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5-hydroxytryptamine synthesized in the aorta-gonad-mesonephros regulates hematopoietic stem and progenitor cell survival.

ABSTRACT: The in vitro or ex vivo production of transplantable hematopoietic stem cells (HSCs) holds great promise for the treatment of hematological diseases in the clinic. However, HSCs have not been produced from either embryonic or induced pluripotent stem cells. In this study, we report that 5-hydroxytryptamine (5-HT; also called serotonin) can enhance the generation of hematopoietic stem and progenitor cells (HSPCs) in vitro and is essential for the survival of HSPCs in vivo during embryogenesis. In tryptophan hydroxylase 2-deficient embryos, a decrease in 5-HT synthesized in the aorta-gonad-mesonephros leads to apoptosis of nascent HSPCs. Mechanistically, 5-HT inhibits the AKT-Foxo1 signaling cascade to protect the earliest HSPCs in intraaortic hematopoietic clusters from excessive apoptosis. Collectively, our results reveal an unexpected role of 5-HT in HSPC development and suggest that 5-HT signaling may be a potential therapeutic target for promoting HSPC survival.

SUBMITTER: Lv J

PROVIDER: S-EPMC5294845 | biostudies-literature |

REPOSITORIES: biostudies-literature

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5-hydroxytryptamine synthesized in the Aorta-Gonad-Mesonephros regulates hematopoietic stem and progenitor cell survival

Project description:Whole-genome gene expression analysis was performed using the AGMs from two littermate pairs of tph2+/+, tph2+/- or tph2-/- at E11.5. The total RNA was extracted using TRNzol (Tiangen, Beijing) and cDNA samples were sequenced using Illumina HiSeq3000 (RiboBio Co. Ltd, Guangzhou). The reference Mus musculus genome and gene information were downloaded from the National Center for Biotechnology Information Database (NCBI: http://www.ncbi.nlm.nih.gov/).

2016-12-19 | GSE90130 | GEO

Endothelium and NOTCH specify and amplify aorta-gonad-mesonephros-derived hematopoietic stem cells.

Project description:Hematopoietic stem cells (HSCs) first emerge during embryonic development within vessels such as the dorsal aorta of the aorta-gonad-mesonephros (AGM) region, suggesting that signals from the vascular microenvironment are critical for HSC development. Here, we demonstrated that AGM-derived endothelial cells (ECs) engineered to constitutively express AKT (AGM AKT-ECs) can provide an in vitro niche that recapitulates embryonic HSC specification and amplification. Specifically, nonengrafting embryonic precursors, including the VE-cadherin-expressing population that lacks hematopoietic surface markers, cocultured with AGM AKT-ECs specified into long-term, adult-engrafting HSCs, establishing that a vascular niche is sufficient to induce the endothelial-to-HSC transition in vitro. Subsequent to hematopoietic induction, coculture with AGM AKT-ECs also substantially increased the numbers of HSCs derived from VE-cadherin?CD45? AGM hematopoietic cells, consistent with a role in supporting further HSC maturation and self-renewal. We also identified conditions that included NOTCH activation with an immobilized NOTCH ligand that were sufficient to amplify AGM-derived HSCs following their specification in the absence of AGM AKT-ECs. Together, these studies begin to define the critical niche components and resident signals required for HSC induction and self-renewal ex vivo, and thus provide insight for development of defined in vitro systems targeted toward HSC generation for therapeutic applications.

| S-EPMC4463208 | biostudies-literature

Interleukin-1-mediated hematopoietic cell regulation in the aorta-gonad-mesonephros region of the mouse embryo.

Project description:Hematopoiesis during development is a dynamic process, with many factors involved in the emergence and regulation of hematopoietic stem cells (HSCs) and progenitor cells. Whereas previous studies have focused on developmental signaling and transcription factors in embryonic hematopoiesis, the role of well-known adult hematopoietic cytokines in the embryonic hematopoietic system has been largely unexplored. The cytokine interleukin-1 (IL-1), best known for its proinflammatory properties, has radioprotective effects on adult bone marrow HSCs, induces HSC mobilization, and increases HSC proliferation and/or differentiation. Here we examine IL-1 and its possible role in regulating hematopoiesis in the midgestation mouse embryo. We show that IL-1, IL-1 receptors (IL-1Rs), and signaling mediators are expressed in the aorta-gonad-mesonephros (AGM) region during the time when HSCs emerge in this site. IL-1 signaling is functional in the AGM, and the IL-1RI is expressed ventrally in the aortic subregion by some hematopoietic, endothelial, and mesenchymal cells. In vivo analyses of IL-1RI-deficient embryos show an increased myeloid differentiation, concomitant with a slight decrease in AGM HSC activity. Our results suggest that IL-1 is an important homeostatic regulator at the earliest time of HSC development, acting to limit the differentiation of some HSCs along the myeloid lineage.

| S-EPMC2597597 | biostudies-literature

Kit ligand has a critical role in mouse yolk sac and aorta-gonad-mesonephros hematopoiesis.

Project description: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.

| S-EPMC6172468 | biostudies-literature

Pro-infammatory Aorta-Gonad-Mesonephros-associated macrophages are involved in embryonic development of hematopoietic stem cells

Project description:Hematopoietic stem cells (HSC) are generated from specialized endothelial cells of the embryonic aorta. Previously, inflammatory factors have been implicated in regulating mouse HSC development, but it is unclear what cells in the embryonic aorta-gonad- mesonephros (AGM) microenvironment produce these factors. In the adult, macrophages play both pro- and anti-inflammatory roles. We sought to examine whether macrophages or other hematopoietic cells found in the embryo prior to HSC generation are involved in the AGM HSC-generative microenvironment. Our CyTOF results indicate two abundant myeloid cell types - mannose-receptor positive AGM- associated macrophages (AGM-aM) and mannose-receptor negative macrophages/progenitors. We show that the appearance of macrophages in the AGM is dependent on CX3CR1. AGM-aM express a pro-inflammatory signature, localize to the embryonic aorta and dynamically interact with nascent and emerging intra-aortic hematopoietic cells (IAHC). Importantly, upon macrophage depletion, no adult- repopulating HSCs are detected, thus implicating unique pro-inflammatory AGM- associated macrophages in regulating the embryonic development of HSCs.

2019-06-01 | GSE130579 | GEO

Expression data from mouse aorta-gonad-mesonephros(AGM) derived stromal cells

2008-10-10 | GSE11891 | GEO

Pak2 regulates hematopoietic progenitor cell proliferation, survival, and differentiation.

Project description:p21-Activated kinase 2 (Pak2), a serine/threonine kinase, has been previously shown to be essential for hematopoietic stem cell (HSC) engraftment. However, Pak2 modulation of long-term hematopoiesis and lineage commitment remain unreported. Using a conditional Pak2 knockout mouse model, we found that disruption of Pak2 in HSCs induced profound leukopenia and a mild macrocytic anemia. Although loss of Pak2 in HSCs leads to less efficient short- and long-term competitive hematopoiesis than wild-type cells, it does not affect HSC self-renewal per se. Pak2 disruption decreased the survival and proliferation of multicytokine stimulated immature progenitors. Loss of Pak2 skewed lineage differentiation toward granulocytopoiesis and monocytopoiesis in mice as evidenced by (a) a three- to sixfold increase in the percentage of peripheral blood granulocytes and a significant increase in the percentage of granulocyte-monocyte progenitors in mice transplanted with Pak2-disrupted bone marrow (BM); (b)Pak2-disrupted BM and c-kit(+) cells yielded higher numbers of more mature subsets of granulocyte-monocyte colonies and polymorphonuclear neutrophils, respectively, when cultured in the presence of granulocyte-macrophage colony-stimulating factor. Pak2 disruption resulted, respectively, in decreased and increased gene expression of transcription factors JunB and c-Myc, which may suggest underlying mechanisms by which Pak2 regulates granulocyte-monocyte lineage commitment. Furthermore, Pak2 disruption led to (a) higher percentage of CD4(+) CD8(+) double positive T cells and lower percentages of CD4(+) CD8(-) or CD4(-) CD8(+) single positive T cells in thymus and (b) decreased numbers of mature B cells and increased numbers of Pre-Pro B cells in BM, suggesting defects in lymphopoiesis.

| S-EPMC4409559 | biostudies-literature

Transcription profiling of mouse aorta-gonad-mesonephros(AGM) derived stromal cells

Project description:A mouse AGM-derived cell line, AGM-s3, was shown to support the development of hematopoietic stem cells. To elucidate the molecular mechanisms regulating early hematopoiesis, we obtained subclones from AGM-s3, some of which were hematopoiesis supportive (s3-A9) and others which were non-supportive (s3-A7), and we analyzed the gene expression profiles by gene chip analysis. Experiment Overall Design: Genome-wide gene expression was examined using Affymetrix GeneChip array. Assays were performed according to the manufacturer's protocol. Total RNA was isolated from each stromal cell lines. We analysed 3 cell lines, AGM-s3-A9, AGM-s3-A7 and OP9. AGM-s3-A9 and OP9 are hematopoiesis supportive cell lines. AGM-s3-A7 is a hematopoiesis non-supportive cell line.

2008-10-26 | E-GEOD-11891 | biostudies-arrayexpress

RNA sequence of embryonic dorsal skin and AGM (Aorta-gonad-mesonephros) tissues

Project description:Purpose: The goals of this study are to identify the different gene expresion level in dorsal skin cells or AGM region at different embryonic stages Methods: Dorsal skin cells were collected from different-staged embryo: E9.5, E10.5 E12.5 and E14.5. AGM were collected from different-staged embryo: E9.5, E10.5 and E11.5. In duplicate. RNA were extrated and analyzed using RNA sequencing. For dorsal skine tissues, we screened the genes were highly expressed at early embryonic stage E9.5, but not later stages (E10.5, E12.5, and E14.5). For embryonic AGM tissues, we selected the genes were highly expressed at early embryonic stage E9.5, but not later stages (E10.5 and E11.5). The gene list were filtered based on secreted potein candidates. These gene candidates might function as novel embryonic anti-tumor factors Results: Using an optimized data analysis workflow, we mapped the gene list for potential secretory anti-tumor factors. Conclusions: One of the top gene from the gene lists is NEPN which we hypotherze it has unique anti-tumor function in the early embryonic microenvirnemt and might be used as a novel cancer therapeutic drug

2021-06-01 | GSE125271 | GEO

Effects of shear stress on cells of the aorta-gonad-mesonephros (AGM)

Project description:Blood flow promotes emergence of definitive hematopoietic stem cells (HSCs) in the developing embryo, yet the signals generated by hemodynamic forces that influence hematopoietic potential remain poorly defined. In transplantation assays of hematopoietic reconstitution, we find that fluid shear stress endows long-term multilineage engraftment potential upon early hematopoietic tissues at E9.5 not previously described to harbor HSCs. Effects on hematopoiesis appear to be mediated in part by prostaglandin E2 (PGE2) and the cyclic AMP-protein kinase A (cAMP-PKA) signaling axis. Studies of Ncx1 cardiac mutants corroborate that blood flow is required for sufficient COX2 levels and phosphorylation of CREB. Further implicating PGE2 in mediating the effects of shear stress, we find that E10.5 and E11.5 AGM treated transiently with the synthetic analog dmPGE2 engraft more robustly and contribute to greater lymphoid reconstitution. These data provide a mechanism by which biomechanical forces induced by blood flow modulate hematopoietic potential. -

2015-04-05 | GSE62463 | GEO

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