Biology subjects

Geissmann, F.

Publications and source records attributed to Geissmann, F..

13 recordsLinked to original sources

bioRxiv2026

A comprehensive atlas of somatic mutation rates and mutational signatures in normal human cells

Over the course of a lifetime, somatic mutations accrue in normal human cells, causing variation in cell phenotype and engendering somatic evolution with outcomes ranging from the adaptive immune system to cancer. To inform understanding of somatic evolution in the human body we report the mutation rates and mutational signatures of 53 normal cell types. Most show evidence of linear mutation accumulation over time with single base substitution mutation rates ranging from ~3.5/year/diploid genome in spermatogonia and sperm, to ~20/year in postmitotic neurons, ~50/year in mitotically active colorectal epithelial cells, ~60/year in kidney proximal tubule cells and hepatocytes, 100s/year in sun-exposed skin epidermal cells and 10-50/year in the remainder. Certain cell types, including skin epidermis, cardiac myocytes, bladder urothelium, kidney proximal tubule cells, and hepatocytes, show substantial variability in mutation burdens around the linear age trend, indicating the influence of additional factors which differ between individuals and modulate mutation accumulation, including exogenous mutagen exposures. At least 18 single-base substitution and nine small insertion and deletion mutational signatures are present, some in all cell types, some in a subset and others in a single cell type. Known exogenous mutagen exposures and endogenous mutational processes account for some mutational signatures, but the origins and mechanisms underlying many are uncertain. This comprehensive survey of mutagenesis provides a foundation for understanding somatic evolution of human cell populations in health and disease.

genomics↗

bioRxiv2025

Human iPSC derived alveolar macrophages reveal macrophage subtype specific functions of itaconate in M. tuberculosis host defense

Mycobacterium tuberculosis (Mtb) must survive within multiple macrophage populations during infection, including alveolar macrophages (AM) and recruited inflammatory macrophages. In mice, itaconate, produced in macrophages by ACOD1 mediated decarboxylation of aconitate, has direct antimicrobial activity, modulates inflammatory cytokines, and is required for resistance to M. tuberculosis (Mtb) infection. The role of itaconate in human macrophages is less clear and whether itaconate mediates distinct effects in macrophage subtypes is unknown. Here, we investigated the role of itaconate in human iPSC-derived macrophages, either induced by GM-CSF to resemble alveolar macrophages (AM-Like cells), or treated with M-CSF to generate control macrophages (MCDM cells). Both types of human macrophages produce substantially less itaconate than mouse macrophages and AM-Ls produced 4-fold less itaconate than MCDMs. Surprisingly, ACOD1 deficient AM-L macrophages, but not MCDM macrophages, were permissive for Mtb growth. Moreover, itaconate functioned to dampen the Mtb induced inflammatory response in MCDMs, but not AM-L macrophages, affecting both the Type I IFN and TNF pathways. These results indicate that itaconate is involved in human macrophage responses to TB, with distinct roles in different macrophage subsets. These results also show that genetically tractable hiPSC-derived macrophages are a robust and versatile model to dissect cellular host pathogen interactions.

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

Mechanism of neurodegeneration mediated by clonal inflammatory microglia

Langerhans cell Histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders, associated with MAP-Kinase activating mutations and an increased risk of neurodegeneration. Surprisingly, we found pervasive PU.1+ microglia mutant clones across the brain of LCH and ECD patients with and without neurological symptoms, associated with microgliosis, reactive astrocytosis, and neuronal loss. The disease predominated in the grey nuclei of the rhombencephalon, a topography attributable to a local proliferative advantage of mutant microglia. Presence of clinical symptoms was associated with a longer evolution of the disease and a larger size of PU.1+ clones (p= 0.0003). Genetic lineage tracing of PU.1+ clones suggest a resident macrophage lineage or a bone marrow precursor origin depending on patients. Finally, a CSF1R-inhibitor depleted mutant microglia and limited neuronal loss in mice suggesting an alternative to MAPK inhibitors. These studies characterize a progressive neurodegenerative disease, caused by clonal proliferation of inflammatory microglia (CPIM), with a decade(s)-long preclinical stage of incipient disease that represent a therapeutic window for prevention of neuronal death.

immunology↗

bioRxiv2024

A microglia clonal inflammatory disorder in Alzheimer's Disease

Somatic genetic heterogeneity resulting from post-zygotic DNA mutations is widespread in human tissues and can cause diseases, however few studies have investigated its role in neurodegenerative processes such as Alzheimers Disease (AD). Here we report the selective enrichment of microglia clones carrying pathogenic variants, that are not present in neuronal, glia/stromal cells, or blood, from patients with AD in comparison to age-matched controls. Notably, microglia-specific AD-associated variants preferentially target the MAPK pathway, including recurrent CBL ring-domain mutations. These variants activate ERK and drive a microglia transcriptional program characterized by a strong neuro-inflammatory response, both in vitro and in patients. Although the natural history of AD-associated microglial clones is difficult to establish in human, microglial expression of a MAPK pathway activating variant was previously shown to cause neurodegeneration in mice, suggesting that AD-associated neuroinflammatory microglial clones may contribute to the neurodegenerative process in patients. One-Sentence SummaryA subset of Alzheimer Disease patients carry mutant microglia somatic clones which promote neuro-inflammation.

neuroscience↗

bioRxiv2023

Breast Cancer Macrophage Heterogeneity and Self-renewal are Determined by Spatial Localization

Tumor-infiltrating macrophages support critical steps in tumor progression, and their accumulation in the tumor microenvironment (TME) is associated with adverse outcomes and therapeutic resistance across human cancers. In the TME, macrophages adopt diverse phenotypic alterations, giving rise to heterogeneous immune activation states and induction of cell cycle. While the transcriptional profiles of these activation states are well-annotated across human cancers, the underlying signals that regulate macrophage heterogeneity and accumulation remain incompletely understood. Here, we leveraged a novel ex vivo organotypic TME (oTME) model of breast cancer, in vivo murine models, and human samples to map the determinants of functional heterogeneity of TME macrophages. We identified a subset of F4/80highSca-1+ self-renewing macrophages maintained by type-I interferon (IFN) signaling and requiring physical contact with cancer-associated fibroblasts. We discovered that the contact-dependent self-renewal of TME macrophages is mediated via Notch4, and its inhibition abrogated tumor growth of breast and ovarian carcinomas in vivo, as well as lung dissemination in a PDX model of triple-negative breast cancer (TNBC). Through spatial multi-omic profiling of protein markers and transcriptomes, we found that the localization of macrophages further dictates functionally distinct but reversible phenotypes, regardless of their ontogeny. Whereas immune-stimulatory macrophages (CD11C+CD86+) populated the tumor epithelial nests, the stroma-associated macrophages (SAMs) were proliferative, immunosuppressive (Sca-1+CD206+PD-L1+), resistant to CSF-1R depletion, and associated with worse patient outcomes. Notably, following cessation of CSF-1R depletion, macrophages rebounded primarily to the SAM phenotype, which was associated with accelerated growth of mammary tumors. Our work reveals the spatial determinants of macrophage heterogeneity in breast cancer and highlights the disruption of macrophage self-renewal as a potential new therapeutic strategy.

cancer biology↗

bioRxiv2023

Plasma membrane abundance dictates phagocytic capacity and functional crosstalk in myeloid cells

Professional phagocytes like neutrophils and macrophages tightly control what they eat, how much they eat, and when they move after eating. We show that plasma membrane abundance is a key arbiter of these cellular behaviors. Neutrophils and macrophages lacking the G-protein subunit G{beta}4 exhibit profound plasma membrane expansion due to enhanced production of sphingolipids. This increased membrane allocation dramatically enhances phagocytosis of bacteria, fungus, apoptotic corpses, and cancer cells. G{beta}4 deficient neutrophils are also defective in the normal inhibition of migration following cargo uptake. In G{beta}4 knockout mice, myeloid cells exhibit enhanced phagocytosis of inhaled fungal conidia in the lung but also increased trafficking of engulfed pathogens to other organs. These results reveal an unexpected, biophysical control mechanism lying at the heart of myeloid functional decision-making.

cell biology↗

bioRxiv2023

Distinct adrenal gland macrophages regulate corticosteroid production

The adrenal glands are hormone secreting glands that sit on top of the kidneys. Adrenal glands produce glucocorticoids, mineralocorticoids, and catecholamines, and are therefore critical regulators of the stress response, the immune response, metabolism, and blood pressure. Despite being identified for more that 30 years, our understanding of adrenal macrophages remains incomplete. In numerous other tissues, macrophages carry out a plethora of physiological and homeostatic roles in addition to their classical immune functions. The aim of this study was to characterise the macrophage compartment of the adrenal gland and assess its contribution to adrenal function. Using an in vivo approach, we herein describe two morphologically and spatially distinct subsets of adrenal macrophages - dendritic-like macrophages that are present throughout the gland in young and old mice, and "foamy" lipid-laden macrophages that accumulate in the murine adrenal cortex in an age and diet-dependent manner. Furthermore, we present data showing that these foamy-like macrophages accumulate cholesterol and thereby regulate adrenal hormonal output, at steady state and in the context of obesity. We hereby provide novel insights into the physiological roles of macrophages in the adrenal gland and the mechanisms by which adrenal hormone production is regulated.

immunology↗

bioRxiv2023

Early life high fructose exposure disrupts microglia function and impedes neurodevelopment

Despite the success of fructose as a low-cost food additive, recent epidemiological evidence suggests that high fructose consumption by pregnant mothers or during adolescence is associated with disrupted neurodevelopment1-7. An essential step in appropriate mammalian neurodevelopment is the synaptic pruning and elimination of newly-formed neurons by microglia, the central nervous systems (CNS) resident professional phagocyte8-10. Whether early life high fructose consumption affects microglia function and if this directly impacts neurodevelopment remains unknown. Here, we show that both offspring born to dams fed a high fructose diet and neonates exposed to high fructose exhibit decreased microglial density, increased uncleared apoptotic cells, and decreased synaptic pruning in vivo. Importantly, deletion of the high affinity fructose transporter SLC2A5 (GLUT5) in neonates completely reversed microglia dysfunction, suggesting that high fructose directly affects neonatal development. Mechanistically, we found that high fructose treatment of both mouse and human microglia suppresses synaptic pruning and phagocytosis capacity which is fully reversed in GLUT5-deficient microglia. Using a combination of in vivo and in vitro nuclear magnetic resonance- and mass spectrometry-based fructose tracing, we found that high fructose drives significant GLUT5-dependent fructose uptake and catabolism, rewiring microglia metabolism towards a hypo-phagocytic state. Importantly, mice exposed to high fructose as neonates exhibited cognitive defects and developed anxiety-like behavior which were rescued in GLUT5-deficient animals. Our findings provide a mechanistic explanation for the epidemiological observation that early life high fructose exposure is associated with increased prevalence of adolescent anxiety disorders.

immunology↗

bioRxiv2023

The macrophage genetic cassette inr/dtor/pvf2 is a nutritional status checkpoint for developmental timing.

A small number of signaling molecules, used reiteratively, control differentiation programs, but the mechanisms that adapt developmental timing to environmental cues are less understood. We report here that a macrophage inr/dtor/pvf2 genetic cassette is a developmental timing checkpoint in Drosophila, which either licenses or delays biosynthesis of the steroid hormone in the endocrine gland and metamorphosis according to the larval nutritional status. Insulin-Receptor/dTor signaling in macrophages is required and sufficient for production of the PDGF/VEGF family growth factor Pvf2, which turns on transcription of the sterol biosynthesis Halloween genes in the prothoracic gland via its receptor Pvr. In response to a starvation event or genetic manipulation, low Pvf2 signal delays steroid biosynthesis until it becomes Pvr-independent, thereby prolonging larval growth before pupation. The significance of this developmental timing checkpoint for host fitness is illustrated by the observation that it regulates the size of the pupae and adult flies. One sentence summaryA macrophage Inr/dtor/pvf2 cassette is a nutritional status checkpoint that controls developmental timing via steroid hormone biosynthesis in the endocrine gland.

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↗

bioRxiv2019

Blood cells of adult Drosophila do not expand, but control survival after bacterial infection by induction of Drosocin around their reservoir at the respiratory epithelia

Drosophila melanogaster has been an excellent model for innate immunity, but the role and regulation of adult blood cells and organismal immunity have remained incompletely understood. Here we address these questions in a comprehensive investigation of the blood cell system in adult Drosophila. As a central finding, we reveal the largest reservoir of blood cells (hemocytes) at the respiratory epithelia (tracheal air sacs) and fat body of the thorax and head. We show that most hemocytes of adult Drosophila are phagocytic macrophages (plasmatocytes), derived by more than 60% from the embryonic lineage that parallels vertebrate tissue macrophages. Surprisingly, in contrast to hemocytes at the larval stage, we find no capacity of the adult blood cell system to expand. Instead, we demonstrate its central role in relaying an innate immune response to tissues surrounding the blood cell reservoir: Hemocytes, through Imd signaling and the Jak/Stat pathway ligand Upd3, act as sentinels of bacterial infection that induce expression of the antimicrobial peptide gene Drosocin in the respiratory epithelia and colocalizing domains of the fat body. We demonstrate that endogenous Drosocin expression in these tissues promotes animal survival after bacterial infection. Our work identifies the first molecular step in a new relay of organismal immunity, establishing adult Drosophila as model to dissect mechanisms of inter-organ immunity.

immunology↗

bioRxiv2017

IRF4 haploinsufficiency in a family with Whipples disease

The pathogenesis of Whipples disease (WD) remains largely unknown, as WD strikes only a very small minority of the individuals infected with Tropheryma whipplei (Tw). Asymptomatic carriage of Tw is less rare. We studied a large multiplex French kindred, containing four otherwise healthy WD patients (mean age: 76.7 years) and five healthy carriers of Tw (mean age: 55 years). We used a strategy combining genome-wide linkage analysis and whole-exome sequencing to test the hypothesis that WD is inherited in an autosomal dominant (AD) manner, with age-dependent incomplete penetrance. WD was linked to 12 genomic regions covering 27 megabases in the four patients. These regions contained only one very rare non-synonymous variation: the R98W variant of IRF4. The five Tw carriers were heterozygous for R98W. Interferon regulatory factor 4 (IRF4) is a transcription factor with pleiotropic roles in immunity. We showed that R98W was a loss-of-function allele, like only five other exceedingly rare IRF4 alleles of a total of 39 rare and common non-synonymous alleles tested. Furthermore, heterozygosity for R98W led to a distinctive pattern of transcription in leukocytes following stimulation with BCG or Tw. Finally, we found that IRF4 had evolved under purifying selection and that R98W was not dominant-negative, suggesting that the IRF4 deficiency in this kindred was due to haploinsufficiency. Overall, haploinsufficiency at the IRF4 locus selectively underlies WD in this multiplex kindred. This deficiency displays AD inheritance with incomplete penetrance, and chronic carriage probably precedes WD by several decades in Tw-infected heterozygotes.

immunology↗