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ABSTRACT: SETBP1 mutations are found in various clonal myeloid disorders. However, it is unclear whether they can initiate leukemia, because SETBP1 mutations typically appear as later events during oncogenesis. To answer this question, we generated a mouse model expressing mutated SETBP1 in hematopoietic tissue: this model showed profound alterations in the differentiation program of hematopoietic progenitors and developed a myeloid neoplasm with megakaryocytic dysplasia, splenomegaly, and bone marrow fibrosis, prompting us to investigate SETBP1 mutations in a cohort of 36 triple-negative primary myelofibrosis (TN-PMF) cases. We identified 2 distinct subgroups, one carrying SETBP1 mutations and the other completely devoid of somatic variants. Clinically, a striking difference in disease aggressiveness was noted, with patients with SETBP1 mutation showing a much worse clinical course. In contrast to myelodysplastic/myeloproliferative neoplasms, in which SETBP1 mutations are mostly found as a late clonal event, single-cell clonal hierarchy reconstruction in 3 patients with TN-PMF from our cohort revealed SETBP1 to be a very early event, suggesting that the phenotype of the different SETBP1+ disorders may be shaped by the opposite hierarchy of the same clonal SETBP1 variants.
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Sistema Hematopoyético , Enfermedades Mielodisplásicas-Mieloproliferativas , Trastornos Mieloproliferativos , Mielofibrosis Primaria , Animales , Ratones , Humanos , Mielofibrosis Primaria/genética , Trastornos Mieloproliferativos/genética , Mutación , Proteínas Portadoras/genética , Proteínas Nucleares/genéticaRESUMEN
During embryogenesis, yolk-sac and intra-embryonic-derived hematopoietic progenitors, comprising the precursors of adult hematopoietic stem cells, converge into the fetal liver. With a new staining strategy, we defined all non-hematopoietic components of the fetal liver and found that hepatoblasts are the major producers of hematopoietic growth factors. We identified mesothelial cells, a novel component of the stromal compartment, producing Kit ligand, a major hematopoietic cytokine. A high-definition imaging dataset analyzed using a deep-learning based pipeline allowed the unambiguous identification of hematopoietic and stromal populations, and enabled determining a neighboring network composition, at the single cell resolution. Throughout active hematopoiesis, progenitors preferentially associate with hepatoblasts, but not with stellate or endothelial cells. We found that, unlike yolk sac-derived progenitors, intra-embryonic progenitors respond to a chemokine gradient created by CXCL12-producing stellate cells. These results revealed that FL hematopoiesis is a spatiotemporal dynamic process, defined by an environment characterized by low cytokine concentrations.
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Infant acute myeloid leukemia (AML) is a heterogeneous disease, genetically distinct from its adult counterpart. Chromosomal translocations involving the KMT2A gene (MLL) are especially common in affected infants of less than 1 year of age, and are associated with a dismal prognosis. While these rearrangements are likely to arise in utero, the cell of origin has not been conclusively identified. This knowledge could lead to a better understanding of the biology of the disease and support the identification of new therapeutic vulnerabilities. Over the last few years, important progress in understanding the dynamics of fetal hematopoiesis has been made. Several reports have highlighted how hematopoietic stem cells (HSC) provide little contribution to fetal hematopoiesis, which is instead largely sustained by HSC-independent progenitors. Here, we used conditional Cre-Lox transgenic mouse models to engineer the Mll-Af9 translocation in defined subsets of embryonic hematopoietic progenitors. We show that embryonic hematopoiesis is generally permissive for Mll-Af9-induced leukemic transformation. Surprisingly, the selective introduction of Mll-Af9 in HSC-independent progenitors generated a transplantable myeloid leukemia, whereas it did not when introduced in embryonic HSC-derived cells. Ex vivo engineering of the Mll-Af9 rearrangement in HSC-independent progenitors using a CRISPR/Cas9-based approach resulted in the activation of an aberrant myeloid-biased self-renewal program. Overall, our results demonstrate that HSC-independent hematopoietic progenitors represent a permissive environment for Mll-Af9-induced leukemic transformation, and can likely act as cells of origin of infant AML.
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Within the chromatin, distal elements interact with promoters to regulate specific transcriptional programs. Histone acetylation, interfering with the net charges of the nucleosomes, is a key player in this regulation. Here, we report that the oncoprotein SET is a critical determinant for the levels of histone acetylation within enhancers. We disclose that a condition in which SET is accumulated, the severe Schinzel-Giedion Syndrome (SGS), is characterized by a failure in the usage of the distal regulatory regions typically employed during fate commitment. This is accompanied by the usage of alternative enhancers leading to a massive rewiring of the distal control of the gene transcription. This represents a (mal)adaptive mechanism that, on one side, allows to achieve a certain degree of differentiation, while on the other affects the fine and corrected maturation of the cells. Thus, we propose the differential in cis-regulation as a contributing factor to the pathological basis of SGS and possibly other the SET-related disorders in humans.
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Elementos de Facilitación Genéticos , Histonas , Humanos , Histonas/genética , Histonas/metabolismo , Elementos de Facilitación Genéticos/genética , Diferenciación Celular/genética , Cromatina/genética , Regiones Promotoras Genéticas/genéticaRESUMEN
Blood vessels form vast networks in all vertebrate organs to sustain tissue growth, repair and homeostatic metabolism, but they also contribute to a range of diseases with neovascularisation. It is, therefore, important to define the molecular mechanisms that underpin blood vessel growth. The receptor tyrosine kinase KIT is required for the normal expansion of hematopoietic progenitors that arise during embryogenesis from hemogenic endothelium in the yolk sac and dorsal aorta. Additionally, KIT has been reported to be expressed in endothelial cells during embryonic brain vascularisation and has been implicated in pathological angiogenesis. However, it is neither known whether KIT expression is widespread in normal organ endothelium nor whether it promotes blood vessel growth in developing organs. Here, we have used single-cell analyses to show that KIT is expressed in endothelial cell subsets of several organs, both in the adult and in the developing embryo. Knockout mouse analyses revealed that KIT is dispensable for vascularisation of growing organs in the midgestation embryo, including the lung, liver and brain. By contrast, vascular changes emerged during late-stage embryogenesis in these organs from KIT-deficient embryos, concurrent with severe erythrocyte deficiency and growth retardation. These findings suggest that KIT is not required for developmental tissue vascularisation in physiological conditions, but that KIT deficiency causes foetal anaemia at late gestation and thereby pathological vascular remodelling.
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Células Endoteliales , Neovascularización Fisiológica , Animales , Embrión de Mamíferos , Femenino , Ratones , Ratones Noqueados , Neovascularización Patológica , Neovascularización Fisiológica/genética , Embarazo , Saco Vitelino/irrigación sanguíneaRESUMEN
Our knowledge of the complexity of the developing hematopoietic system has dramatically expanded over the course of the last few decades. We now know that, while hematopoietic stem cells (HSCs) firmly reside at the top of the adult hematopoietic hierarchy, multiple HSC-independent progenitor populations play variegated and fundamental roles during fetal life, which reflect on adult physiology and can lead to disease if subject to perturbations. The importance of obtaining a high-resolution picture of the mechanisms by which the developing embryo establishes a functional hematopoietic system is demonstrated by many recent indications showing that ontogeny is a primary determinant of function of multiple critical cell types. This review will specifically focus on exploring the diversity of hematopoietic stem and progenitor cells unique to embryonic and fetal life. We will initially examine the evidence demonstrating heterogeneity within the hemogenic endothelium, precursor to all definitive hematopoietic cells. Next, we will summarize the dynamics and characteristics of the so-called "hematopoietic waves" taking place during vertebrate development. For each of these waves, we will define the cellular identities of their components, the extent and relevance of their respective contributions as well as potential drivers of heterogeneity.
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Hematopoyesis , Células Madre Hematopoyéticas , Embrión de Mamíferos , Células Madre Hematopoyéticas/metabolismoRESUMEN
In 2002 we published an article describing a population of vessel-associated progenitors that we termed mesoangioblasts (MABs). During the past decade evidence had accumulated that during muscle development and regeneration things may be more complex than a simple sequence of binary choices (e.g., dorsal vs. ventral somite). LacZ expressing fibroblasts could fuse with unlabelled myoblasts but not among themselves or with other cell types. Bone marrow derived, circulating progenitors were able to participate in muscle regeneration, though in very small percentage. Searching for the embryonic origin of these progenitors, we identified them as originating at least in part from the embryonic aorta and, at later stages, from the microvasculature of skeletal muscle. While continuing to investigate origin and fate of MABs, the fact that they could be expanded in vitro (also from human muscle) and cross the vessel wall, suggested a protocol for the cell therapy of muscular dystrophies. We tested this protocol in mice and dogs before proceeding to the first clinical trial on Duchenne Muscular Dystrophy patients that showed safety but minimal efficacy. In the last years, we have worked to overcome the problem of low engraftment and tried to understand their role as auxiliary myogenic progenitors during development and regeneration.
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Late fetal liver hematopoiesis was thought to primarily rely on hematopoietic stem cells (HSCs). Using new genetic-tracing tools, a study shows that EVI1-positive HSCs mainly undergo expansion in the fetal liver, while differentiated blood cell production depends on HSC-independent intermediate hematopoietic progenitors.
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Yolk sac (YS) hematopoiesis is critical for the survival of the embryo and a major source of tissue-resident macrophages that persist into adulthood. Yet, the transcriptional and epigenetic regulation of YS hematopoiesis remains poorly characterized. Here we report that the epigenetic regulator Ezh2 is essential for YS hematopoiesis but dispensable for subsequent aorta-gonad-mesonephros (AGM) blood development. Loss of EZH2 activity in hemogenic endothelium (HE) leads to the generation of phenotypically intact but functionally deficient erythro-myeloid progenitors (EMPs), while the generation of primitive erythroid cells is not affected. EZH2 activity is critical for the generation of functional EMPs at the onset of the endothelial-to-hematopoietic transition but subsequently dispensable. We identify a lack of Wnt signaling downregulation as the primary reason for the production of non-functional EMPs. Together, our findings demonstrate a critical and stage-specific role of Ezh2 in modulating Wnt signaling during the generation of EMPs from YS HE.
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Proteína Potenciadora del Homólogo Zeste 2/genética , Células Eritroides/metabolismo , Regulación del Desarrollo de la Expresión Génica , Células Madre Embrionarias de Ratones/metabolismo , Células Progenitoras Mieloides/metabolismo , Proteínas de Transporte Vesicular/genética , Saco Vitelino/metabolismo , Animales , Diferenciación Celular , Embrión de Mamíferos , Proteína Potenciadora del Homólogo Zeste 2/deficiencia , Epigénesis Genética , Células Eritroides/citología , Femenino , Feto , Genes Reporteros , Hematopoyesis/genética , Hígado/citología , Hígado/crecimiento & desarrollo , Hígado/metabolismo , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células Madre Embrionarias de Ratones/citología , Células Progenitoras Mieloides/patología , Cultivo Primario de Células , Proteínas de Transporte Vesicular/metabolismo , Vía de Señalización Wnt , Saco Vitelino/citología , Saco Vitelino/crecimiento & desarrollo , Proteína Fluorescente RojaRESUMEN
Hematopoietic stem cells (HSCs) emerge during development from the vascular wall of the main embryonic arteries. The onset of circulation triggers several processes that provide critical external factors for HSC generation. Nevertheless, it is not fully understood how and when the onset of circulation affects HSC emergence. Here we show that in Ncx1-/- mouse embryos devoid of circulation the HSC lineage develops until the phenotypic pro-HSC stage. However, these cells reside in an abnormal microenvironment, fail to activate the hematopoietic program downstream of Runx1, and are functionally impaired. Single-cell transcriptomics shows that during the endothelial-to-hematopoietic transition, Ncx1-/- cells fail to undergo a glycolysis to oxidative phosphorylation metabolic switch present in wild-type cells. Interestingly, experimental activation of glycolysis results in decreased intraembryonic hematopoiesis. Our results suggest that the onset of circulation triggers metabolic changes that allow HSC generation to proceed.
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Diferenciación Celular , Linaje de la Célula , Endotelio Vascular/patología , Glucólisis , Hematopoyesis , Células Madre Hematopoyéticas/patología , Intercambiador de Sodio-Calcio/fisiología , Animales , Endotelio Vascular/metabolismo , Femenino , Células Madre Hematopoyéticas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación Oxidativa , Análisis de la Célula Individual , TranscriptomaRESUMEN
Several lines of evidence suggest that childhood leukemia, the most common cancer in young age, originates during in utero development. However, our knowledge of the cellular origin of this large and heterogeneous group of malignancies is still incomplete. The identification and characterization of their cell of origin is of crucial importance in order to define the processes that initiate and sustain disease progression, to refine faithful animal models and to identify novel therapeutic approaches. During embryogenesis, hematopoiesis takes place at different anatomical sites in sequential waves, and occurs in both a hematopoietic stem cell (HSC)-dependent and a HSC-independent fashion. Despite the recently described relevance and complexity of HSC-independent hematopoiesis, few studies have so far investigated its potential involvement in leukemogenesis. Here, we review the current knowledge on prenatal origin of leukemias in the context of recent insights in developmental hematopoiesis.
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Few studies report on the in vivo requirement for hematopoietic niche factors in the mammalian embryo. Here, we comprehensively analyze the requirement for Kit ligand (Kitl) in the yolk sac and aorta-gonad-mesonephros (AGM) niche. In-depth analysis of loss-of-function and transgenic reporter mouse models show that Kitl-deficient embryos harbor decreased numbers of yolk sac erythro-myeloid progenitor (EMP) cells, resulting from a proliferation defect following their initial emergence. This EMP defect causes a dramatic decrease in fetal liver erythroid cells prior to the onset of hematopoietic stem cell (HSC)-derived erythropoiesis, and a reduction in tissue-resident macrophages. Pre-HSCs in the AGM require Kitl for survival and maturation, but not proliferation. Although Kitl is expressed widely in all embryonic hematopoietic niches, conditional deletion in endothelial cells recapitulates germline loss-of-function phenotypes in AGM and yolk sac, with phenotypic HSCs but not EMPs remaining dependent on endothelial Kitl upon migration to the fetal liver. In conclusion, our data establish Kitl as a critical regulator in the in vivoAGM and yolk sac endothelial niche.
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Desarrollo Embrionario/genética , Hematopoyesis/genética , Células Madre Hematopoyéticas/citología , Factor de Células Madre/genética , Animales , Aorta/crecimiento & desarrollo , Linaje de la Célula/genética , Proliferación Celular/genética , Células Endoteliales/citología , Células Endoteliales/metabolismo , Eritropoyesis/genética , Regulación del Desarrollo de la Expresión Génica/genética , Gónadas/crecimiento & desarrollo , Mesonefro/crecimiento & desarrollo , Ratones , Ratones Transgénicos , Nicho de Células Madre/genética , Saco Vitelino/crecimiento & desarrolloRESUMEN
Despite the well-established cell-intrinsic role of epigenetic factors in normal and malignant hematopoiesis, their cell-extrinsic role remains largely unexplored. Herein we investigated the hematopoietic impact of inactivating Ezh2, a key component of polycomb repressive complex 2 (PRC2), in the fetal liver (FL) vascular niche. Hematopoietic specific (Vav-iCre) Ezh2 inactivation enhanced FL hematopoietic stem cell (HSC) expansion with normal FL erythropoiesis. In contrast, endothelium (Tie2-Cre) targeted Ezh2 inactivation resulted in embryonic lethality with severe anemia at embryonic day 13.5 despite normal emergence of functional HSCs. Ezh2-deficient FL endothelium overexpressed Mmp9, which cell-extrinsically depleted the membrane-bound form of Kit ligand (mKitL), an essential hematopoietic cytokine, in FL. Furthermore, Mmp9 inhibition in vitro restored mKitL expression along with the erythropoiesis supporting capacity of FL endothelial cells. These data establish that Ezh2 is intrinsically dispensable for FL HSCs and provides proof of principle that modulation of epigenetic regulators in niche components can exert a marked cell-extrinsic impact.
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Células Endoteliales/citología , Células Endoteliales/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Feto , Hematopoyesis Extramedular , Hígado/fisiología , Anemia/genética , Anemia/metabolismo , Animales , Biomarcadores , Células Cultivadas , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Técnica del Anticuerpo Fluorescente , Expresión Génica , Silenciador del Gen , Hematopoyesis Extramedular/genética , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Inmunohistoquímica , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Fenotipo , Receptor TIE-2/genética , Receptor TIE-2/metabolismo , Factor de Células Madre/metabolismoRESUMEN
Embryonic VE-Cadherin-expressing progenitors (eVE-Cad+), including hemogenic endothelium, have been shown to generate hematopoietic stem cells and a variety of other progenitors, including mesoangioblasts, or MABs. MABs are vessel-associated progenitors with multilineage mesodermal differentiation potential that can physiologically contribute to skeletal muscle development and regeneration, and have been used in an ex vivo cell therapy setting for the treatment of muscular dystrophy. There is currently a therapeutic need for molecules that could improve the efficacy of cell therapy protocols; one such good candidate is nitric oxide. Several studies in animal models of muscle dystrophy have demonstrated that nitric oxide donors provide several beneficial effects, including modulation of the activity of endogenous cell populations involved in muscle repair and the delay of muscle degeneration. Here we used a genetic lineage tracing approach to investigate whether the therapeutic effect of nitric oxide in muscle repair could derive from an improvement in the myogenic differentiation of eVE-Cad+ progenitors during embryogenesis. We show that early in vivo treatment with the nitric oxide donor molsidomine enhances eVE-Cad+ contribution to embryonic and fetal myogenesis, and that this effect could originate from a modulation of the properties of yolk sac hemogenic endothelium.
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Hemangioblastos/citología , Molsidomina/administración & dosificación , Desarrollo de Músculos/efectos de los fármacos , Donantes de Óxido Nítrico/administración & dosificación , Animales , Antígenos CD/metabolismo , Cadherinas/metabolismo , Diferenciación Celular/efectos de los fármacos , Embrión de Mamíferos/citología , Embrión de Mamíferos/efectos de los fármacos , Embrión de Mamíferos/metabolismo , Hemangioblastos/efectos de los fármacos , Hemangioblastos/metabolismo , Ratones , Molsidomina/farmacología , Distrofia Muscular Animal/tratamiento farmacológico , Distrofia Muscular Animal/patología , Donantes de Óxido Nítrico/farmacologíaRESUMEN
The final stages of restriction to the T cell lineage occur in the thymus after the entry of thymus-seeding progenitors (TSPs). The identity and lineage potential of TSPs remains unclear. Because the first embryonic TSPs enter a non-vascularized thymic rudiment, we were able to directly image and establish the functional and molecular properties of embryonic thymopoiesis-initiating progenitors (T-IPs) before their entry into the thymus and activation of Notch signaling. T-IPs did not include multipotent stem cells or molecular evidence of T cell-restricted progenitors. Instead, single-cell molecular and functional analysis demonstrated that most fetal T-IPs expressed genes of and had the potential to develop into lymphoid as well as myeloid components of the immune system. Moreover, studies of embryos deficient in the transcriptional regulator RBPJ demonstrated that canonical Notch signaling was not involved in pre-thymic restriction to the T cell lineage or the migration of T-IPs.
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Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas/metabolismo , Células Progenitoras Linfoides/fisiología , Células Progenitoras Mieloides/fisiología , Receptores Notch/metabolismo , Linfocitos T/fisiología , Timo/inmunología , Animales , Diferenciación Celular , Linaje de la Célula , Movimiento Celular , Células Cultivadas , Feto , Regulación del Desarrollo de la Expresión Génica , Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Transducción de SeñalRESUMEN
Definitive hematopoiesis emerges via an endothelial-to-hematopoietic transition in the embryo and placenta; however, the precursor cells to hemogenic endothelium are not defined phenotypically. We previously demonstrated that the induction of hematopoietic progenitors from fibroblasts progresses through hemogenic precursors that are Prom1(+)Sca1(+)CD34(+)CD45(-) (PS34CD45(-)). Guided by these studies, we analyzed mouse placentas and identified a population with this phenotype. These cells express endothelial markers, are heterogeneous for early hematopoietic markers, and localize to the vascular labyrinth. Remarkably, global gene expression profiles of PS34CD45(-) cells correlate with reprogrammed precursors and establish a hemogenic precursor cell molecular signature. PS34CD45(-) cells are also present in intra-embryonic hemogenic sites. After stromal co-culture, PS34CD45(-) cells give rise to all blood lineages and engraft primary and secondary immunodeficient mice. In summary, we show that reprogramming reveals a phenotype for in vivo precursors to hemogenic endothelium, establishing that direct in vitro conversion informs developmental processes in vivo.
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Diferenciación Celular/fisiología , Linaje de la Célula/fisiología , Reprogramación Celular , Hematopoyesis/genética , Células Madre Hematopoyéticas/citología , Células Madre Embrionarias de Ratones/citología , Animales , Células Cultivadas , Endotelio/metabolismo , Femenino , Fibroblastos/citología , Ratones , Ratones Endogámicos C57BL , EmbarazoRESUMEN
Most haematopoietic cells renew from adult haematopoietic stem cells (HSCs), however, macrophages in adult tissues can self-maintain independently of HSCs. Progenitors with macrophage potential in vitro have been described in the yolk sac before emergence of HSCs, and fetal macrophages can develop independently of Myb, a transcription factor required for HSC, and can persist in adult tissues. Nevertheless, the origin of adult macrophages and the qualitative and quantitative contributions of HSC and putative non-HSC-derived progenitors are still unclear. Here we show in mice that the vast majority of adult tissue-resident macrophages in liver (Kupffer cells), brain (microglia), epidermis (Langerhans cells) and lung (alveolar macrophages) originate from a Tie2(+) (also known as Tek) cellular pathway generating Csf1r(+) erythro-myeloid progenitors (EMPs) distinct from HSCs. EMPs develop in the yolk sac at embryonic day (E) 8.5, migrate and colonize the nascent fetal liver before E10.5, and give rise to fetal erythrocytes, macrophages, granulocytes and monocytes until at least E16.5. Subsequently, HSC-derived cells replace erythrocytes, granulocytes and monocytes. Kupffer cells, microglia and Langerhans cells are only marginally replaced in one-year-old mice, whereas alveolar macrophages may be progressively replaced in ageing mice. Our fate-mapping experiments identify, in the fetal liver, a sequence of yolk sac EMP-derived and HSC-derived haematopoiesis, and identify yolk sac EMPs as a common origin for tissue macrophages.
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Linaje de la Célula , Eritrocitos/citología , Hematopoyesis , Macrófagos/citología , Células Madre/citología , Saco Vitelino/citología , Animales , Proliferación Celular , Rastreo Celular , Femenino , Feto/citología , Granulocitos/citología , Macrófagos del Hígado/citología , Células de Langerhans/citología , Hígado/citología , Hígado/embriología , Macrófagos Alveolares/citología , Masculino , Ratones , Microglía/citología , Monocitos/citología , Receptor de Factor Estimulante de Colonias de Macrófagos/metabolismo , Receptor TIE-2/metabolismo , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
The embryonic endothelium is a known source of hematopoietic stem cells. Moreover, vessel-associated progenitors/stem cells with multilineage mesodermal differentiation potential, such as the 'embryonic mesoangioblasts', originate in vitro from the endothelium. Using a genetic lineage tracing approach, we show that early extra-embryonic endothelium generates, in a narrow time-window and prior to the hemogenic endothelium in the major embryonic arteries, hematopoietic cells that migrate to the embryo proper, and are subsequently found within the mesenchyme. A subpopulation of these cells, distinct from embryonic macrophages, co-expresses mesenchymal and hematopoietic markers. In addition, hemogenic endothelium-derived cells contribute to skeletal and smooth muscle, and to other mesodermal cells in vivo, and display features of embryonic mesoangioblasts in vitro. Therefore, we provide new insights on the distinctive characteristics of the extra-embryonic and embryonic hemogenic endothelium, and we identify the putative in vivo counterpart of embryonic mesoangioblasts, suggesting their identity and developmental ontogeny.
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Linaje de la Célula , Hemangioblastos/citología , Mesodermo/citología , Animales , Biomarcadores/metabolismo , Cadherinas/metabolismo , Embrión de Mamíferos/citología , Embrión de Mamíferos/metabolismo , Regulación de la Expresión Génica , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Integrasas/metabolismo , Macrófagos/citología , Macrófagos/metabolismo , Mesodermo/embriología , Ratones , Ratones Transgénicos , Modelos Biológicos , Músculo Esquelético/citología , Músculo Esquelético/embriología , Músculo Liso/citología , Músculo Liso/embriología , Receptores de Complemento 3b/metabolismo , Recombinación Genética/genéticaRESUMEN
Definitive hematopoietic cells are generated de novo during ontogeny from a specialized subset of endothelium, the so-called hemogenic endothelium. In this review we give a brief overview of the identification of hemogenic endothelium, explore its links with the HSC lineage, and summarize recent insights into the nature of hemogenic endothelium and the microenvironmental and intrinsic regulators contributing to its transition into blood. Ultimately, a better understanding of the processes controlling the transition of endothelium into blood will advance the generation and expansion of hematopoietic stem cells for therapeutic purposes.