scholarly journals HSC-independent definitive hematopoietic cells persist into adult life

2021 ◽  
Author(s):  
Michihiro Kobayashi ◽  
Haichao Wei ◽  
Takashi Yamanashi ◽  
David J Shih ◽  
Nathalia Azevedo Portilho ◽  
...  
Keyword(s):  
Stem Cell ◽  
Blood Cells ◽  
Fetal Liver ◽  
Adult Life ◽  
Lineage Tracing ◽  
Hematopoietic Stem ◽  
Multipotent Progenitors ◽  
Lymphoid Progenitors ◽  
B Lymphoid ◽  
Developmental Dynamics

SummaryThe stem cell theory that all blood cells are derived from hematopoietic stem cell (HSC) is a central dogma in hematology. However, various types of blood cells are already produced from hemogenic endothelial cells (HECs) before the first HSCs appear at embryonic day (E)11 in the mouse embryo. This early blood cell production from HECs, called HSC-independent hematopoiesis, includes primitive and definitive erythromyeloid progenitors that transiently support fetal blood homeostasis until HSC-derived hematopoiesis is established. Lymphoid potential has traditionally been detected in the extra-embryonic yolk sac (YS) and/or embryos before HSC emergence, but the actual presence of lymphoid progenitors at this stage remains unknown. In addition, whether HSCs in the fetal liver are the main source of innate-like B-1a cells has been controversial. Here, using complementary lineage tracing mouse models, we show that HSC-independent multipotent progenitors (MPPs) and HSC-independent adoptive B-lymphoid progenitors persist into adult life. Furthermore, HSCs minimally contribute to the peritoneal B-1a cell pool; most B-1a cells are originated directly from ECs in the YS and embryo and HSC-independent for life. Our discovery of extensive HSC-independent MPP and B-lymphoid progenitors in adults attests to the complex blood developmental dynamics through embryo to adult that underpin the immune system and challenges the paradigm of HSC theory in hematology.

scholarly journals Murine HSCs contribute actively to native hematopoiesis but with reduced differentiation capacity upon aging

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Petter Säwen ◽  
Mohamed Eldeeb ◽  
Eva Erlandsson ◽  
Trine A Kristiansen ◽  
Cecilia Laterza ◽  
...  
Keyword(s):  
Stem Cell ◽  
Steady State ◽  
Progenitor Cells ◽  
Blood Cells ◽  
Lineage Tracing ◽  
Compensatory Mechanism ◽  
Fetal Origins ◽  
Hematopoietic Stem ◽  
Differentiation Capacity ◽  
Hsc Transplantation

A hallmark of adult hematopoiesis is the continuous replacement of blood cells with limited lifespans. While active hematopoietic stem cell (HSC) contribution to multilineage hematopoiesis is the foundation of clinical HSC transplantation, recent reports have questioned the physiological contribution of HSCs to normal/steady-state adult hematopoiesis. Here, we use inducible lineage tracing from genetically marked adult HSCs and reveal robust HSC-derived multilineage hematopoiesis. This commences via defined progenitor cells, but varies substantially in between different hematopoietic lineages. By contrast, adult HSC contribution to hematopoietic cells with proposed fetal origins is neglible. Finally, we establish that the HSC contribution to multilineage hematopoiesis declines with increasing age. Therefore, while HSCs are active contributors to native adult hematopoiesis, it appears that the numerical increase of HSCs is a physiologically relevant compensatory mechanism to account for their reduced differentiation capacity with age.

Identification of a Developmentally-Restricted Hematopoietic Stem Cell That Gives Rise to Innate-like Lymphocytes

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4302-4302
Author(s):  
Anna E Beaudin ◽  
Scott W. Boyer ◽  
Gloria Hernandez ◽  
Camilla E Forsberg
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Conflicts Of Interest ◽  
Fetal Liver ◽  
Lineage Tracing ◽  
Lymphoid Cells ◽  
Gfp Expression ◽  
Hematopoietic Stem

Abstract The generation of innate-like immune cells distinguishes fetal hematopoiesis from adult hematopoiesis, but the cellular mechanisms underlying differential cell production during development remain to be established. Specifically, whether differential lymphoid output arises as a consequence of discrete hematopoietic stem cell (HSC) populations present during development or whether the fetal/neonatal microenvironment is required for their production remains to be established. We recently established a Flk2/Flt3 lineage tracing mouse model wherein Flk2-driven expression of Cre recombinase results in the irreversible switching of a ubiquitous dual-color reporter from Tomato to GFP expression. Because the switch from Tom to GFP expression in this model involves an irreversible genetic excision of the Tomato gene, a GFP+ cell can never give rise to Tom+ progeny. Using this model, we have definitively demonstrated that all functional, adult HSC remain Tomato+ and therefore that all developmental precursors of adult HSC lack a history of Flk2 expression. In contrast, adoptive transfer experiments of Tom+ and GFP+ fetal liver Lin-cKit+Sca1+ (KLS) fractions demonstrated that both Tom+ and GFP+ fetal HSC support serial, long-term multilineage reconstitution (LTR) in irradiated adult recipients. We have therefore identified a novel, developmentally restricted HSC that supports long-term multilineage reconstitution upon transplantation into an adult recipient but does not normally persist into adulthood. Developmentally-restricted GFP+ HSC display greater lymphoid potential, and regenerated both innate-like B-1 lymphocytes and Vg3-expressing T lymphocytes to a greater extent than coexisting Tom+ FL and adult HSC. Interestingly, whereas developmental regulation of fetal-specific B-cell subsets appears to be regulated cell-instrinsically, as fetal HSC generated more innate-like B-cells than adult HSC even within an adult environment, T-cell development may be regulated both cell intrinsically and extrinsically, as both the cell-of-origin and the fetal microenvironment regulated the generation of innate-like T-cells. Our results provide direct evidence for a developmentally restricted HSC that gives rise to a layered immune system and describes a novel mechanism underlying the source of developmental hematopoietic waves. As early lymphoid cells play essential roles in establishing self-recognition and tolerance, these findings are critical for understanding the development of autoimmune diseases, allergies, and tolerance induction upon organ transplantation. Furthermore, by uncoupling self-renewal capacity in situ with that observed upon transplantation, our data suggests that transplantation- and/or irradiation-induced cues may allow for the engraftment of developmental HSC populations that do not normally persist in situ. As LTR upon transplantation has served as the prevailing definition of adult HSC origin during development, our data challenge the current conceptual framework of adult HSC origin. Disclosures No relevant conflicts of interest to declare.

scholarly journals Yolk sac erythromyeloid progenitors sustain erythropoiesis throughout embryonic life

2020 ◽  
Author(s):  
Francisca Soares-da-Silva ◽  
Odile Burlen-Defranoux ◽  
Ramy Elsaid ◽  
Lorea Iturri ◽  
Laina Freyer ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem Cell ◽  
Fetal Liver ◽  
Selective Advantage ◽  
Yolk Sac ◽  
Lineage Tracing ◽  
Hematopoietic Stem ◽  
Embryonic Life

AbstractThe 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.

scholarly journals The Ets2 Repressor Factor (Erf) Is Required for Effective Primitive and Definitive Hematopoiesis

2017 ◽  
Vol 37 (19) ◽  
Author(s):  
Ioanna Peraki ◽  
James Palis ◽  
George Mavrothalassitis
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Blood Cells ◽  
Fetal Liver ◽  
Normal Function ◽  
Severe Anemia ◽  
Hematopoietic Stem ◽  
Stem Cell Maintenance ◽  
Definitive Hematopoiesis ◽  
Cell Maintenance

ABSTRACT Erf is a gene for a ubiquitously expressed Ets DNA-binding domain-containing transcriptional repressor. Erf haploinsufficiency causes craniosynostosis in humans and mice, while its absence in mice leads to failed chorioallantoic fusion and death at embryonic day 10.5 (E10.5). In this study, we show that Erf is required in all three waves of embryonic hematopoiesis. Mice lacking Erf in the embryo proper exhibited severe anemia and died around embryonic day 14.5. Erf epiblast-specific knockout embryos had reduced numbers of circulating blood cells from E9.5 onwards, with the development of severe anemia by E14.5. Elimination of Erf resulted in both reduced and more immature primitive erythroblasts at E9.5 to E10.5. Reduced definitive erythroid colony-forming activity was found in the bloodstream of E10.5 embryos and in the fetal liver at E11.5 to E13.5. Finally, elimination of Erf resulted in impaired repopulation ability, indicating that Erf is necessary for hematopoietic stem cell maintenance or differentiation. We conclude that Erf is required for both primitive and erythromyeloid progenitor waves of hematopoietic stem cell (HSC)-independent hematopoiesis as well as for the normal function of HSCs.

Tie2Cre-mediated gene ablation defines the stem-cell leukemia gene (SCL/tal1)–dependent window during hematopoietic stem-cell development

Blood ◽  
2005 ◽  
Vol 105 (10) ◽  
pp. 3871-3874 ◽  
Author(s):  
Thorsten M. Schlaeger ◽  
Hanna K. A. Mikkola ◽  
Christos Gekas ◽  
Hildur B. Helgadottir ◽  
Stuart H. Orkin
Keyword(s):  
Stem Cell ◽  
Blood Cells ◽  
Fetal Liver ◽  
Cell Leukemia ◽  
Hematopoietic Stem ◽  
Gene Ablation ◽  
Epidermal Growth ◽  
Fetal Hematopoiesis ◽  
Stem Cell Leukemia

AbstractThe stem-cell leukemia gene (SCL/tal1) is essential for the formation of all blood lineages. SCL is first expressed in mesodermal cells that give rise to embryonic blood cells, and continues to be expressed in fetal and adult hematopoietic stem cells (HSCs). However, SCL is not required for the maintenance of established long-term repopulating (LTR) HSCs in the adult. The time point at which HSC development becomes SCL independent has not been defined. Tyrosine kinase with immunoglobulin and epidermal growth factor homology domains–2 (Tie2) expression appears in hemogenic and vasculogenic sites shortly after SCL. We therefore used the Tie2Cre mouse to inactivate SCL early during embryonic and fetal hematopoiesis. Tie2Cre completely inactivated SCL in yolk sac, the aortagonad-mesonephros (AGM) region, and fetal liver hematopoietic cells and circulating blood cells. However, the fetal liver was colonized by functional LTR-HSCs. Yet SCL remained crucial for proper differentiation of both primitive and definitive red cells and megakaryocytes. These results indicate that the SCL-dependent phase of HSC development ends before Tie2Cre-mediated gene ablation becomes effective.

scholarly journals Yolk sac, but not hematopoietic stem cell–derived progenitors, sustain erythropoiesis throughout murine embryonic life

2021 ◽  
Vol 218 (4) ◽  
Author(s):  
Francisca Soares-da-Silva ◽  
Laina Freyer ◽  
Ramy Elsaid ◽  
Odile Burlen-Defranoux ◽  
Lorea Iturri ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem Cell ◽  
Fetal Liver ◽  
Yolk Sac ◽  
Lineage Tracing ◽  
Erythroid Progenitors ◽  
Hematopoietic Stem ◽  
Embryonic Life

In the embryo, the first hematopoietic cells derive from the yolk sac and are thought to be rapidly replaced by the progeny of hematopoietic stem cells. We used three lineage-tracing mouse models to show that, contrary to what was previously assumed, hematopoietic stem cells do not contribute significantly to erythrocyte production up until birth. Lineage tracing of yolk sac erythromyeloid progenitors, which generate tissue resident macrophages, identified highly proliferative erythroid progenitors that rapidly differentiate after intra-embryonic injection, persisting as the major contributors to the embryonic erythroid compartment. We show that erythrocyte progenitors of yolk sac origin require 10-fold lower concentrations of erythropoietin than their hematopoietic stem cell–derived counterparts for efficient erythrocyte production. We propose that, in a low erythropoietin environment in the fetal liver, yolk sac–derived erythrocyte progenitors efficiently outcompete hematopoietic stem cell progeny, which fails to generate megakaryocyte and erythrocyte progenitors.

The Ski oncoprotein regulates Hematopoietic Stem Cell Fitness and Functions as a Corepressor for Gfi1.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1403-1403
Author(s):  
Chinavenmeni S. Velu ◽  
Michael Berk ◽  
Haiming Xu ◽  
Tristan Bourdeau ◽  
Avedis Kazanjian ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Target Genes ◽  
Fetal Liver ◽  
Embryonic Stem ◽  
Loss Of Function ◽  
Hematopoietic Stem ◽  
Myeloid Progenitor ◽  
Multipotent Progenitors

Abstract Ski is a corepressor protein originally identified as a retrovirally transduced oncoprotein. Genetic deletion of Ski has revealed essential roles in multiple developmental processes. Suggestion that Ski may play a role in hematopoiesis first came from expression of v-Ski and c-Kit, which induced the continuous in vitro growth of primary avian multipotent progenitors. However, the hematopoietic phenotype of Ski−/− mice has not been described. Here, we show that Ski loss of function results in loss of hematopoietic stem cell (HSC) fitness and abnormal regulation of myeloid progenitor numbers. Fetal liver Ski−/− HSC engraft well in ablated recipients, but are not competitive in engraftment. Moreover, Ski null embryonic stem cells generate many tissues in chimeras, but infrequently participate in hematopoiesis. Thus, Ski null HSC are not competitive in both transplant and chimera settings, indicating a defect in stem cell fitness. Engrafted Ski−/− fetal liver cells generate fewer myeloid lineage cells than wild type littermates, and accumulate granulocytemonocyte progenitors. Growth factor independent -1 (Gfi1) is a transcriptional repressor that controls HSC maintenance and myeloid progenitor differentiation. Gfi1−/− and Ski−/− hematopoietic stem and myeloid progenitor phenotypes are strikingly similar. We find that Ski functions as a corepressor for Gfi1. Both endogenous and synthetic Gfi1 and Ski physically interact in vitro and upon Gfi1 target genes. Knockdown of Gfi1 or Ski results in derepression of these targets. Thus, our results provide a molecular link between the similar HSC and myeloid progenitor phenotypes engendered by Gfi1 or Ski deletion.

Runx1 Interactions in Stem Cell Biology.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. sci-15-sci-15
Author(s):  
Nancy A. Speck ◽  
Michael Chen ◽  
Tomomasa Yokomizo ◽  
Brandon Zeigler ◽  
Elaine Dzierzak
Keyword(s):  
Stem Cell ◽  
Cell Biology ◽  
Bone Marrow Cells ◽  
Fetal Liver ◽  
Adult Life ◽  
Yolk Sac ◽  
Specific Marker ◽  
Vascular Endothelial ◽  
Hematopoietic Stem ◽  
Almost All

Abstract The study of developmental hematopoiesis has provided important insights into the molecules that establish and sustain this process throughout adult life. At the base of the hematopoietic hierarchy is the hematopoietic stem cell (HSC), which emerges in the mouse conceptus starting at 10.5 days post coitus (≥ 34 somite pair stages).1 HSCs have been found in several distinct sites: the yolk sac, umbilical and vitelline arteries, the dorsal aorta in the aorta/gonad/mesonephros (AGM) region, fetal liver, and, more recently, the placenta.1–4 HSCs emerge from these sites (yolk sac, umbilical and vitelline arteries, and AGM region) through the formation of intra-aortic hematopoietic clusters that develop from endothelium.5–7 Studies in mouse, zebrafish, chick, and frog embryos established that Runx1 (AML1) is the earliest specific marker of all definitive hematopoietic sites in the conceptus. Runx1 is expressed in endothelial and mesenchymal cells and in intraaortic hematopoietic clusters, and marks all committed HPs and HSCs in both the embryo and the adult.6,8–10 It has been proposed that Runx1 functions during the transition from a “hemogenic endothelium” to intra-aortic clusters and HSCs.8 Here, we show that deletion of Runx1 in vascular endothelial cadherin (VEC) positive cells blocks the emergence of intra-aortic hematopoietic clusters, HPs, and HSCs. Greater than 95% of adult bone marrow cells are marked when VEC-Cre is used to delete a Rosa26 reporter allele, demonstrating that almost all blood cells have transited through a VEC+ intermediate at some point in their life. On the other hand, Runx1 deletion with Vav-Cre, which occurs in fetal liver HPs and HSCs, does not block hematopoiesis. Collectively, these data demonstrate that Runx1 is absolutely required in endothelial cells for hematopoietic cluster, HP, and HSC formation, but after HSCs are born from endothelium, Runx1 is no longer required to maintain them.

Efficient lentiviral gene transfer to canine repopulating cells using an overnight transduction protocol

Blood ◽  
2004 ◽  
Vol 103 (10) ◽  
pp. 3710-3716 ◽  
Author(s):  
Peter A. Horn ◽  
Kirsten A. Keyser ◽  
Laura J. Peterson ◽  
Tobias Neff ◽  
Bobbie M. Thomasson ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Gene Transfer ◽  
Peripheral Blood ◽  
Blood Cells ◽  
Lentiviral Vectors ◽  
Large Animal ◽  
Hematopoietic Stem ◽  
Lentiviral Transduction ◽  
Mobilized Peripheral Blood

Abstract The use of lentiviral vectors for the transduction of hematopoietic stem cells has evoked much interest owing to their ability to stably integrate into the genome of nondividing cells. However, published large animal studies have reported highly variable gene transfer rates of typically less than 1%. Here we report the use of lentiviral vectors for the transduction of canine CD34+ hematopoietic repopulating cells using a very short, 18-hour transduction protocol. We compared lentiviral transduction of hematopoietic repopulating cells from either stem cell factor (SCF)– and granulocyte-colony stimulating factor (G-CSF)–primed marrow or mobilized peripheral blood in a competitive repopulation assay in 3 dogs. All dogs engrafted rapidly within 9 days. Transgene expression was detected in all lineages (B cells, T cells, granulocytes, and red blood cells as well as platelets) indicating multilineage engraftment of transduced cells, with overall long-term marking levels of up to 12%. Gene transfer levels in mobilized peripheral blood cells were slightly higher than in primed marrow cells. In conclusion, we show efficient lentiviral transduction of canine repopulating cells using an overnight transduction protocol. These results have important implications for the design of stem cell gene therapy protocols, especially for those diseases in which the maintenance of stem cells in culture is a major limitation.

scholarly journals Delineating spatiotemporal and hierarchical development of human fetal innate lymphoid cells

Cell Research ◽  
2021 ◽  
Author(s):  
Chen Liu ◽  
Yandong Gong ◽  
Han Zhang ◽  
Hua Yang ◽  
Yang Zeng ◽  
...  
Keyword(s):  
Single Cell ◽  
Progenitor Cells ◽  
Fetal Liver ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Lymphoid Tissues ◽  
Hematopoietic Stem ◽  
Molecular Features ◽  
Lymphoid Progenitors ◽  
B Lineage

AbstractWhereas the critical roles of innate lymphoid cells (ILCs) in adult are increasingly appreciated, their developmental hierarchy in early human fetus remains largely elusive. In this study, we sorted human hematopoietic stem/progenitor cells, lymphoid progenitors, putative ILC progenitor/precursors and mature ILCs in the fetal hematopoietic, lymphoid and non-lymphoid tissues, from 8 to 12 post-conception weeks, for single-cell RNA-sequencing, followed by computational analysis and functional validation at bulk and single-cell levels. We delineated the early phase of ILC lineage commitment from hematopoietic stem/progenitor cells, which mainly occurred in fetal liver and intestine. We further unveiled interleukin-3 receptor as a surface marker for the lymphoid progenitors in fetal liver with T, B, ILC and myeloid potentials, while IL-3RA– lymphoid progenitors were predominantly B-lineage committed. Notably, we determined the heterogeneity and tissue distribution of each ILC subpopulation, revealing the proliferating characteristics shared by the precursors of each ILC subtype. Additionally, a novel unconventional ILC2 subpopulation (CRTH2– CCR9+ ILC2) was identified in fetal thymus. Taken together, our study illuminates the precise cellular and molecular features underlying the stepwise formation of human fetal ILC hierarchy with remarkable spatiotemporal heterogeneity.

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