Biology subjects

Gomez-Perdiguero, E.

Publications and source records attributed to Gomez-Perdiguero, E..

7 recordsLinked to original sources

bioRxiv2025

Ontogeny drives stage-specific effects of a Gata1 mutation

The biography of an organism, including, for instance, its genetic background and exposure to environmental influences, determines the penetrance and expressivity of monogenic diseases between individuals. This also applies at the single-cell level. Interestingly, mature blood and immune cells originate from anatomically and temporally distinct stem and progenitor populations at different stages of development. Here we show that the ontogeny or progenitor origin of megakaryocytes determines their developmental trajectory at the cellular and transcriptional level. As a result, a mutation in the key transcription factor Gata1 dysregulates megakaryopoiesis in an ontogeny-specific manner causing a stage-specific disorder. Particularly, only early extraembryonic hematopoietic progenitors drive blast-like cell development leading to a transient accumulation of megakaryocytes in the fetus but not in the adult. Therefore, pediatric blood disorders may differ functionally from adult diseases due to changing progenitor sources of mature blood and immune cells throughout development. HighlightsO_LIFetal and adult megakaryopoiesis pass through distinct immunophenotypic stages C_LIO_LIOntogeny of megakaryocytes dictates their unique transcriptional trajectory C_LIO_LIProgenitor origin rather than the differentiation pathway determines the effect of mutant Gata1 C_LIO_LIBlock in maturation at the progenitor level causes the accumulation of yolk sac-derived megakaryocytes in the presence of mutant Gata1 C_LIO_LIMutant Gata1 drives blast cell formation exclusively in yolk sac-derived lineages C_LI

developmental biology↗

bioRxiv2025

Distinct origin and fate for fetal hematopoietic progenitors

It was proposed that two sequential sources of intraembryonic multipotent progenitors ensure blood cell production from late gestation into adulthood, with only the latter producing self-renewing hematopoietic stem cells (HSC). How these two populations differ and how they impact the establishment of the postnatal immune system, remains poorly understood. Using complementary lineage tracing models, we showed that the first emerging embryonic multipotent progenitors (eMPP) are responsible for late gestation hematopoiesis. They are distinct from HSC that do not significantly contribute to embryonic mature blood cells. eMPP are the predominant source of embryonic lymphocytes and lymphoid tissue inducer cells, some of which persist for life. Between E12.5 and E16.5 eMPP rapidly differentiate, whereas HSC expand 20-fold. Altogether, these results support the notion that eMPP establish the embryonic adaptive immune system and shape the lymphoid organs where later adaptive immune responses occur, while HSC expand to sustain blood cell production throughout life.

developmental biology↗

bioRxiv2023

Resident and recruited macrophages differentially contribute to cardiac healing after myocardial ischemia

Cardiac macrophages are heterogenous in phenotype and functions, which has been associated with differences in their ontogeny. Despite extensive research, our understanding of the precise role of different subsets of macrophages in ischemia/reperfusion injury remains incomplete. We here investigated macrophage lineages and ablated tissue macrophages in homeostasis and after I/R injury in a CSF1R-dependent manner. Genomic deletion of a fms-intronic regulatory element (FIRE) in the Csf1r locus resulted in specific absence of resident homeostatic and antigen-presenting macrophages, without affecting the recruitment of monocyte-derived macrophages to the infarcted heart. Specific absence of homeostatic, monocyte-independent macrophages altered the immune cell crosstalk in response to injury and induced proinflammatory neutrophil polarization, resulting in impaired cardiac remodelling without influencing infarct size. In contrast, continuous CSF1R inhibition led to depletion of both resident and recruited macrophage populations. This augmented adverse remodelling after I/R and led to an increased infarct size and deterioration of cardiac function. In summary, resident macrophages orchestrate inflammatory responses improving cardiac remodelling, while recruited macrophages determine infarct size after I/R injury. These findings attribute distinct beneficial effects to different macrophage populations in the context of myocardial infarction. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/539799v4_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@14fa4bcorg.highwire.dtl.DTLVardef@1c86bbborg.highwire.dtl.DTLVardef@118edfcorg.highwire.dtl.DTLVardef@1b06916_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Inflammation drives age-induced loss of tissue resident macrophages

Low-grade chronic systemic inflammation, or inflammageing, is a hallmark of ageing and a risk factor for both morbidity and mortality in elderly people. Resident macrophages are tissue homeostasis sentinels that are embedded in their tissue of residence since embryonic development, thus been exposed to cumulative tissue insults throughout life. Therefore, resident macrophages, among other immune cells, emerge as potential key contributors to age-associated tissue dysfunction. Contrary to what is currently postulated, we demonstrate here that the pool of embryo-derived resident macrophages exhibits an age-dependent depletion in liver, and other solid organs and that they are not replaced by Hematopoietic Stem Cell (HSCs)-derived monocytes throughout life. Further, we demonstrate that gradual, cumulative inflammation during ageing induces this specific loss of tissue resident macrophages. Preserving a "youthful" density of resident macrophages attenuates classical hallmarks of liver age-associated dysfunction. SummaryThe pool of embryo-derived resident macrophages dwindles with age in most tissues, without compensation from Hematopoietic Stem Cell (HSC)-derived cells. This loss is not due to impaired self-renewal in old tissues but rather to increased cell death, which is driven by sustained inflammation. Attenuating inflammation sensing during ageing prevents age-induce macrophage loss and improves hallmarks of liver ageing.

immunology↗

bioRxiv2020

Overlapping Definitive Progenitor Waves Divide and Conquer to Build a Layered Hematopoietic System

Adult innate immune cells are part of a layered hematopoietic system constructed from definitive hematopoietic stem and progenitor cells (HSPC) with diverse origins during development. One source of HSPC are fetal hematopoietic stem cells (HSC) that provide long-term reconstitution throughout life. However, the extent to which HSC produce mature cells in utero is only recently being uncovered. This is in part due to the added complexity of an overlapping wave of definitive progenitors that derive from yolk sac erythro-myeloid progenitors (EMP). HSC and EMP are generated from spatiotemporally distinct hemogenic endothelia, yet they both migrate to the fetal liver niche where they co-habitate and are presumed to reach their full potential. Delineation of the respective HSC and EMP pathways towards developmental immune cell differentiation has been confounded by challenges in ontogeny-specific cell labeling. In this study, in vivo inducible pulse chase labeling revealed that HSC contribute little to fetal myelopoiesis and that EMP are the predominant source of mature myeloid cells until birth. This is similar to what has been reported for the erythroid branch of hematopoiesis thereby establishing a developmentally-restricted privilege for erythro-myeloid differentiation from EMP compared to HSC. Tracing the origins of mature cells to the progenitor level by immunophenotyping and single cell RNA sequencing uncovered a dichotomy in the allocation of fetal liver EMP and HSC to myeloid progenitor subsets, both in timing and lineage bias. This has exposed an uncoupling between developmental granulopoiesis and monopoiesis from EMP and HSC pathways, and provides a framework for future studies of HSC-dependent and -independent hematopoiesis. HIGHLIGHTSO_LIEMP-to-HSC switch in fetal liver myelopoiesis occurs late in gestation C_LIO_LIEMP are efficient at producing early transit amplifying erythroid and myeloid intermediates C_LIO_LIscRNA-seq reveals three trajectories of EMP myelopoiesis C_LIO_LIMyeloid lineage commitment during development is cell type and ontogeny specific C_LI

immunology↗

bioRxiv2020

Functionally distinct resident macrophage subsets differentially shape responses to infection in the bladder

Resident macrophages are abundant in the bladder, playing key roles in immunity to uropathogens. Yet, whether they are heterogeneous, where they come from, and how they respond to infection remain largely unknown. We identified two macrophage subsets in mouse bladders, MacM in the muscle and MacL in the lamina propria, with distinct protein expression and transcriptomes. Using a urinary tract infection model, we validated our transcriptomic analyses, finding that MacM macrophages phagocytosed more bacteria and polarized to a more anti-inflammatory profile, whereas the MacL subset died rapidly during infection. During resolution, monocyte-derived cells contributed to tissue-resident macrophage pools and both subsets acquired transcriptional profiles distinct from naive macrophages. Depletion of these altered macrophages resulted in the induction of a type 1 biased immune response to a second urinary tract infection, improving bacterial clearance. Our study uncovers the biology of resident macrophages and their response to an exceedingly common infection in a largely overlooked organ, the bladder.

immunology↗

bioRxiv2020

Yolk sac erythromyeloid progenitors sustain erythropoiesis throughout embryonic life

The first hematopoietic cells are produced in the yolk sac and are thought to be rapidly replaced by the progeny of hematopoietic stem cells. Here we document that hematopoietic stem cells do not contribute significantly to erythrocyte production up until birth. Lineage tracing of yolk sac-derived erythromyeloid progenitors, that also contribute to tissue resident macrophages, shows a progeny of highly proliferative erythroblasts, that after intra embryonic injection, rapidly differentiate. These progenitors, similar to hematopoietic stem cells, are c-Myb dependent and are developmentally restricted as they are not found in the bone marrow. We show that erythrocyte progenitors of yolk sac origin require lower concentrations of erythropoietin than their hematopoietic stem cell-derived counterparts for efficient erythrocyte production. Consequently, fetal liver hematopoietic stem cells fail to generate megakaryocyte and erythrocyte progenitors. We propose that large numbers of yolk sac-derived erythrocyte progenitors have a selective advantage and efficiently outcompete hematopoietic stem cell progeny in an environment with limited availability of erythropoietin.

developmental biology↗