The Experts below are selected from a list of 5022 Experts worldwide ranked by ideXlab platform
Tatsutoshi Nakahata - One of the best experts on this subject based on the ideXlab platform.
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biomimetic aorta gonad mesonephros on a chip to study human developmental hematopoiesis
bioRxiv, 2019Co-Authors: Ryohichi Sugimura, Ryo Ohta, Chihiro Mori, Takafumi Mano, Emi Sano, Kaori Kosugi, Tatsutoshi Nakahata, Akira Niwa, Megumu K Saito, Yusuke TorisawaAbstract:ABSTRACT A fundamental limitation in the derivation of hematopoietic stem and progenitor cells is the imprecise understanding of human developmental hematopoiesis. Herein we established a multilayer microfluidic Aorta-Gonad-Mesonephros (AGM)-on-a-chip to emulate developmental hematopoiesis from human pluripotent stem cells. We show that the AGM-chip efficiently derives endothelial to hematopoietic transition (EHT) in the presence of both mesenchymal stroma and endothelial cells. The AGM-chip could dissect the cellular and molecular mechanisms of human developmental hematopoiesis.
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Role of the microenvironment of the embryonic aorta-gonad-mesonephros region in hematopoiesis.
Annals of the New York Academy of Sciences, 2006Co-Authors: Mitsuo Nishikawa, Tatsutoshi Nakahata, Tomoyuki Tahara, Atsushi Hinohara, Atushi Miyajima, Akihiro ShimosakaAbstract:Although various cytokines, growth factors, and chemokines are known to regulate hematopoiesis, expansion of hematopoietic stem cells (HSCs) in vitro with the use of such agents has proved problematic. Stromal cells are major components of the microenvironment that surrounds hematopoietic cells and are thought to play an important role in hematopoiesis in vivo. Co-culture of HSCs with stromal cells promotes hematopoiesis and self-renewal of HSCs. Definitive hematopoietic cells first appear during mammalian embryonic development in the aorta-gonad-mesonephros (AGM) region, and it is therefore thought that the microenvironment of this region plays an important role in HSC ontogeny. We have adopted two approaches to studying the contribution of the AGM microenvironment to hematopoiesis. In the first approach, we have developed an in vitro culture system for mouse AGM explants. Hematopoiesis is enhanced in such cultures by the presence of the combination of stem cell factor (SCF), basic fibroblast growth factor, leukemia inhibitory factor, and oncostatin M (SFLO culture). However, transplantation assays revealed that HSCs capable of long-term reconstitution of the hematopoietic compartment of irradiated mice (LTR-HSCs) do not expand in AGM-SFLO cultures; rather, these cultures appear to provide a favorable microenvironment for hematogenic angioblasts that are precursors of both endothelial and hematopoietic cells. In our second approach, we have established various stromal cell lines from the mouse AGM region. The AGM-S3 cell line supports human and mouse primitive hematopoietic cells as well as mouse LTR-HSCs. Maintenance of LTR-HSCs is mediated by a mechanism other than SCF signaling through its receptor (c-Kit). These two in vitro approaches should prove useful for further elucidation of the mechanisms that underlie hematopoiesis and HSC self-renewal.
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hepatic differentiation induced by oncostatin m attenuates fetal liver hematopoiesis
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Takashi Sekiguchi, Kohichiro Tsuji, Yoshiaki Ito, Tatsutoshi NakahataAbstract:Embryonic liver is a transient site for definitive hematopoiesis. Along with maturation of the bone marrow and spleen, hematopoietic cells relocate from the liver to their final destinations while the liver starts organizing its own structure and develops numerous metabolic functions toward adult. Recently, it was demonstrated that the signal exerted by oncostatin M (OSM) through gp130 plays a pivotal role in the maturation process of the liver both in vitro and in vivo. However, the molecular basis underlying the termination of embryonic hematopoiesis remains unknown. In this study, we report that primary culture of fetal hepatic cells from embryonic day 14.5 murine embryos supported expansion of blood cells from Lin−Sca-1+c-Kit+ cells, giving rise to myeloid, lymphoid, and erythroid lineages. Of interest, promotion of hepatic development by OSM and glucocorticoid strongly suppressed in vitro hematopoiesis. Consistent with these results, hepatic culture from the embryonic day 18.5 liver no longer supported hematopoiesis. These data together with the previous observations suggest that the signals exerted by OSM and glucocorticoid induce hepatic differentiation, which in turn terminate embryonic hematopoiesis and promote relocation of hematopoietic cells.
Mirjana Efremova - One of the best experts on this subject based on the ideXlab platform.
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Decoding human fetal liver Haematopoiesis
Nature, 2019Co-Authors: Dorin-mirel Popescu, Emily Calderbank, Rachel Botting, Emily Stephenson, Kile Green, Simone Webb, Laura Jardine, Krzysztof Polanski, Issac Goh, Mirjana EfremovaAbstract:Definitive Haematopoiesis in the fetal liver supports self-renewal and differentiation of haematopoietic stem cells/multipotent progenitors (HSC/MPPs) but remains poorly defined in humans. Using single cell transcriptome profiling of ~140,000 liver and ~74,000 skin, kidney and yolk sac cells, we identify the repertoire of human blood and immune cells during development. We infer differentiation trajectories from HSC/MPPs and evaluate the impact of tissue microenvironment on blood and immune cell development. We reveal physiological erythropoiesis in fetal skin and the presence of mast cells, NK and ILC precursors in the yolk sac. We demonstrate a shift in fetal liver haematopoietic composition during gestation away from being erythroid-predominant, accompanied by a parallel change in HSC/MPP differentiation potential, which we functionally validate. Our integrated map of fetal liver Haematopoiesis provides a blueprint for the study of paediatric blood and immune disorders, and a valuable reference for harnessing the therapeutic potential of HSC/MPPs.
Kohichiro Tsuji - One of the best experts on this subject based on the ideXlab platform.
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generation of definitive hematopoietic stem cells from murine early yolk sac and paraaortic splanchnopleures by aorta gonad mesonephros region derived stromal cells
Blood, 2001Co-Authors: Sahoko Matsuoka, Kohichiro Tsuji, Hiroaki Hisakawa, Yasuhiro EbiharaAbstract:There is controversy as to whether murine definitive hematopoiesis originates from yolk sac (YS) or the intraembryonic region. This study reports the generation of definitive hematopoietic stem cells (HSCs) from both early YS and intraembryonic paraaortic splanchnopleures (P-Sp) on AGM-S3 stromal cells derived from the aorta-gonad-mesonephros (AGM) region at 10.5 days post coitum (dpc). YS and P-Sp cells at 8.5 dpc generated no definitive hematopoiesis-derived colony-forming cells in cocultures with AGM-S3 cells, but spleen colony-forming cells and HSCs capable of reconstituting definitive hematopoiesis in adult mice simultaneously appeared on day 4 of coculture. Precursors for definitive HSCs were present in YS and P-Sp at 8.0 dpc, a time when YS and embryo were not connected by blood vessels. It is proposed that precursors with the potential to generate definitive HSCs appear independently in YS and intraembryonic P-Sp and that the P-Sp or AGM region affords the microenvironment that facilitates generation of definitive hematopoiesis from precursors.
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hepatic differentiation induced by oncostatin m attenuates fetal liver hematopoiesis
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Takashi Sekiguchi, Kohichiro Tsuji, Yoshiaki Ito, Tatsutoshi NakahataAbstract:Embryonic liver is a transient site for definitive hematopoiesis. Along with maturation of the bone marrow and spleen, hematopoietic cells relocate from the liver to their final destinations while the liver starts organizing its own structure and develops numerous metabolic functions toward adult. Recently, it was demonstrated that the signal exerted by oncostatin M (OSM) through gp130 plays a pivotal role in the maturation process of the liver both in vitro and in vivo. However, the molecular basis underlying the termination of embryonic hematopoiesis remains unknown. In this study, we report that primary culture of fetal hepatic cells from embryonic day 14.5 murine embryos supported expansion of blood cells from Lin−Sca-1+c-Kit+ cells, giving rise to myeloid, lymphoid, and erythroid lineages. Of interest, promotion of hepatic development by OSM and glucocorticoid strongly suppressed in vitro hematopoiesis. Consistent with these results, hepatic culture from the embryonic day 18.5 liver no longer supported hematopoiesis. These data together with the previous observations suggest that the signals exerted by OSM and glucocorticoid induce hepatic differentiation, which in turn terminate embryonic hematopoiesis and promote relocation of hematopoietic cells.
Tiago C Luis - One of the best experts on this subject based on the ideXlab platform.
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canonical wnt signaling regulates hematopoiesis in a dosage dependent fashion
Cell Stem Cell, 2011Co-Authors: Tiago C Luis, Brigitta A E Naber, Paul P C Roozen, Martijn H Brugman, Edwin F E De Haas, Mehrnaz Ghazvini, Willem E Fibbe, Jacques J M Van DongenAbstract:Canonical Wnt signaling has been implicated in the regulation of hematopoiesis. By employing a Wnt-reporter mouse, we observed that Wnt signaling is differentially activated during hematopoiesis, suggesting an important regulatory role for specific Wnt signaling levels. To investigate whether canonical Wnt signaling regulates hematopoiesis in a dosage-dependent fashion, we analyzed the effect of different mutations in the Adenomatous polyposis coli gene (Apc), a negative modulator of the canonical Wnt pathway. By combining different targeted hypomorphic alleles and a conditional deletion allele of Apc, a gradient of five different Wnt signaling levels was obtained in vivo. We here show that different, lineage-specific Wnt dosages regulate hematopoietic stem cells (HSCs), myeloid precursors, and T lymphoid precursors during hematopoiesis. Differential, lineage-specific optimal Wnt dosages provide a unifying concept that explains the differences reported among inducible gain-of-function approaches, leading to either HSC expansion or depletion of the HSC pool.
Joachim Pircher - One of the best experts on this subject based on the ideXlab platform.
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The AIM2 inflammasome exacerbates atherosclerosis in clonal Haematopoiesis
Nature, 2021Co-Authors: Trevor P. Fidler, Chenyi Xue, Mustafa Yalcinkaya, Brian Hardaway, Sandra Abramowicz, Tong Xiao, Wenli Liu, David G. Thomas, Mohammad Ali Hajebrahimi, Joachim PircherAbstract:Accelerated atherosclerosis in a mouse model of clonal Haematopoiesis is prevented by genetic interruption of AIM2 inflammasome activation or by inhibition of interleukin-1β. Clonal Haematopoiesis, which is highly prevalent in older individuals, arises from somatic mutations that endow a proliferative advantage to haematopoietic cells. Clonal Haematopoiesis increases the risk of myocardial infarction and stroke independently of traditional risk factors^ 1 . Among the common genetic variants that give rise to clonal Haematopoiesis, the JAK2 ^ V617F ( JAK2 ^ VF ) mutation, which increases JAK–STAT signalling, occurs at a younger age and imparts the strongest risk of premature coronary heart disease^ 1 , 2 . Here we show increased proliferation of macrophages and prominent formation of necrotic cores in atherosclerotic lesions in mice that express Jak2 ^ VF selectively in macrophages, and in chimeric mice that model clonal Haematopoiesis. Deletion of the essential inflammasome components caspase 1 and 11, or of the pyroptosis executioner gasdermin D, reversed these adverse changes. Jak2 ^ VF lesions showed increased expression of AIM2, oxidative DNA damage and DNA replication stress, and Aim2 deficiency reduced atherosclerosis. Single-cell RNA sequencing analysis of Jak2 ^ VF lesions revealed a landscape that was enriched for inflammatory myeloid cells, which were suppressed by deletion of Gsdmd . Inhibition of the inflammasome product interleukin-1β reduced macrophage proliferation and necrotic formation while increasing the thickness of fibrous caps, indicating that it stabilized plaques. Our findings suggest that increased proliferation and glycolytic metabolism in Jak2 ^ VF macrophages lead to DNA replication stress and activation of the AIM2 inflammasome, thereby aggravating atherosclerosis. Precise application of therapies that target interleukin-1β or specific inflammasomes according to clonal Haematopoiesis status could substantially reduce cardiovascular risk.