Biology subjects

Freyer, L.

Publications and source records attributed to Freyer, L..

5 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↗

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

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↗

bioRxiv2019

A wave of hematopoietic stem cell-derived T/ILC-restricted progenitors initiates thymopoiesis and shapes the embryonic thymus architecture.

Multiple waves of hematopoietic progenitors with distinct lineage potentials are differentially regulated in time and space. We show that the first thymic seeding progenitors comprise a unique population of bipotent cells that generate lymphoid tissue inducer and invariant V{gamma}5+ T cells. Both populations are of embryonic origin and induce the maturation of medullary thymic epithelial cells. Indeed, temporal depletion of the first wave of thymocytes results in a five-fold reduction of mature medullary thymic epithelial cells, after birth. We further show that these progenitors are of hematopoietic stem cell, and not, of yolk sac origin, despite the temporal overlap between the onset of lymphopoiesis and the transient expression of lymphoid transcripts in yolk sac precursors, that does not impact their strict erythro-myeloid potential. Our work highlights the relevance of the developmental timing on the emergence of different lymphoid subsets required for the establishment of a functionally diverse immune system.

immunology↗