The Sequential Expression of CD40 and Icam2 Defines Progressive Steps in the Formation of Blood Precursors from the Mesoderm Germ Layer

Pearson, Stella; Lancrin, Christophe; Lacaud, Georges; Kouskoff, Valérie

doi:10.1002/stem.434

Cited by 12 publications

(12 citation statements)

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“…It will be of interest to examine Eng expression on the various cell populations we have analyzed here. CD40 and Icam2 are expressed sequentially during the earliest stages of blood specification both in vitro and in vivo [53]. Their temporal relationship to Podxl and Eng remain to be determined.…”

Section: Discussionmentioning

confidence: 99%

Expression of Podocalyxin Separates the Hematopoietic and Vascular Potentials of Mouse Embryonic Stem Cell-Derived Mesoderm

et al. 2014

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In the mouse embryo and differentiating embryonic stem cells, the hematopoietic, endothelial and cardiomyocyte lineages are derived from Flk1+ mesodermal progenitors. Here we report that surface expression of Podocalyxin (Podxl), a member of the CD34 family of sialomucins, can be used to subdivide the Flk1+ cells in differentiating embryoid bodies at day 4.75 into populations that develop into distinct mesodermal lineages. Definitive hematopoietic potential was restricted to the Flk1+Podxl+ population, while the Flk1-negative Podxl+ population displayed only primitive erythroid potential. The Flk1+Podxl-negative population contained endothelial cells and cardiomyocyte potential. Podxl expression distinguishes Flk1+ mesoderm populations in mouse embryos at days 7.5, 8.5 and 9.5 and is a marker of progenitor stage primitive erythroblasts. These findings identify Podxl as a useful tool for separating distinct mesodermal lineages.

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Section: Discussionmentioning

confidence: 99%

Expression of Podocalyxin Separates the Hematopoietic and Vascular Potentials of Mouse Embryonic Stem Cell-Derived Mesoderm

et al. 2014

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“…Staining was done as described previously 29 and analyses were performed with a FACSCalibur or LSRII (BD Biosciences). Sorts were performed with a FACSAria or a BD Influx (BD Biosciences) or by using magnetic sorting (Miltenyi Biotec).…”

Section: Flow Cytometry and Cell Sortingmentioning

confidence: 99%

GFI1 and GFI1B control the loss of endothelial identity of hemogenic endothelium during hematopoietic commitment

Lancrin

Mazan

Stefanska

et al. 2012

Blood

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160

181

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Recent studies have established that during embryonic development, hematopoietic progenitors and stem cells are generated from hemogenic endothelium precursors through a process termed endothelial to hematopoietic transition (EHT). The transcription factor RUNX1 is essential for this process, but its main downstream effectors remain largely unknown. Here, we report the identification of Gfi1 and Gfi1b as direct targets of RUNX1 and critical regulators of EHT. GFI1 and GFI1B are able to trigger, in the absence of RUNX1, the down-regulation of endothelial markers and the formation of round cells, a morphologic change characteristic of EHT. Conversely, blood progenitors in Gfi1-and Gfi1b-deficient embryos maintain the expression of endothelial genes. Moreover, those cells are not released from the yolk sac and disseminated into embryonic tissues. Taken together, our findings demonstrate a critical and specific role of the GFI1 transcription factors in the first steps of the process leading to the generation of hematopoietic progenitors from hemogenic endothelium. (Blood. 2012;120(2):314-322) IntroductionHematopoietic stem cells (HSCs) are pivotal to the continuous generation and maintenance of mature blood cells throughout adult life. Although they reside mainly in the bone marrow at the time of birth and thereafter, they are initially generated during embryonic life in large blood vessels located in the developing embryo. 1 Recent studies in mice 2-4 and zebrafish 5,6 have established that hematopoietic progenitors and stem cells are produced at these sites from endothelial cells by a process termed endothelial to hematopoietic transition (EHT).Besides these in vivo studies, the in vitro differentiation of embryonic stem (ES) cells represents a powerful system to study these early events of hematopoietic development. Using this system, it was shown that blood cell development is initiated by a clonal hemangioblast precursor, which gives rise to blast colonies with both endothelial and hematopoietic cells, 7 a finding subsequently confirmed in vivo. 8 More recently, hemangioblasts were shown to generate first a hemogenic endothelium intermediate cell population, which subsequently gives rise to hematopoietic progenitors. 9 During this process, hemogenic endothelial cells lose their endothelial identity by altering their flat, adherent appearance into the characteristic round shape of mobile hematopoietic precursor cells. 9,10 This transition critically relies on the presence of the transcription factor RUNX1. 3,9 Although these studies have together clearly established that the EHT process is the pivotal event in the generation of the first blood cells, 9,10 the molecular and cellular mechanisms orchestrating this critical transition remain essentially unknown.To identify downstream RUNX1 effectors that drive the development of hematopoietic precursor cells from the hemogenic endothelium, we compared the transcriptomes of Runx1 ϩ/Ϫ and Runx1 Ϫ/Ϫ hemogenic endothelium and identified the Gfi1 and Gfi1b genes as direc...

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“…VEGF confers dose-dependent survival to primitive progenitors (Martin et al, 2004), and FLK1 marks primitive streak mesoderm predictive of hematopoietic potential (Era et al, 2008). Additional studies have identified markers to differentiate between hemangioblast and hemogenic endothelium, such as cell-surface intercellular adhesion molecule 2 (ICAM2) (Pearson et al, 2010) and the Ets-related protein encoding transcription factor ETV2 (Wareing et al, 2012). Other molecules such as podocalyxin (Zhang et al, 2014) have been shown to distinguish primitive from definitive hematopoietic potentials.…”

Section: The Next Step: How Observations In Yolk Sac Hematopoiesis Camentioning

confidence: 99%

Modeling murine yolk sac hematopoiesis with embryonic stem cell culture systems

Cook

2014

Front. Biol.

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The onset of hematopoiesis in mammals is defined by generation of primitive erythrocytes and macrophage progenitors in embryonic yolk sac. Laboratories have met the challenge of transient and swiftly changing specification events from ventral mesoderm through multipotent progenitors and maturing lineage-restricted hematopoietic subtypes, by developing powerful in vitro experimental models to interrogate hematopoietic ontogeny. Most importantly, studies of differentiating embryonic stem cell derivatives in embryoid body and stromal coculture systems have identified crucial roles for transcription factor networks (e.g. Gata1, Runx1, Scl) and signaling pathways (e.g. BMP, VEGF, WNT) in controlling stem and progenitor cell output. These and other relevant pathways have pleiotropic biological effects, and are often associated with early embryonic lethality in knockout mice. Further refinement in subsequent studies has allowed conditional expression of key regulatory genes, and isolation of progenitors via cell surface markers (e.g. FLK1) and reporter-tagged constructs, with the purpose of measuring their primitive and definitive hematopoietic potential. These observations continue to inform attempts to direct the differentiation, and augment the expansion, of progenitors in human cell culture systems that may prove useful in cell replacement therapies for hematopoietic deficiencies. The purpose of this review is to survey the extant literature on the use of differentiating murine embryonic stem cells in culture to model the developmental process of yolk sac hematopoiesis.

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The Sequential Expression of CD40 and Icam2 Defines Progressive Steps in the Formation of Blood Precursors from the Mesoderm Germ Layer

Cited by 12 publications

References 47 publications

Expression of Podocalyxin Separates the Hematopoietic and Vascular Potentials of Mouse Embryonic Stem Cell-Derived Mesoderm

Expression of Podocalyxin Separates the Hematopoietic and Vascular Potentials of Mouse Embryonic Stem Cell-Derived Mesoderm

GFI1 and GFI1B control the loss of endothelial identity of hemogenic endothelium during hematopoietic commitment

Modeling murine yolk sac hematopoiesis with embryonic stem cell culture systems

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