanding and (re-)using data. Various metadata standards exist for different methods, systems and contexts. However, relevant information resides at differing stages across the data-lifecycle. Often, this information is defined and standardized only at publication stage, which can lead to data loss and workload increase. In this study, we developed Metadatasheet, a metadata standard based on interviews with members of two biomedical consortia and systematic screening of data repositories. It aligns with the data-lifecycle allowing synchronous metadata recording within Microsoft Excel, a widespread data recording software. Additionally, we provide an implementation, the Metadata Workbook, that offers user-friendly features like automation, dynamic adaption, metadata integrity checks, and export options for various metadata standards. By design and due to its extensive documentation, the proposed metadata standard simplifies recording and structuring of metadata for biomedical scientists, promoting practicality and convenience in data management. This framework can accelerate scientific progress by enhancing collaboration and knowledge transfer throughout the intermediate steps of data creation.

bioinformatics↗

bioRxiv2024

BBSome-dependent ciliary Hedgehog signaling governs cell fate in the white adipose tissue

The primary cilium has emerged as critical in regulating whole-body energy metabolism, as reflected in the Bardet-Biedl syndrome (BBS), where primary cilia dysfunction leads to obesity due to hyperphagia and white adipose tissue (WAT) remodeling. The regulation of cell fate and differentiation of adipocyte precursor cells (APCs) is key to maintaining WAT homeostasis during obesity. Using mice that recapitulated the BBS patient phenotype (Bbs8-/-), we demonstrate that primary cilia dysfunction reduces the stem-cell-like P1 APC subpopulation by inducing a phenotypic switch into a fibrogenic progenitor state, characterized by extracellular matrix (ECM) remodeling and upregulation of CD9. Single-cell RNA sequencing revealed a direct transition of stem-cell-like P1 cells into fibrogenic progenitors, bypassing the committed P2 cells. Ectopic ciliary Hedgehog signaling upon loss of BBS8 emerged as a central driver of the molecular changes in Bbs8-/- APCs, altering differentiation into adipocytes and lipid uptake. These findings unravel a novel role for primary cilia in governing APC fate, determining the delicate balance between adipogenesis and fibrogenesis. The identified molecular mechanisms provide insights into potential therapeutic targets for obesity.

cell biology↗

bioRxiv2023

Fetal liver macrophages contribute to the hematopoietic stem cell niche by controlling granulopoiesis

During embryogenesis, the fetal liver becomes the main hematopoietic organ, where stem and progenitor cells as well as immature and mature immune cells form an intricate cellular network. Hematopoietic stem cells (HSCs) reside in a specialized niche, which is essential for their proliferation and differentiation. However, the cellular and molecular determinants contributing to this fetal HSC niche remain largely unknown. Macrophages are the first differentiated hematopoietic cells found in the developing liver, where they are important for fetal erythropoiesis by promoting erythrocyte maturation and phagocytosing expelled nuclei. Yet, whether macrophages play a role in fetal hematopoiesis beyond serving as a niche for maturing erythroblasts remains elusive. Here, we investigate the heterogeneity of macrophage populations in the fetal liver to define their specific roles during hematopoiesis. Using a single-cell omics approach combined with spatial proteomics and genetic fate-mapping models, we found that fetal liver macrophages cluster into distinct yolk sac-derived subpopulations and that long-term HSCs are interacting preferentially with one of the macrophage subpopulations. Fetal livers lacking macrophages show a delay in erythropoiesis and have an increased number of granulocytes, which can be attributed to transcriptional reprogramming and altered differentiation potential of long-term HSCs. Together, our data provide a detailed map of fetal liver macrophage subpopulations and implicate macrophages as part of the fetal HSC niche.

developmental biology↗

bioRxiv2022

GPR183 targets lung-resident CD301b+ conventional dendritic cells type 2 to a subtissular TSLP-TSLP receptor-mediated survival niche within the adventitial cuff

Conventional dendritic cells (cDCs) are strategically localized throughout non-lymphoid tissues. How such spatially regulated subtissular placement is achieved remains largely elusive. Here, we reveal that GPR183 targets CD301b+ cDC2 to a TSLP-dependent survival niche within the adventital cuff. We identified a close association of CD301b+ cDC2 with PDGFR+ fibroblasts within the adventitial region of the lung. Genetic ablation of GPR183 within the cDC lineage leads to a selective loss of CD301b+ cDC2 in conjunction with the loss of CD301b+ cDC2 : fibroblast colocalization. Next bone marrow chimeric experiments and expression studies suggested adventitial fibroblasts as the main source of 7,25 hydroxycholesterol, the natural ligand of GPR183. Single cell transcriptomic receptor ligand inference and subsequent genetic validation revealed TSLP receptor signalling as a crucial fibroblast derived CD301b+ cDC2 survival factor. These data expose a subtissular localization mechanism for tissue-specific functionalization of CD301b+ cDC2.

immunology↗

bioRxiv2020

Resident macrophages establish and control lipid stores via PDGFcc production

Macrophages control inflammation in obese animals, and may also directly or indirectly regulate energy storage. In a genetic screen we identify a PDGF-family growth factor, Pvf3, produced by macrophages and required for lipid storage in Drosophila larvaes fat body cells. We next demonstrate using genetic and pharmacological approaches that Pvf3 ortholog PDGFcc, produced by Ccr2-independent embryo-derived tissue macrophages, is also required for storage in mammalian white adipose tissue. PDGFcc production by resident macrophages is regulated by diet, acts on white adipocytes in a paracrine manner, and controls adipocyte hypertrophy in high-fat diet fed and genetically hyperphagic mice. Upon PDGFcc blockade, excess lipids are redirected at the organismal level toward thermogenesis and hepatic storage in adults. This process is altogether independent from inflammation and insulin resistance promoted by Ccr2-dependent monocytes/macrophages. Our data identify a conserved macrophagedependent mechanism that controls energy storage, conducive to the design of pharmacological interventions.

immunology↗

bioRxiv2020

Creld2 function during unfolded protein response is essential for liver metabolism homeostasis

The unfolded protein response (UPR) is associated with the hepatic metabolic function, yet it is not well understood how endoplasmic reticulum (ER) disturbance might influence metabolic homeostasis. Here, we describe the physiological function of Cysteine-rich with EGF-like domains 2 (Creld2), previously characterized as a downstream target of the ER-stress signal transducer Atf6. To this end we generated Creld2-deficient mice and induced UPR by injection of tunicamycin. Creld2 augments protein folding and creates an interlink between the UPR axes through its interaction with proteins involved in UPR. Thereby, Creld2 promotes tolerance to ER stress and recovery from acute stress. Creld2-deficiency leads to a dysregulated UPR, and causes the development of hepatic steatosis during ER stress conditions. Moreover, Creld2 enhancement of the UPR assists in the regulation of energy expenditure. Furthermore, we observed a sex dimorphism in humans with fatty liver disease, with only males showing an accumulation of CRELD2 protein in the liver. These results reveal a Creld2 function at the intersection between UPR and metabolic homeostasis and suggest a mechanism in which chronic ER stress underlies fatty liver disease in males.

molecular biology↗

bioRxiv2019

Genetic inhibition of PCSK9, atherogenic lipoprotein concentrations, and calcific aortic valve stenosis

BackgroundProprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition reduces plasma concentrations of low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apoB) and lipoprotein(a) [Lp(a)]. Atherogenic lipoprotein levels have been linked with calcific aortic valve stenosis (CAVS). Our objectives were to determine the association between variants in PCSK9 and lipoprotein-lipid levels, coronary artery disease (CAD) and CAVS, and to evaluate if PCSK9 could be implicated in aortic valve interstitial cells (VICs) calcification. MethodsWe built a genetic risk score weight for LDL-C levels (wGRS) using 10 independent PCSK9 single nucleotide polymorphisms and determined its association with lipoprotein-lipid levels in 9692 participants of the EPIC-Norfolk study. We investigated the association between the wGRS and CAD and CAVS in the UK Biobank, as well as the association between the PCSK9 R46L variant and CAVS in a meta-analysis of published prospective, population-based studies (Copenhagen studies, 1463 cases/101,620 controls) and unpublished studies (UK Biobank, 1350 cases/349,043 controls, Malmo Diet and Cancer study, 682 cases/5963 controls and EPIC-Norfolk study, 508 cases/20,421 controls). We evaluated PCSK9 expression and localization in explanted aortic valves by capillary Western blot and immunohistochemistry in patients with and without CAVS. Von Kossa staining was used to visualize aortic leaflet calcium deposits. PCSK9 expression under oxidative stress conditions in VICs was assessed. ResultsThe wGRS was significantly associated with lower LDL-C and apoB (p<0.001), but not with Lp(a). In the UK Biobank, the association of PCSK9 variants with CAD were positively correlated with their effects on apoB levels. CAVS was less prevalent in carriers of the PCSK9 R46L variant [odds ratio=0.71 (95% confidence interval, 0.57-0.88), p<0.001]. PCSK9 expression was elevated in the aortic valves of patients with aortic sclerosis and CAVS compared to controls. In calcified leaflets, PCSK9 co-localized with calcium deposits. PCSK9 expression was induced by oxidative stress in VICs. ConclusionGenetic inhibition of PCSK9 is associated with lifelong reductions in the levels of non-Lp(a) apoB-containing lipoproteins as well as lower odds of CAD and CAVS. PCSK9 is abundant in fibrotic and calcified aortic leaflets. Oxidative stress increases PCSK9 expression in VICs. These results provide a rationale for performing randomized clinical trials of PCSK9 inhibition in CAVS.

genetics↗