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1
Nathan, David G. "Regulation of Hematopoiesis." Pediatric Research 27, no. 5 (May 1990): 423–31. http://dx.doi.org/10.1203/00006450-199005000-00001.
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Li, Haiyan, Jin Jin, shao-Cong Sun, and Stephanie S. Watowich. "Molecular Regulation of Adult Hematopoiesis By GATA-2." Blood 124, no. 21 (December 6, 2014): 4337. http://dx.doi.org/10.1182/blood.v124.21.4337.4337.
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Abstract GATA-2 is a zinc finger-containing transcriptional regulator that plays important roles in embryonic and adult hematopoiesis. Mutations in human GATA2 are associated with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), as well as immunodeficiency disorders that present with a profound loss of monocytes, dendritic cells and other myeloid lineage populations. Recent work reveals crucial roles for GATA-2 in definitive hematopoietic stem/progenitor cell activity, vascular integrity and lymphatic development. However, the molecular mechanisms by which GATA-2 controls adult hematopoiesis via hematopoietic-cell autonomous functions are largely unknown. To address this question, we generated a tamoxifen-inducible Gata2-deficient mouse strain by breeding Gata2flox/flox mice with Cre-ER transgenic animals. Following tamoxifen treatment, Cre-ER Gata2flox/flox mice show a rapid and profound loss of circulating neutrophils, monocytes and lymphocytes, concomitant with development of anemia. These results are consistent with the requirement for GATA-2 in hematopoietic stem/progenitor cells, and may also reflect GATA-2 function in endothelial cells within the vascular niche. To explore hematopoietic-specific GATA-2 activity, we generated bone marrow chimeric mice with hematopoietic-restricted Gata2-deficiency by transplanting Cre-ER Gata2flox/flox hematopoietic cells into wild type recipients. Cre-ER Gata2flox/flox bone marrow chimeras show rapid development of cytopenias upon tamoxifen exposure, suggesting a cell autonomous role for GATA-2 in maintaining adult hematopoiesis. Strikingly, hematopoietic progenitor cells rapidly lose c-Kit expression upon inducible Gata2 deletion. Chromatin immunoprecipitation and reporter assays suggest GATA-2 cooperates with C/EBPa in regulating kit transcription. Our study suggests conditional deletion of Gata2 restricted to the hematopoietic compartment provides a model for bone marrow failure associated with MDS and mutant GATA2 human immunodeficiencies that may enable further insight into the molecular network by which GATA-2 mediates definitive hematopoiesis. Supported by grants from NIH (AI098099) and the MD Anderson Center for Cancer Epigenetics.(SSW) and the MD Anderson Center for Cancer and Inflammation (HSL). Disclosures No relevant conflicts of interest to declare.
3
Zon, LI. "Developmental biology of hematopoiesis." Blood 86, no. 8 (October 15, 1995): 2876–91. http://dx.doi.org/10.1182/blood.v86.8.2876.bloodjournal8682876.
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The cellular and environmental regulation of hematopoiesis has been generally conserved throughout vertebrate evolution, although subtle species differences exist. The factors that regulate hematopoietic stem cell homeostasis may closely resemble the inducers of embryonic patterning, rather than the factors that stimulate hematopoietic cell proliferation and differentiation. Comparative study of embryonic hematopoiesis in lower vertebrates can generate testable hypotheses that similar mechanisms occur during hematopoiesis in higher species.
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Zon, LI. "Developmental biology of hematopoiesis." Blood 86, no. 8 (October 15, 1995): 2876–91. http://dx.doi.org/10.1182/blood.v86.8.2876.2876.
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Abstract The cellular and environmental regulation of hematopoiesis has been generally conserved throughout vertebrate evolution, although subtle species differences exist. The factors that regulate hematopoietic stem cell homeostasis may closely resemble the inducers of embryonic patterning, rather than the factors that stimulate hematopoietic cell proliferation and differentiation. Comparative study of embryonic hematopoiesis in lower vertebrates can generate testable hypotheses that similar mechanisms occur during hematopoiesis in higher species.
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de Rooij, Laura P. M. H., Derek C. H. Chan, Ava Keyvani Chahi, and Kristin J. Hope. "Post-transcriptional regulation in hematopoiesis: RNA binding proteins take control." Biochemistry and Cell Biology 97, no. 1 (February 2019): 10–20. http://dx.doi.org/10.1139/bcb-2017-0310.
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Normal hematopoiesis is sustained through a carefully orchestrated balance between hematopoietic stem cell (HSC) self-renewal and differentiation. The functional importance of this axis is underscored by the severity of disease phenotypes initiated by abnormal HSC function, including myelodysplastic syndromes and hematopoietic malignancies. Major advances in the understanding of transcriptional regulation of primitive hematopoietic cells have been achieved; however, the post-transcriptional regulatory layer that may impinge on their behavior remains underexplored by comparison. Key players at this level include RNA-binding proteins (RBPs), which execute precise and highly coordinated control of gene expression through modulation of RNA properties that include its splicing, polyadenylation, localization, degradation, or translation. With the recent identification of RBPs having essential roles in regulating proliferation and cell fate decisions in other systems, there has been an increasing appreciation of the importance of post-transcriptional control at the stem cell level. Here we discuss our current understanding of RBP-driven post-transcriptional regulation in HSCs, its implications for normal, perturbed, and malignant hematopoiesis, and the most recent technological innovations aimed at RBP–RNA network characterization at the systems level. Emerging evidence highlights RBP-driven control as an underappreciated feature of primitive hematopoiesis, the greater understanding of which has important clinical implications.
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Chen, Sisi, and Omar Abdel-Wahab. "Splicing regulation in hematopoiesis." Current Opinion in Hematology 28, no. 4 (May 10, 2021): 277–83. http://dx.doi.org/10.1097/moh.0000000000000661.
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QUESENBERRY, PETER J., IAN K. MCNIECE, H. ELIZABETH MCGRATH, DANIEL S. TEMELES, GWEN B. BABER, and DONNA H. DEACON. "Stromal Regulation of Hematopoiesis." Annals of the New York Academy of Sciences 554, no. 1 Molecular and (May 1989): 116–24. http://dx.doi.org/10.1111/j.1749-6632.1989.tb22414.x.
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Sashida, Goro, and Atsushi Iwama. "Epigenetic regulation of hematopoiesis." International Journal of Hematology 96, no. 4 (September 29, 2012): 405–12. http://dx.doi.org/10.1007/s12185-012-1183-x.
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North, Trista. "Regulation of vertebrate hematopoiesis." Experimental Hematology 53 (September 2017): S40. http://dx.doi.org/10.1016/j.exphem.2017.06.042.
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Wimmer, Antonia, Sophia K. Khaldoyanidi, Martin Judex, Naira Serobyan, Richard G. DiScipio, and Ingrid U. Schraufstatter. "CCL18/PARC stimulates hematopoiesis in long-term bone marrow cultures indirectly through its effect on monocytes." Blood 108, no. 12 (December 1, 2006): 3722–29. http://dx.doi.org/10.1182/blood-2006-04-014399.
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AbstractChemokines play a role in regulating hematopoietic stem cell function, including migration, proliferation, and retention. We investigated the involvement of CCL18 in the regulation of bone marrow hematopoiesis. Treatment of human long-term bone marrow cultures (LTBMCs) with CCL18 resulted in significant stimulation of hematopoiesis, as measured by the total number of hematopoietic cells and their committed progenitors produced in culture. Monocytes/macrophages, whose survival was almost doubled in the presence of CCL18 compared with controls, were the primary cells mediating this effect. Conditioned media from CCL18-treated mature monocytes fostered colony-promoting activity that increased the number of colonies formed by hematopoietic progenitor cells. Gene expression profiling of CCL18-stimulated monocytes demonstrated more than 200 differentially expressed genes, including those regulating apoptosis (caspase-8) and proliferation (IL-6, IL-15, stem cell factor [SCF]). Up-regulation of these cytokines was confirmed on the protein expression level. The contribution of SCF and IL-6 in CCL18-mediated stimulatory activity for hematopoiesis was confirmed by SCF- and IL-6–blocking antibodies that significantly inhibited the colony-promoting activity of CCL18-stimulated conditioned medium. In addition to the effect on monocytes, CCL18 facilitated the formation of the adherent layer in LTBMCs and increased the proliferation of stromal fibroblast-like cells.
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Sood, Raman, and Paul Liu. "Novel Insights into the Genetic Controls of Primitive and Definitive Hematopoiesis from Zebrafish Models." Advances in Hematology 2012 (2012): 1–13. http://dx.doi.org/10.1155/2012/830703.
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Hematopoiesis is a dynamic process where initiation and maintenance of hematopoietic stem cells, as well as their differentiation into erythroid, myeloid and lymphoid lineages, are tightly regulated by a network of transcription factors. Understanding the genetic controls of hematopoiesis is crucial as perturbations in hematopoiesis lead to diseases such as anemia, thrombocytopenia, or cancers, including leukemias and lymphomas. Animal models, particularly conventional and conditional knockout mice, have played major roles in our understanding of the genetic controls of hematopoiesis. However, knockout mice for most of the hematopoietic transcription factors are embryonic lethal, thus precluding the analysis of their roles during the transition from embryonic to adult hematopoiesis. Zebrafish are an ideal model organism to determine the function of a gene during embryonic-to-adult transition of hematopoiesis since bloodless zebrafish embryos can develop normally into early larval stage by obtaining oxygen through diffusion. In this review, we discuss the current status of the ontogeny and regulation of hematopoiesis in zebrafish. By providing specific examples of zebrafish morphants and mutants, we have highlighted the contributions of the zebrafish model to our overall understanding of the roles of transcription factors in regulation of primitive and definitive hematopoiesis.
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Davis, Amanda G., Jaclyn M. Einstein, Dinghai Zheng, Nathan D. Jayne, Xiang-Dong Fu, Bin Tian, Gene W. Yeo, and Dong-Er Zhang. "A CRISPR RNA-binding protein screen reveals regulators of RUNX1 isoform generation." Blood Advances 5, no. 5 (March 3, 2021): 1310–23. http://dx.doi.org/10.1182/bloodadvances.2020002090.
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Abstract The proper balance of hematopoietic stem cell (HSC) self-renewal and differentiation is critical for normal hematopoiesis and is disrupted in hematologic malignancy. Among regulators of HSC fate, transcription factors have a well-defined central role, and mutations promote malignant transformation. More recently, studies have illuminated the importance of posttranscriptional regulation by RNA-binding proteins (RBPs) in hematopoiesis and leukemia development. However, the RBPs involved and the breadth of regulation are only beginning to be elucidated. Furthermore, the intersection between posttranscriptional regulation and hematopoietic transcription factor function is poorly understood. Here, we studied the posttranscriptional regulation of RUNX1, a key hematopoietic transcription factor. Alternative polyadenylation (APA) of RUNX1 produces functionally antagonistic protein isoforms (RUNX1a vs RUNX1b/c) that mediate HSC self-renewal vs differentiation, an RNA-processing event that is dysregulated in malignancy. Consequently, RBPs that regulate this event directly contribute to healthy and aberrant hematopoiesis. We modeled RUNX1 APA using a split GFP minigene reporter and confirmed the sensitivity of our model to detect changes in RNA processing. We used this reporter in a clustered regularly interspaced short palindromic repeats (CRISPR) screen consisting of single guide RNAs exclusively targeting RBPs and uncovered HNRNPA1 and KHDRBS1 as antagonistic regulators of RUNX1a isoform generation. Overall, our study provides mechanistic insight into the posttranscriptional regulation of a key hematopoietic transcription factor and identifies RBPs that may have widespread and important functions in hematopoiesis.
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Fielding, Claire, and Simón Méndez-Ferrer. "Neuronal regulation of bone marrow stem cell niches." F1000Research 9 (June 16, 2020): 614. http://dx.doi.org/10.12688/f1000research.22554.1.
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The bone marrow (BM) is the primary site of postnatal hematopoiesis and hematopoietic stem cell (HSC) maintenance. The BM HSC niche is an essential microenvironment which evolves and responds to the physiological demands of HSCs. It is responsible for orchestrating the fate of HSCs and tightly regulates the processes that occur in the BM, including self-renewal, quiescence, engraftment, and lineage differentiation. However, the BM HSC niche is disturbed following hematological stress such as hematological malignancies, ionizing radiation, and chemotherapy, causing the cellular composition to alter and remodeling to occur. Consequently, hematopoietic recovery has been the focus of many recent studies and elucidating these mechanisms has great biological and clinical relevance, namely to exploit these mechanisms as a therapeutic treatment for hematopoietic malignancies and improve regeneration following BM injury. The sympathetic nervous system innervates the BM niche and regulates the migration of HSCs in and out of the BM under steady state. However, recent studies have investigated how sympathetic innervation and signaling are dysregulated under stress and the subsequent effect they have on hematopoiesis. Here, we provide an overview of distinct BM niches and how they contribute to HSC regulatory processes with a particular focus on neuronal regulation of HSCs under steady state and stress hematopoiesis.
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Kotsianidis, Ioannis, Jonathan D. Silk, Scott Patterson, Antonio Almeida, Costas Tsatalas, George Bourikas, Vincenzo Cerundolo, Irene A. G. Roberts, and Anastasios Karadimitris. "Regulation of Hematopoiesis In Vitro and In Vivo by Invariant NKT Cells." Blood 106, no. 11 (November 16, 2005): 2277. http://dx.doi.org/10.1182/blood.v106.11.2277.2277.
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Abstract Invariant NKT cells (iNKT cells) are a small subset of immunoregulatory T cells highly conserved in humans and mice. Upon activation by glycolipids presented by the MHC-like molecule CD1d, iNKT cells promptly secrete Th1/2 cytokines but also cytokines with hematopoietic potential such as IL-3 and GM-CSF. In mice, NKT cells activated by alpha-galactosylceramide (alphaGC), a potent glycolipid ligand, cause an in increase in extramedullary hematopoietic committed progenitor activity through secretion of these cytokines. We tested the role of iNKT cells in regulating hematopoiesis under conditions of activation and in steady state hematopoiesis. We found that GM-CSF-secreting alphaGC -activated iNKT cells enhanced (by 64%, n=5, p<0.05) the myeloid clonogenic potential of human cord blood hematopoietic progenitors; conversely, in the absence of NKT cells short- and long-term progenitor activity is decreased: 48% reduction in GFU-GM frequency, n=6; p<0.05 and a reduction of 18–60% in LTC-IC frequency in 4 independent experiments. These findings suggest that NKT cells are implicated in the regulation of hematopoiesis both in the presence and absence of immune activation. In accordance with these findings, iNKT cell-deficient mice compared to wild type animals display impaired hematopoiesis characterized by peripheral blood cytopenia (43% and 32% reduction in leucocyte and platelet counts respectively, n=10, p<0.001), reduced marrow cellularity (reduced by 35%, n=13, p<0.001), lower frequency and absolute numbers per hind limb of hematopoietic stem cells (HSC) as assessed by the cKit+Lin-Sca-1+ phenotype (reduced by 40% n=8, p<0.05, and 61% n=8, p<0.001, respectively), and reduced early (50% and 68% reduction in frequency and absolute numbers of LTC-IC respectively, n=4, p<0.05) and late (40% and 57% reduction in frequency and total number of CFU-GM per hind limb respectively, n=8, p<0.05) hematopoietic progenitors. We also show that CD1d is expressed on human HSC and CD1d-expressing HSC display short- and long-term clonogenic potential and can present the glycolipid a-galactosylceramide to iNKT cells suggesting that the iNKT cell-mediated regulation of hematopoiesis might operate through cell contact of NKT cells with HSC and interaction of the invariant TCR with CD1d on HSC. In conclusion, iNKT cells when activated enhance the clonogenic capacity of myeloid progenitors and can thus modulate innate immune responses. Additionally, they are required for maintenance of normal hematopoiesis in the absence of immune activation. Our findings offer further evidence for a concerted regulation of the immune and hematopoietic systems and the potential for new therapeutic approaches for the manipulation of hematopoiesis.
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Uckun, F. M., D. A. Vallera, and S. L. Wee. "B lymphocyte regulation of human hematopoiesis." Journal of Immunology 135, no. 6 (December 1, 1985): 3817–22. http://dx.doi.org/10.4049/jimmunol.135.6.3817.
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Abstract Epstein Barr virus (EBV)-transformed B lymphoblastoid cell lines (BLCL) were derived from seven different individuals. The ability of BLCL supernatants to stimulate hematopoietic colony formation in vitro was tested in a conventional stem cell assay system. Supernatants promoted the growth of single (GM, E, MK) as well as multi-lineage (GEMM) colonies in bone marrow cultures. Our results indicate that EBV-transformed B lymphocytes produce cytokines that affect in vitro stem cell proliferation and differentiation. These studies demonstrate the regulatory potential of activated B lymphocytes in human hematopoiesis.
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Takizawa, Hitoshi, Steffen Boettcher, and Markus G. Manz. "Demand-adapted regulation of early hematopoiesis in infection and inflammation." Blood 119, no. 13 (March 29, 2012): 2991–3002. http://dx.doi.org/10.1182/blood-2011-12-380113.
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AbstractDuring systemic infection and inflammation, immune effector cells are in high demand and are rapidly consumed at sites of need. Although adaptive immune cells have high proliferative potential, innate immune cells are mostly postmitotic and need to be replenished from bone marrow (BM) hematopoietic stem and progenitor cells. We here review how early hematopoiesis has been shaped to deliver efficient responses to increased need. On the basis of most recent findings, we develop an integrated view of how cytokines, chemokines, as well as conserved pathogen structures, are sensed, leading to divisional activation, proliferation, differentiation, and migration of hematopoietic stem and progenitor cells, all aimed at efficient contribution to immune responses and rapid reestablishment of hematopoietic homeostasis. We also outline how chronic inflammatory processes might impinge on hematopoiesis, potentially fostering hematopoietic stem cell diseases, and, how clinical benefit is and could be achieved by learning from nature.
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Remillieux-Leschelle, Nathalie, Pedro Santamaria, and Neel B. Randsholt. "Regulation of Larval Hematopoiesis in Drosophila melanogaster: A Role for the multi sex combs Gene." Genetics 162, no. 3 (November 1, 2002): 1259–74. http://dx.doi.org/10.1093/genetics/162.3.1259.
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Abstract Drosophila larval hematopoietic organs produce circulating hemocytes that ensure the cellular host defense by recognizing and neutralizing non-self or noxious objects through phagocytosis or encapsulation and melanization. Hematopoietic lineage specification as well as blood cell proliferation and differentiation are tightly controlled. Mutations in genes that regulate lymph gland cell proliferation and hemocyte numbers in the body cavity cause hematopoietic organ overgrowth and hemocyte overproliferation. Occasionally, mutant hemocytes invade self-tissues, behaving like neoplastic malignant cells. Two alleles of the Polycomb group (PcG) gene multi sex combs (mxc) were previously isolated as such lethal malignant blood neoplasm mutations. PcG genes regulate Hox gene expression in vertebrates and invertebrates and participate in mammalian hematopoiesis control. Hence we investigated the need for mxc in Drosophila hematopoietic organs and circulating hemocytes. We show that mxc-induced hematopoietic hyperplasia is cell autonomous and that mxc mainly controls plasmatocyte lineage proliferation and differentiation in lymph glands and circulating hemocytes. Loss of the Toll pathway, which plays a similar role in hematopoiesis, counteracted mxc hemocyte proliferation but not mxc hemocyte differentiation. Several PcG genes tested in trans had no effects on mxc hematopoietic phenotypes, whereas the trithorax group gene brahma is important for normal and mutant hematopoiesis control. We propose that mxc provides one of the regulatory inputs in larval hematopoiesis that control normal rates of plasmatocyte and crystal lineage proliferation as well as normal rates and timing of hemocyte differentiation.
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Jenkins, Brendan J., Andrew W. Roberts, Meri Najdovska, Dianne Grail, and Matthias Ernst. "The threshold of gp130-dependent STAT3 signaling is critical for normal regulation of hematopoiesis." Blood 105, no. 9 (May 1, 2005): 3512–20. http://dx.doi.org/10.1182/blood-2004-09-3751.
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Abstract The interleukin-6 (IL-6) cytokine family plays an important role in regulating cellular responses during hematopoiesis. We report here that mice homozygous for a knock-in mutation in the IL-6 cytokine family receptor signaling subunit glycoprotein (gp) 130 (gp130Y757F/Y757F) that leads to gp130-dependent signal transducers and activators of transcription (STAT) 1/3 hyperactivation develop a broad spectrum of hematopoietic abnormalities, including splenomegaly, lymphadenopathy, and thrombocytosis. To determine whether STAT3 hyperactivation was responsible for the perturbed hematopoiesis in gp130Y757F/Y757F mice, we generated gp130Y757F/Y757F mice on a Stat3 heterozygous (Stat3+/-) background to specifically reduce gp130-dependent activation of STAT3, but not STAT1. Normal hematopoiesis was observed in gp130Y757F/Y757F:Stat3+/- bone marrow and spleen, with no evidence of the splenomegaly and thrombocytosis displayed by gp130Y757F/Y757F mice. The perturbed cellular composition of thymus and lymph nodes in gp130Y757F/Y757F mice was also alleviated in gp130Y757F/Y757F: Stat3+/- mice. Furthermore, we show that hematopoietic cells from gp130Y757F/Y757F mice exhibited increased survival and proliferation in response to IL-6 family cytokines. Collectively, these data provide genetic evidence that gp130-dependent STAT3 hyperactivation during hematopoiesis has pathological consequences affecting multiple organs, and therefore identify the threshold of STAT3 signaling elicited by IL-6 family cytokines as a critical determinant for hematopoietic homeostasis.
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Orelio, Claudia, Esther Haak, Marian Peeters, and Elaine Dzierzak. "Interleukin-1–mediated hematopoietic cell regulation in the aorta-gonad-mesonephros region of the mouse embryo." Blood 112, no. 13 (December 15, 2008): 4895–904. http://dx.doi.org/10.1182/blood-2007-12-123836.
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Abstract 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.
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Kotsianidis, Ioannis, Jonathan D. Silk, Emmanouil Spanoudakis, Scott Patterson, Antonio Almeida, Richard R. Schmidt, Costas Tsatalas, et al. "Regulation of hematopoiesis in vitro and in vivo by invariant NKT cells." Blood 107, no. 8 (April 15, 2006): 3138–44. http://dx.doi.org/10.1182/blood-2005-07-2804.
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AbstractInvariant natural killer T cells (iNKT cells) are a small subset of immunoregulatory T cells highly conserved in humans and mice. On activation by glycolipids presented by the MHC-like molecule CD1d, iNKT cells promptly secrete T helper 1 and 2 (Th1/2) cytokines but also cytokines with hematopoietic potential such as GM-CSF. Here, we show that the myeloid clonogenic potential of human hematopoietic progenitors is increased in the presence of glycolipid-activated, GM-CSF–secreting NKT cells; conversely, short- and long-term progenitor activity is decreased in the absence of NKT cells, implying regulation of hematopoiesis in both the presence and the absence of immune activation. In accordance with these findings, iNKT-cell–deficient mice display impaired hematopoiesis characterized by peripheral-blood cytopenias, reduced marrow cellularity, lower frequency of hematopoietic stem cells (HSCs), and reduced early and late hematopoietic progenitors. We also show that CD1d is expressed on human HSCs. CD1d-expressing HSCs display short- and long-term clonogenic potential and can present the glycolipid α-galactosylceramide to iNKT cells. Thus, iNKT cells emerge as the first subset of regulatory T cells that are required for effective hematopoiesis in both steady-state conditions and under conditions of immune activation.
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Liu, Ying, Khalid Timani, Charlie Mantel, Yan Fan, Giao Hangoc, Scott Cooper, Johnny J. He, and Hal E. Broxmeyer. "TIP110/p110nrb/SART3/p110 regulation of hematopoiesis through CMYC." Blood 117, no. 21 (May 26, 2011): 5643–51. http://dx.doi.org/10.1182/blood-2010-12-325332.
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Abstract Intracellular factors are involved in and essential for hematopoiesis. HIV-1 Tat-interacting protein of 110 kDa (TIP110; p110nrb/SART3/p110) is an RNA-binding nuclear protein implicated in the regulation of HIV-1 gene and host gene transcription, pre-mRNA splicing, and cancer immunology. In the present study, we demonstrate a role for TIP110 in the regulation of hematopoiesis. TIP110 was expressed in human CD34+ cells and decreased with differentiation of CD34+ cells. TIP110 mRNA was also expressed in phenotyped mouse marrow hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs). Using TIP110 transgenic (TIP110TG) and haploinsufficient (TIP110+/−) mice, we found that increased TIP110 expression enhanced HPC numbers, survival, and cell cycling, whereas decreased TIP110 expression had the opposite effects. Moreover, TIP110+/− bone marrow HPCs responded more effectively, and TIP110TG HPCs less effectively, than those of wild-type control mice to recovery from the cell-cycle–active drug 5-fluorouracil (5-FU). Unexplained sex differences were noted in HSC competitive repopulating ability, but not HPC numbers, in TIP110TG mice. Intracellularly, TIP110 regulated CMYC and GATA2 expression at the transcriptional level, and TIP110 and CMYC reciprocally regulated the expression of each other. These results demonstrate a role for TIP110 in the regulation of hematopoiesis, effects that are likely linked to TIP110 regulation of CMYC.
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Dent, Alexander, L. "T cell regulation of hematopoiesis." Frontiers in Bioscience Volume, no. 13 (2008): 6229. http://dx.doi.org/10.2741/3150.
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Zhao, Jimmy L., and David Baltimore. "Regulation of stress-induced hematopoiesis." Current Opinion in Hematology 22, no. 4 (July 2015): 286–92. http://dx.doi.org/10.1097/moh.0000000000000149.
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Anderson, Georgina A., Melanie Rodriguez, and Katie L. Kathrein. "Regulation of stress-induced hematopoiesis." Current Opinion in Hematology 27, no. 4 (May 6, 2020): 279–87. http://dx.doi.org/10.1097/moh.0000000000000589.
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Chitteti, Brahmananda R., Monique Bethel, Melissa A. Kacena, and Edward F. Srour. "CD166 and regulation of hematopoiesis." Current Opinion in Hematology 20, no. 4 (July 2013): 273–80. http://dx.doi.org/10.1097/moh.0b013e32836060a9.
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Tall, Alan R. "Regulation of Hematopoiesis by Cholesterol." Blood 124, no. 21 (December 6, 2014): SCI—53—SCI—53. http://dx.doi.org/10.1182/blood.v124.21.sci-53.sci-53.
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Abstract Leukocytosis is a risk factor for athero-thrombotic disease in humans, and develops in animal models of atherosclerosis in response to feeding high-fat, high-cholesterol diets. The ATP binding cassette transporters ABCA1 and ABCG1 promote cholesterol efflux to apoA-1 and high density lipoprotein (HDL), respectively and are targets of liver X receptor (LXR) transcription factors. Mice lacking ABCA1/G1 develop a dramatic myeloproliferative phenotype with monocytosis and neutrophilia, associated with expansion and proliferation of hematopoietic stem and myeloid progenitor populations (HSPCs). The transporters are highly expressed in HSPCs where they act to control proliferative responses to growth factors (IL-3, GM-CSF) by regulating plasma membrane lipid rafts and cell surface expression of the common β subunit of the IL-3/GM-CSF receptor. ABCG4 is closely related to ABCG1 but is expressed primarily in the megakaryocyte progenitor (MkP) population of the bone marrow. ABCG4-deficient mice have MkP proliferation and expansion, thrombocytosis, increased platelet/leukocyte aggregates and accelerated atherosclerosis. ABCG4 promotes cholesterol efflux onto HDL, and thereby reduces the cell surface expression of the thrombopoietin (TPO) receptor. This appears to involve membrane cholesterol enrichment and interruption of a negative feedback loop involving the TPO receptor and mediated by Lyn Kinase and c-CBL which mediate ubiquitination and internalization/degradation of the receptor. Overall results suggest that ATP binding cassette transporters promote cholesterol efflux, decrease membrane lipid raft formation and enhance the feedback downregulation of growth factor receptors in response to growth factor binding, with anti-proliferative responses that may be beneficial in atherosclerosis and myeloproliferative neoplasms. Disclosures No relevant conflicts of interest to declare.
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Pantel, K., and A. Nakeff. "Lymphoid cell regulation of hematopoiesis." International Journal of Cell Cloning 7, no. 1 (1989): 2–12. http://dx.doi.org/10.1002/stem.5530070103.
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Hoggatt, J., and L. M. Pelus. "Eicosanoid regulation of hematopoiesis and hematopoietic stem and progenitor trafficking." Leukemia 24, no. 12 (September 30, 2010): 1993–2002. http://dx.doi.org/10.1038/leu.2010.216.
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Guo, Fukun, Wei Liu, Kankana Chava, Jose Cancelas, George Thomas, Sara C. Kozma, and Yi Zheng. "Role of mTOR in Hematopoiesis and Hematopoietic Stem Cell Regulation." Blood 114, no. 22 (November 20, 2009): 1490. http://dx.doi.org/10.1182/blood.v114.22.1490.1490.
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Abstract Abstract 1490 Poster Board I-513 The mammalian target of rapamycin (mTOR) integrates nutrients, growth factors, and cellular energy status to control protein synthesis that determines cell growth and metabolism. It is also known that mTOR plays an essential role in cell survival by regulating Akt/PKB signaling. By using the inhibitor rapamycin, mTOR has previously been suggested to regulate proliferation of megakaryocyte progenitors and late stage of megakaryocyte differentiation without a general impact on normal hematopoiesis or hematopoietic stem cell (HSC) function. Due to limitations of rapamycin and the early lethality of conventional mTOR gene targeted mice, the physiological role of mTOR in blood development remains undefined. In this study, we have utilized an inducible conditional mTOR knockout mouse model by crossbreeding mTORflox/flox mice with Mx-Cre mice that allow interferon-induced mTOR deletion in the bone marrow following a transplantation and polyI:C induction protocol, in an effort to determine the genetic role of mTOR in hematopoiesis. Depletion of mTOR drastically affected hematopoiesis in a blood cell autonomous manner in Mx-Cre;mTORflox/flox bone marrow transplant recipients: the mice showed marked reduction in BM cellularity and in the numbers of myeloid and lymphoid lineage cells, erythrocytes, and platelets in peripheral blood, bone marrow, and thymus, leading to bone marrow failure, blood cell exhaustion and lethality. In vitro colony-forming activities by bone marrow or spleen progenitors were completely abolished in the absence of mTOR. Interestingly, the number and frequency of HSCs in bone marrow (Lin−Sca-1+c-Kit+) increased transiently while the number of early progenitors (CMP, GMP, MEP, CLP) detected by cell surface markers remained unchanged or only mildly affected in the mutant mice within 14 days after polyI:C treatment. Concomitantly, mTOR deletion led to a massive egress of HSCs from bone marrow to distal organs including spleen (∼60-fold increase). Transplantation of mTOR−/− bone marrow cells into NOD-SCID mice or competitive transplantation of mTOR−/− bone marrow cells into BoyJ mice further demonstrated that mTOR deficiency caused a complete failure in HSC engraftment and repopulation. Surprisingly, at the cellular level these phenotypes are associated with increased proliferation of HSCs in vivo and in vitro by 60% and 2.5-fold, respectively, as assessed by 5-bromodeoxyuridine incorporation assays whereas the cell survival index appears to be unaffected. Moreover, mTOR−/− HSCs and progenitor cells displayed impaired adhesion to fibronectin CH296 fragment (∼30% decrease) and migration toward SDF-1α gradients (∼30% decrease). At the molecular level, gene chip microarray analysis of mTOR−/− HSCs revealed that the cell cycle regulators myb, wee1, FANCD2, and FANCE were significantly downregulated while Rb and E2F5 were upregulated, the survival/apoptosis regulators MCL1 and BCL2L1 were upregulated, and the actin cytoskeleton and cell extracellular matrix adhesion regulators Arp2/3 complex subunit 5, paxillin, laminin α5, integrin β3, and myosin light chain 6B were upregulated. Further, immunoblotting analysis of isolated Lin− cells showed that SCF-stimulated activation of translational regulators S6K and 4E-BP and survival regulator Akt were abolished upon mTOR deletion. Taken together, these data suggest that mTOR is a critical regulator of HSC quiescence, self-renewal, and engraftment through the regulation of cell cycle, survival and actin cytoskeleton signals, and is essential in multiple stages of hematopoiesis. Disclosures Cancelas: CERUS CO: Research Funding; CARIDIAN BCT: Research Funding; HEMERUS INC: Research Funding.
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Choi, Kyunghee. "Hemangioblast development and regulation." Biochemistry and Cell Biology 76, no. 6 (December 1, 1998): 947–56. http://dx.doi.org/10.1139/o99-007.
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Hematopoietic and endothelial cell lineages are the first to mature from mesoderm in the developing embryo. However, little is known about the molecular and (or) cellular events leading to hematopoietic commitment. The recent applications of technology utilizing gene targeted mice and the employment of many available in vitro systems have facilitated our understanding of hematopoietic establishment in the developing embryo. It is becoming clear that embryonic hematopoiesis occurs both in the extra-embryonic yolk sac and within the embryo proper in the mouse. The existence of the long pursued hemangioblast, a common progenitor of hematopoietic and endothelial cells, is now formally demonstrated. Based on this new information, many studies are being conducted to understand hematopoietic commitment events from mesoderm. In this review, we will first discuss the establishment of the hematopoietic system with special emphasis on the most primitive hematopoietic committed cells, the hemangioblast. We will then discuss mesoderm-inducing factors and their possible role in hematopoietic lineage commitment.Key words: hematopoietic commitment, hemangioblast, in vitro embryonic stem cell differentiation.
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Jeanson, Nathaniel T., and David T. Scadden. "Vitamin D receptor deletion leads to increased hematopoietic stem and progenitor cells residing in the spleen." Blood 116, no. 20 (November 18, 2010): 4126–29. http://dx.doi.org/10.1182/blood-2010-04-280552.
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Abstract Bone components participate in the regulation of hematopoietic stem cells in the adult mammal. Vitamin D regulates bone mineralization and is associated with pleiotropic effects in many cell types, including putative roles in hematopoietic differentiation. We report that deletion of the vitamin D receptor (VDR) in hematopoietic cells did not result in cell autonomous perturbation of hematopoietic stem cell or progenitor function. However, deletion of VDR in the microenvironment resulted in a marked accumulation of hematopoietic stem cells in the spleen that could be reversed by calcium dietary supplementation. These data suggest that VDR participates in restricting splenic hematopoiesis through maintenance of bone calcium homeostasis and are consistent with the concept that calcium regulation through VDR is a central participant in localizing adult hematopoiesis preferentially to bone marrow.
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Basu, Sreemanti, Irene Hernandez, Mark Zogg, Karen-Sue B. Carlson, and Hartmut Weiler. "Regulation of Hematopoiesis By the Coagulation Receptor Thrombomodulin." Blood 126, no. 23 (December 3, 2015): 4750. http://dx.doi.org/10.1182/blood.v126.23.4750.4750.
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Abstract BACKGROUND: Pharmacologic supplementation of protein C pathway function by infusion of recombinant Thbd or activated protein C supports recovery of hematopoietic function from lethal radiation injury in mice [Geiger et al., Nature Medicine, 2012]. Partial Thbd deficiency in hematopoietic stem and progenitor cells (HSPC) or bone marrow endothelium results in augmented sensitivity towards radiation injury [Geiger et al., Nature Medicine, 2012]. The underlying cellular and molecular mechanisms of Thbd function in hematopoiesis are not yet characterized. The objective of the current study was to determine the expression pattern and functional role of Thbd in HSPC. RESULTS: Flow cytometric analysis was employed to detect Thbd expression in defined subsets of murine HSPC. Thbd was co-expressed with the endothelial protein C receptor (Procr/EPCR) in the majority of bona fide stem cells with long-term-repopulating capacity (LT-HSC), and was also expressed on EPCR-negative stem cells with short-term repopulating capacity (ST-HSC), multipotent progenitors (MPP), common lymphoid progenitors (CLP), common myeloid progenitors (CMP), and granulocyte-monocyte progenitors (GMP). In contrast, only a subset of megakaryocyte-erythrocyte progenitors (MEP) expressed low levels of Thbd. In the bone marrow, Thbd was also expressed by B cells in early stages of maturation (from progenitor B cell stage till immature stage). In this lineage, the fraction of Thbd-positive cells was inversely correlated with the stage of B cell maturation. In addition, Thbd was detected in three distinct subsets of bone marrow-resident myeloid cells (CD11b+CD115+, CD11b+CD11c+ and CD11b-CD115+). Thbd expression outside the bone marrow was limited to a small fraction of hematopoietic cells (2-5% in the peripheral blood and spleen). These cells included myeloid cells (macrophage/monocyte and dendritic cells). Approximately 1-2% of all B cells in the peripheral blood and the spleen expressed Thbd, possibly reflecting recent bone marrow emigrants. Thbd expression was largely absent from splenic follicular and marginal zone B cells. Adult mice with complete, ubiquitous ablation of Thbd gene function (Meox2Cre-ThbdloxP -mice; "Thbd-null") were generated to analyze the functional role of Thbd in hematopoiesis. Thbd-null mice exhibited low birth weight, but only a mild prothrombotic diathesis, reflected in occasional peripheral vascular occlusion limited to the tail vein. Flow cytometric analyses revealed increased frequency of LT- and ST-HSC, a trend towards reduced CLP frequency, but normal relative abundance of MPP, CMP, GMP, and MEP. Thbd deficiency was also associated with a significant increase in the absolute number of LT-HSC and a reduction in the absolute number of CLP in the bone marrow. No such derangements were observed in mice lacking EPCR. In functional assays, bone marrow from wildtype and mutant mice yielded comparable numbers of CFU-GM. In contrast, the number of CFU-GM was increased in the spleen and peripheral blood of Thbd-null animals. The absolute number and frequency of all B cell precursors, as well as mature B cells in the bone marrow was reduced by ~50%. In the spleen, the absolute number of B cells was increased, whereas other hematopoietic populations in peripheral organs of Thbd-null mice were identical to that of wildtype controls. CONCLUSION: Thbd is expressed in the majority of hematopoietic progenitor cells in the bone marrow, including LT- and ST-HSC, and B cell precursors. Despite abundant Thbd expression in bone marrow resident cells and a modest prothrombotic phenotype, complete Thbd deficiency had only mild effects on steady-state hematopoiesis. Hematopoietic derangements were limited to the B cell compartment, and an Increased presence of CFU-GM in the spleen and peripheral blood of Thbd-null mice, possibly reflecting stimaulation of extramedullary hematopoiesis and/or altered bone marrow retention of precursors. Disclosures No relevant conflicts of interest to declare.
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Ganapati, Uma, Lynne A. Bui, Maureen Lynch, Milana Dolezal, Hongying Tina Tan, Sven deVos, and Judith C. Gasson. "Regulated Expression of Activated Notch 1 during Embryonic Stem Cell Differentiation Preserves Multipotential Progenitors and Promotes Erythroid Cell Fate." Blood 104, no. 11 (November 16, 2004): 4151. http://dx.doi.org/10.1182/blood.v104.11.4151.4151.
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Abstract Hematopoietic stem cells pass sequentially through a series of developmental decision points regulating self-renewal and lineage-specific differentiation. In normal hematopoiesis proliferation is tightly linked to differentiation in ways that are poorly understood. The Notch gene family has been shown to be evolutionarily conserved and to play an important role in determining cell fate, survival, and proliferation in multiple organisms. Numerous in vitro and in vivo studies strongly support a role for Notch signaling in the regulation of stem cell signaling and hematopoiesis. To define the function of Notch in the earliest stages of hematopoiesis, a Tetracycline-inducible system regulating expression of a ligand-independent, constitutively active form of Notch1 was introduced into murine E14Tg2a embryonic stem cells. (Era and Witte, PNAS, 97;1737–1742,2000). During co-culture, OP9 stromal cells induce the embryonic stem cells to differentiate first to hemangioblasts and subsequently to hematopoietic cells. Our studies indicate that activation of Notch signaling in flk+ hemangioblasts dramatically reduces their proliferative capacity without inducing apoptosis. Furthermore, Notch1 activation significantly reduces the levels of hematopoietic stem cell markers CD34, c-Kit and the myeloid marker CD11b. These reversible effects suggest that Notch signaling maintains the hemangioblasts in an immature state and blocks hematopoietic differentiation. When activated Notch is induced in committed hematopoietic progenitors, a shift towards definitive erythroid differentiation and decreased myeloid differentiation is observed. Microarray analysis of day8 hematopoietic progenitors following Notch activation in hemangioblasts indicates upregulation of known downstream targets of Notch signaling. Based on these results, we propose that Notch signaling plays a critical role in the earliest events regulating hematopoiesis.
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Melotti, P., D. H. Ku, and B. Calabretta. "Regulation of the expression of the hematopoietic stem cell antigen CD34: role of c-myb." Journal of Experimental Medicine 179, no. 3 (March 1, 1994): 1023–28. http://dx.doi.org/10.1084/jem.179.3.1023.
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The CD34 antigen defines a subset of hematopoietic progenitor cells with self-renewal capacity and the ability to reconstitute hematopoiesis in irradiated primates and marrow-ablated humans, but its function remains unknown. The c-myb protooncogene plays a fundamental role in hematopoiesis, most likely via its transcriptional regulator function. We report that c-myb protein transactivates the CD34 promoter via specific interaction with multiple Myb binding sites in the 5' flanking region of the gene and induces expression of the endogenous CD34 mRNA in rodent fibroblasts. Also, constitutive expression of c-myb in CD34-negative human glioblastoma cells induces expression of CD34 mRNA and synthesis of the surface membrane antigen. These data directly demonstrate that c-myb regulates the expression of the hematopoietic stem cell antigen CD34 and raise the possibility that c-myb regulates hematopoiesis inducing a cascade of differentiation-related events.
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Lin, Xionghui, and Irene Söderhäll. "Crustacean hematopoiesis and the astakine cytokines." Blood 117, no. 24 (June 16, 2011): 6417–24. http://dx.doi.org/10.1182/blood-2010-11-320614.
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Abstract Major contributions to research in hematopoiesis in invertebrate animals have come from studies in the fruit fly, Drosophila melanogaster, and the freshwater crayfish, Pacifastacus leniusculus. These animals lack oxygen-carrying erythrocytes and blood cells of the lymphoid lineage, which participate in adaptive immune defense, thus making them suitable model animals to study the regulation of blood cells of the innate immune system. This review presents an overview of crustacean blood cell formation, the role of these cells in innate immunity, and how their synthesis is regulated by the astakine cytokines. Astakines are among the first invertebrate cytokines shown to be involved in hematopoiesis, and they can stimulate the proliferation, differentiation, and survival of hematopoietic tissue cells. The astakines and their vertebrate homologues, prokineticins, share similar functions in hematopoiesis; thus, studies of astakine-induced hematopoiesis in crustaceans may not only advance our understanding of the regulation of invertebrate hematopoiesis but may also provide new evolutionary perspectives about this process.
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Zou, Gang-Ming, Mei-Hua Luo, April Reed, Mark R. Kelley, and Mervin C. Yoder. "Ape1 regulates hematopoietic differentiation of embryonic stem cells through its redox functional domain." Blood 109, no. 5 (October 19, 2006): 1917–22. http://dx.doi.org/10.1182/blood-2006-08-044172.
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Abstract Ape1 is a molecule with dual functions in DNA repair and redox regulation of transcription factors. In Ape1-deficient mice, embryos do not survive beyond embryonic day 9, indicating that this molecule is required for normal embryo development. Currently, direct evidence of the role of Ape1 in regulating hematopoiesis is lacking. We used the embryonic stem (ES) cell differentiation system and an siRNA approach to knockdown Ape1 gene expression to test the role of Ape1 in hematopoiesis. Hemangioblast development from ES cells was reduced 2- to 3-fold when Ape1 gene expression was knocked down by Ape1-specific siRNA, as was primitive and definitive hematopoiesis. Impaired hematopoiesis was not associated with increased apoptosis in siRNA-treated cells. To begin to explore the mechanism whereby Ape1 regulates hematopoiesis, we found that inhibition of the redox activity of Ape1 with E3330, a specific Ape1 redox inhibitor, but not Ape1 DNA repair activity, which was blocked using the small molecule methoxyamine, affected cytokine-mediated hemangioblast development in vitro. In summary, these data indicate Ape1 is required in normal embryonic hematopoiesis and that the redox function, but not the repair endonuclease activity, of Ape1 is critical in normal embryonic hematopoietic development.
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Stein, Sarah J., and Albert S. Baldwin. "Deletion of the NF-κB subunit p65/RelA in the hematopoietic compartment leads to defects in hematopoietic stem cell function." Blood 121, no. 25 (June 20, 2013): 5015–24. http://dx.doi.org/10.1182/blood-2013-02-486142.
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Key Points p65 is an important factor in hematopoiesis through the regulation of hematopoietic stem cell function and lineage commitment. p65 controls the expression of genes encoding key factors that promote hematopoietic stem cell homeostasis.
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Stergiou, Ioanna E., and Efstathia K. Kapsogeorgou. "Autophagy and Metabolism in Normal and Malignant Hematopoiesis." International Journal of Molecular Sciences 22, no. 16 (August 9, 2021): 8540. http://dx.doi.org/10.3390/ijms22168540.
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The hematopoietic system relies on regulation of both metabolism and autophagy to maintain its homeostasis, ensuring the self-renewal and multipotent differentiation potential of hematopoietic stem cells (HSCs). HSCs display a distinct metabolic profile from that of their differentiated progeny, while metabolic rewiring from glycolysis to oxidative phosphorylation (OXPHOS) has been shown to be crucial for effective hematopoietic differentiation. Autophagy-mediated regulation of metabolism modulates the distinct characteristics of quiescent and differentiating hematopoietic cells. In particular, mitophagy determines the cellular mitochondrial content, thus modifying the level of OXPHOS at the different differentiation stages of hematopoietic cells, while, at the same time, it ensures the building blocks and energy for differentiation. Aberrations in both the metabolic status and regulation of the autophagic machinery are implicated in the development of hematologic malignancies, especially in leukemogenesis. In this review, we aim to investigate the role of metabolism and autophagy, as well as their interconnections, in normal and malignant hematopoiesis.
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Akashi, Koichi. "Transcriptional Regulation in Normal and Malignant Hematopoiesis." Blood 118, no. 21 (November 18, 2011): SCI—28—SCI—28. http://dx.doi.org/10.1182/blood.v118.21.sci-28.sci-28.
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Abstract SCI-28 Lineage commitment should involve selective and temporally-regulated expression of essential genes. In multi- or oligo-potent progenitors, the expression of oligo-lineage-affiliated genes is primed: oligo-lineage genes are co-expressed prior to the commitment at the single cell level, and once lineage fate is decided, genes of irrelevant lineages are immediately downregulated. For example, single common myeloid progenitors (CMP) co-express both granulocyte/monocyte-affiliated and megakaryocyte/erythroid-affiliated genes. The priming of these lineage-restricted genes could be dependent also upon the priming of lineage-specific transcription factors. Consistent with this hypothesis, a population with potent CMP activity that co-express both PU.1 (myeloid) and GATA-1 (erythroid) transcription factors was newly identified by using mice having PU.1 and GATA-1 reporters. In downstream of such “priming” stage, the order of expression as well as the level of expression of multiple transcription factors plays a critical role in reading-out specific lineages. The precise regulation of transcription factors should be critical to maintain hematopoietic homeostasis, and the deregulation of transcription factor expression could induce leukemic transformation. To understand the regulation machinery upstream of transcription factors, we are currently attempting to model an epigenetic landscape in hematopoietic development. Genome-wide analysis of histone positioning revealed that a histone variant marks hematopoietic transcription factors and other lineage-related genes prior to commitment, and therefore the variant can predict the actively-transcribed region in a later stage of hematopoiesis. For example, in hematopoietic stem cells, the histone marking was observed broadly in genes-related to myelo-erythroid and lymphoid genes, while in committed progenitors, it was restricted to specific lineages such as myeloid, erythroid and/or lymphoid genes. These results suggest that the genome marking by a histone variant should be a primary event for initiating lineage commitment. Disclosures: No relevant conflicts of interest to declare.
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Huang, Gang, Shannon Elf, Xiaomei Yan, Lan Wang, Yan Liu, Goro Sashida, Alex Gural, et al. "Previously Unknown Interactions Between AML1 and MLL Provide Epigenetic Regulation of Gene Expression in Normal Hematopoiesis and in Leukemia." Blood 112, no. 11 (November 16, 2008): 282. http://dx.doi.org/10.1182/blood.v112.11.282.282.
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Abstract In all organisms, the fundamental process of transcriptional regulation requires transcription factors, which bind to DNA in response to extra-cellular signals and regulate transcription of target genes. In eukaryotes, this process also involves epigenetic regulation, which includes DNA and histone modifications. Hematopoiesis and leukemia are excellent model systems for studying the higher eukaryotic regulations of gene expression and for identifying important molecules involved in genetic and epigenetic transcriptional regulation. The Mixed-Lineage Leukemia (MLL) protein, a Set1-like H3K4 methyltransferase, and the heterodimeric transcriptional factor AML1/CBFβ are critical for definitive and adult hematopoiesis. They are required for the generation of all hematopoietic lineages and act as tumor suppressors in human leukemia. We have previously shown that the regulation of PU.1 by AML1 is mediated by 3 AML1 binding sites in the PU.1 upstream regulatory element (URE), located −14 kb relative to the transcription start site in mice (Huang et al. Nat Genet. 2008). To understand whether AML1 plays a critical role in regulating the PU.1 locus at the chromatin level, we have utilized this PU.1 regulation system as a model to study the potential interplay between AML1/CBFβ and MLL. We found that MLL binds to the evolutionarily conserved Runt-domain of AML1, enhances the formation of the AML1/CBFβ heterodimer, and blocks the ubiquitin-proteasome mediated degradation of AML1. We also found that AML1/CBFβ is required for maintenance of the H3K4-me3 histone mark at the PU.1 upstream regulatory element (URE) and promoter region, and that MLL is required for AML1 to regulate PU.1 expression. In contrast, we found that several leukemia-associated MLL fusion proteins, including MLL-AF4, MLL-AF9, MLL-ENL, and MLL-AF10, no longer stabilize AML1 but rather induce AML1 degradation and downregulate PU.1 expression. Taken together, our data indicate that MLL and some of its leukemia-associated fusion proteins physically and functionally interact with AML1. Their effects on target genes, particularly PU.1, may be critical for the normal regulation of hematopoiesis and for the aberrant regulation that underlies acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL).
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Gu, Yue, Wei Yang, Amanda Jones, Shanrun Liu, Qian Dai, C. Scott Swindle, Thomas Ryan, Tim M. Townes, Christopher Klug, and Hengbin Wang. "Regulation of Hematopoietic Stem Cell Function By the Histone H2A Deubiquitinase Usp16." Blood 126, no. 23 (December 3, 2015): 1177. http://dx.doi.org/10.1182/blood.v126.23.1177.1177.
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Abstract Epigenetic mechanism plays important regulatory roles in hematopoiesis and hematopoietic stem cell (HSC) function. Subunits of Polycomb repressive complex 1 (PRC1), the major histone H2A ubiquitin ligase, are critical for both normal and pathological hematopoiesis; however, it was unclear which H2A deubiquitinase pairs with PRC1 to control H2A ubiquitination (ubH2A) level in vivo and regulates hematopoiesis. Here we investigated the function of Usp16 in mouse hematopoiesis. Deletion of Usp16 in bone marrow resulted in a significant increase of global ubH2A level and mouse lethality. Usp16 deletion was associated with a dramatic reduction of progenitor cell populations and unchanged HSC number, revealing a critical role for Usp16 in HSC differentiation. The HSC differentiation defect was correlated with a great reduction of G1 phase cell population. RNA-seq and RT-qPCR studies revealed that Usp16 regulates the expression of many genes associated with HSC differentiation and self-renewal including cell cycle regulator p21. Significantly, knockdown of p21 largely rescued the undifferentiated phenotype of Usp16 deleted HSCs. Usp16 binds to regions flanking transcription start site and knockdown of PRC1 subunits, which reduced ubH2A levels, largely rescued the altered gene expression pattern associated with Usp16 deletion. Therefore, these studies identified Usp16 as the H2A deubiquitinase that pairs with PRC1 to regulate hematopoiesis in vivo and revealed that Usp16 regulates HSC function by affecting HSC cell cycle progression. Disclosures No relevant conflicts of interest to declare.
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Stellrecht, C. M., G. Fraizer, C. Selvanayagam, L. Y. Chao, A. Lee, and G. F. Saunders. "Transcriptional regulation of a hematopoietic proteoglycan core protein gene during hematopoiesis." Journal of Biological Chemistry 268, no. 6 (February 1993): 4078–84. http://dx.doi.org/10.1016/s0021-9258(18)53582-1.
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Migueles, Rosa Portero, Louise Shaw, Neil P. Rodrigues, Gillian May, Korinna Henseleit, Kathryn G. V. Anderson, Hakan Goker, et al. "Transcriptional regulation of Hhex in hematopoiesis and hematopoietic stem cell ontogeny." Developmental Biology 424, no. 2 (April 2017): 236–45. http://dx.doi.org/10.1016/j.ydbio.2016.12.021.
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Lin, Kuan-Hung, Jui-Chung Chiang, Ya-Hsuan Ho, Chao-Ling Yao, and Hsinyu Lee. "Lysophosphatidic Acid and Hematopoiesis: From Microenvironmental Effects to Intracellular Signaling." International Journal of Molecular Sciences 21, no. 6 (March 16, 2020): 2015. http://dx.doi.org/10.3390/ijms21062015.
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Vertebrate hematopoiesis is a complex physiological process that is tightly regulated by intracellular signaling and extracellular microenvironment. In recent decades, breakthroughs in lineage-tracing technologies and lipidomics have revealed the existence of numerous lipid molecules in hematopoietic microenvironment. Lysophosphatidic acid (LPA), a bioactive phospholipid molecule, is one of the identified lipids that participates in hematopoiesis. LPA exhibits various physiological functions through activation of G-protein-coupled receptors. The functions of these LPARs have been widely studied in stem cells, while the roles of LPARs in hematopoietic stem cells have rarely been examined. Nonetheless, mounting evidence supports the importance of the LPA-LPAR axis in hematopoiesis. In this article, we have reviewed regulation of hematopoiesis in general and focused on the microenvironmental and intracellular effects of the LPA in hematopoiesis. Discoveries in these areas may be beneficial to our understanding of blood-related disorders, especially in the context of prevention and therapy for anemia.
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Cooney, Jeffrey D., Ebrahim Shafizadeh, Paul F. McBride, Kelli J. Carroll, Heidi Anderson, Jared J. Ganis, Trista E. North, and Barry H. Paw. "Zebrafish Growth Factor Independence Transcription Factors Establish a New Paradigm for Regulation of Primitive and Definitive Hematopoietic Lineages,." Blood 118, no. 21 (November 18, 2011): 3379. http://dx.doi.org/10.1182/blood.v118.21.3379.3379.
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Abstract Abstract 3379 The Growth Factor Independence (Gfi) zinc finger transcription factors play essential roles in hematopoiesis, differentially activating and repressing transcriptional programs required for hematopoietic lineage specification. In mammals, Gfi1 regulates hematopoietic stem cell (HSC) and lymphoid populations, while Gfi1b is required for megakaryocyte and erythroid development (van der Meer, et al. 2010 Leukemia 11:1834–43). In zebrafish, gfi1.1 plays an essential role in primitive hematopoiesis, preserving primitive HSC populations and regulating the erythroid-myeloid balance (Wei, et al. 2008 Cell Res. 6:677–85). However, little is known about the role of gfi1.1 in definitive hematopoiesis or about the role of additional hematopoietic gfi family members in zebrafish. Here, we report the isolation and characterization of an additional zebrafish gfi family transcription factor, gfi1.2b. We compare and contrast gfi1.1 and gfi1.2b, showing that they are highly expressed in the intermediate cell mass (ICM) and aorta-gonad-mesonephros (AGM), the respective sites of primitive and definitive hematopoiesis in zebrafish. Using antisense morpholino oligos (MO), whole mount in situ hybridization (WISH) and fluorescent activated cell sorting (FACS) of transgenic reporter fish, we demonstrate that gfi1.1 and gfi1.2b have distinct, essential roles in preserving primitive and definitive HSC populations, respectively. Loss of gfi1.1 specifically silences expression of scl and gata-1, markers of primitive HSC and erythroid progenitors. Conversely, loss of gfi1.2b silences expression of Tg(cd41:eGFPlo) cells, indicating an essential role for gfi1.2b in preserving definitive hematopoietic progenitors (Ma, et al. 2011 Blood 118:289–297). Consistent with the discrete roles of gfi1.1 and gfi1.2b in primitive and definitive lineages, knockdown of gfi1.2b silences lymphocyte rag-1 expression in the developing thymus, while knockdown of gfi1.1 has no effect on the thymic lymphocyte population. gfi1.1 and gfi1.2b have overlapping roles in erythropoiesis, as loss of either gfi factor reduces erythrocyte populations, while loss of both gfi paralogs results in a more profound silencing of erythrocytes. We further demonstrate that loss of gata-1 reduces gfi1.1 expression and silences gfi1.2b, suggesting that gata-1 plays an essential role in regulating the transcription of both genes. Together, these studies demonstrate that gfi1.1 and gfi1.2b have distinct and overlapping roles in zebrafish hematopoiesis and establish a new paradigm for the regulation of primitive and definitive hematopoietic lineages by gfi transcription factors. Disclosures: No relevant conflicts of interest to declare.
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Lan, Wenwen, Sumin Liu, Long Zhao, and Ying Su. "Regulation of Drosophila Hematopoiesis in Lymph Gland: From a Developmental Signaling Point of View." International Journal of Molecular Sciences 21, no. 15 (July 24, 2020): 5246. http://dx.doi.org/10.3390/ijms21155246.
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The Drosophila hematopoietic system is becoming increasingly attractive for its simple blood cell lineage and its developmental and functional parallels with the vertebrate system. As the dedicated organ for Drosophila larval hematopoiesis, the lymph gland harbors both multipotent stem-like progenitor cells and differentiated blood cells. The balance between progenitor maintenance and differentiation in the lymph gland must be precisely and tightly controlled. Multiple developmental signaling pathways, such as Notch, Hedgehog, and Wnt/Wingless, have been demonstrated to regulate the hematopoietic processes in the lymph gland. Focusing on blood cell maintenance and differentiation, this article summarizes the functions of several classic developmental signaling pathways for lymph gland growth and patterning, highlighting the important roles of developmental signaling during lymph gland development as well as Drosophila larval hematopoiesis.
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Weiss, L., and U. Geduldig. "Barrier cells: stromal regulation of hematopoiesis and blood cell release in normal and stressed murine bone marrow." Blood 78, no. 4 (August 15, 1991): 975–90. http://dx.doi.org/10.1182/blood.v78.4.975.975.
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Abstract Murine hematopoietic bone marrow is heterogenous in respect to bone- lining cells, hematopoiesis, and release of blood cells. In diaphyseal femoral marrow, bone-lining cells are largely osteoblasts, indifferent endosteum, blood cells, and reticular cells. Hematopoiesis is sustained by rather differentiated progenitors, as myelocytes and polychromatophilic erythroblasts. But in sharply restricted loci within trabeculated bone in the distal medial femoral metaphysis, bone-lining cells are dominated by newly discovered fibroblastic, contractile, stromal barrier cells; activated, multilaminar and branched, enveloping putative stem cells; and extending into the marrow, where they enclose hematopoietic clusters of rather early progenitors, as promyelocytes; and basophilic erythroblasts. Barrier cells may endocytize granules released individually by vicinal differentiating granulocytes, preventing tissue damage. Barrier cells envelope blood vessels and insinuate processes into their wall, augmenting blood-marrow barriers, preventing release of immature cells. Further, extensions of venous sinuses made of extraordinarily thin barrier cell processes receive released blood cells. With heightened hematopoiesis due to mutant hemolytic anemias or after administration of interleukin-1, barrier cells and their associated structures are greatly increased, spreading beyond normally restricted loci. But in microenvironment-deficient mutants, barrier cells are fewer, less activated, and less granulated. Barrier cells thus appear important in hematopoiesis and in the release of blood cells from bone marrow.
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Weiss, L., and U. Geduldig. "Barrier cells: stromal regulation of hematopoiesis and blood cell release in normal and stressed murine bone marrow." Blood 78, no. 4 (August 15, 1991): 975–90. http://dx.doi.org/10.1182/blood.v78.4.975.bloodjournal784975.
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Murine hematopoietic bone marrow is heterogenous in respect to bone- lining cells, hematopoiesis, and release of blood cells. In diaphyseal femoral marrow, bone-lining cells are largely osteoblasts, indifferent endosteum, blood cells, and reticular cells. Hematopoiesis is sustained by rather differentiated progenitors, as myelocytes and polychromatophilic erythroblasts. But in sharply restricted loci within trabeculated bone in the distal medial femoral metaphysis, bone-lining cells are dominated by newly discovered fibroblastic, contractile, stromal barrier cells; activated, multilaminar and branched, enveloping putative stem cells; and extending into the marrow, where they enclose hematopoietic clusters of rather early progenitors, as promyelocytes; and basophilic erythroblasts. Barrier cells may endocytize granules released individually by vicinal differentiating granulocytes, preventing tissue damage. Barrier cells envelope blood vessels and insinuate processes into their wall, augmenting blood-marrow barriers, preventing release of immature cells. Further, extensions of venous sinuses made of extraordinarily thin barrier cell processes receive released blood cells. With heightened hematopoiesis due to mutant hemolytic anemias or after administration of interleukin-1, barrier cells and their associated structures are greatly increased, spreading beyond normally restricted loci. But in microenvironment-deficient mutants, barrier cells are fewer, less activated, and less granulated. Barrier cells thus appear important in hematopoiesis and in the release of blood cells from bone marrow.
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Prosper, Felipe, and Catherine M. Verfaillie. "Regulation of hematopoiesis through adhesion receptors." Journal of Leukocyte Biology 69, no. 3 (March 2001): 307–16. http://dx.doi.org/10.1189/jlb.69.3.307.
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Rafii, Shahin, Robert Mohle, Fred Shapiro, Beat M. Frey, and Malcolm A. S. Moore. "Regulation of Hematopoiesis by Microvascular Endothelium." Leukemia & Lymphoma 27, no. 5-6 (January 1997): 375–86. http://dx.doi.org/10.3109/10428199709058305.
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