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Transposon-modified antigen-specific T lymphocytes for sustained therapeutic protein delivery in vivo.
O'Neil RT, Saha S, Veach RA, Welch RC, Woodard LE, Rooney CM, Wilson MH
(2018) Nat Commun 9: 1325
MeSH Terms: Adoptive Transfer, Animals, Cell Engineering, Cell- and Tissue-Based Therapy, DNA Transposable Elements, Erythropoietin, Gene Expression, Genetic Vectors, Hematopoiesis, Herpesvirus 4, Human, Humans, Mice, Ovalbumin, Receptors, Antigen, T-Cell, T-Lymphocytes, Transgenes, Vaccination
Show Abstract · Added September 24, 2018
A cell therapy platform permitting long-term delivery of peptide hormones in vivo would be a significant advance for patients with hormonal deficiencies. Here we report the utility of antigen-specific T lymphocytes as a regulatable peptide delivery platform for in vivo therapy. piggyBac transposon modification of murine cells with luciferase allows us to visualize T cells after adoptive transfer. Vaccination stimulates long-term T-cell engraftment, persistence, and transgene expression enabling detection of modified cells up to 300 days after adoptive transfer. We demonstrate adoptive transfer of antigen-specific T cells expressing erythropoietin (EPO) elevating the hematocrit in mice for more than 20 weeks. We extend our observations to human T cells demonstrating inducible EPO production from Epstein-Barr virus (EBV) antigen-specific T lymphocytes. Our results reveal antigen-specific T lymphocytes to be an effective delivery platform for therapeutic molecules such as EPO in vivo, with important implications for other diseases that require peptide therapy.
0 Communities
2 Members
0 Resources
17 MeSH Terms
TRAF6 Mediates Basal Activation of NF-κB Necessary for Hematopoietic Stem Cell Homeostasis.
Fang J, Muto T, Kleppe M, Bolanos LC, Hueneman KM, Walker CS, Sampson L, Wellendorf AM, Chetal K, Choi K, Salomonis N, Choi Y, Zheng Y, Cancelas JA, Levine RL, Starczynowski DT
(2018) Cell Rep 22: 1250-1262
MeSH Terms: Animals, Enzyme Activation, Hematopoiesis, Hematopoietic Stem Cells, Homeostasis, I-kappa B Kinase, Mice, Mice, Transgenic, NF-kappa B, Signal Transduction, TNF Receptor-Associated Factor 6
Show Abstract · Added February 26, 2018
Basal nuclear factor κB (NF-κB) activation is required for hematopoietic stem cell (HSC) homeostasis in the absence of inflammation; however, the upstream mediators of basal NF-κB signaling are less well understood. Here, we describe TRAF6 as an essential regulator of HSC homeostasis through basal activation of NF-κB. Hematopoietic-specific deletion of Traf6 resulted in impaired HSC self-renewal and fitness. Gene expression, RNA splicing, and molecular analyses of Traf6-deficient hematopoietic stem/progenitor cells (HSPCs) revealed changes in adaptive immune signaling, innate immune signaling, and NF-κB signaling, indicating that signaling via TRAF6 in the absence of cytokine stimulation and/or infection is required for HSC function. In addition, we established that loss of IκB kinase beta (IKKβ)-mediated NF-κB activation is responsible for the major hematopoietic defects observed in Traf6-deficient HSPC as deletion of IKKβ similarly resulted in impaired HSC self-renewal and fitness. Taken together, TRAF6 is required for HSC homeostasis by maintaining a minimal threshold level of IKKβ/NF-κB signaling.
Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
0 Communities
1 Members
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11 MeSH Terms
Insect immunology and hematopoiesis.
Hillyer JF
(2016) Dev Comp Immunol 58: 102-18
MeSH Terms: Animals, Apoptosis, Autophagy, Hematopoiesis, Hemocytes, Host-Pathogen Interactions, Immunity, Innate, Insect Proteins, Insect Viruses, Insecta, Phagocytosis, Receptors, Pattern Recognition
Show Abstract · Added February 5, 2016
Insects combat infection by mounting powerful immune responses that are mediated by hemocytes, the fat body, the midgut, the salivary glands and other tissues. Foreign organisms that have entered the body of an insect are recognized by the immune system when pathogen-associated molecular patterns bind host-derived pattern recognition receptors. This, in turn, activates immune signaling pathways that amplify the immune response, induce the production of factors with antimicrobial activity, and activate effector pathways. Among the immune signaling pathways are the Toll, Imd, Jak/Stat, JNK, and insulin pathways. Activation of these and other pathways leads to pathogen killing via phagocytosis, melanization, cellular encapsulation, nodulation, lysis, RNAi-mediated virus destruction, autophagy and apoptosis. This review details these and other aspects of immunity in insects, and discusses how the immune and circulatory systems have co-adapted to combat infection, how hemocyte replication and differentiation takes place (hematopoiesis), how an infection prepares an insect for a subsequent infection (immune priming), how environmental factors such as temperature and the age of the insect impact the immune response, and how social immunity protects entire groups. Finally, this review highlights some underexplored areas in the field of insect immunobiology.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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1 Members
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12 MeSH Terms
Revisiting the case for genetically engineered mouse models in human myelodysplastic syndrome research.
Zhou T, Kinney MC, Scott LM, Zinkel SS, Rebel VI
(2015) Blood 126: 1057-68
MeSH Terms: Animals, Disease Models, Animal, Genetic Engineering, Hematopoiesis, Hematopoietic Stem Cells, Humans, Mice, Myelodysplastic Syndromes
Show Abstract · Added April 25, 2016
Much-needed attention has been given of late to diseases specifically associated with an expanding elderly population. Myelodysplastic syndrome (MDS), a hematopoietic stem cell-based blood disease, is one of these. The lack of clear understanding of the molecular mechanisms underlying the pathogenesis of this disease has hampered the development of efficacious therapies, especially in the presence of comorbidities. Mouse models could potentially provide new insights into this disease, although primary human MDS cells grow poorly in xenografted mice. This makes genetically engineered murine models a more attractive proposition, although this approach is not without complications. In particular, it is unclear if or how myelodysplasia (abnormal blood cell morphology), a key MDS feature in humans, presents in murine cells. Here, we evaluate the histopathologic features of wild-type mice and 23 mouse models with verified myelodysplasia. We find that certain features indicative of myelodysplasia in humans, such as Howell-Jolly bodies and low neutrophilic granularity, are commonplace in healthy mice, whereas other features are similarly abnormal in humans and mice. Quantitative hematopoietic parameters, such as blood cell counts, are required to distinguish between MDS and related diseases. We provide data that mouse models of MDS can be genetically engineered and faithfully recapitulate human disease.
© 2015 by The American Society of Hematology.
0 Communities
1 Members
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8 MeSH Terms
TISSUE REGENERATION. Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration.
Zhang Y, Desai A, Yang SY, Bae KB, Antczak MI, Fink SP, Tiwari S, Willis JE, Williams NS, Dawson DM, Wald D, Chen WD, Wang Z, Kasturi L, Larusch GA, He L, Cominelli F, Di Martino L, Djuric Z, Milne GL, Chance M, Sanabria J, Dealwis C, Mikkola D, Naidoo J, Wei S, Tai HH, Gerson SL, Ready JM, Posner B, Willson JK, Markowitz SD
(2015) Science 348: aaa2340
MeSH Terms: Animals, Bone Marrow Transplantation, Colitis, Dinoprostone, Enzyme Inhibitors, Hematopoiesis, Hydroxyprostaglandin Dehydrogenases, Liver Regeneration, Mice, Mice, Knockout, Prostaglandins, Pyridines, Regeneration, Thiophenes
Show Abstract · Added March 10, 2016
Agents that promote tissue regeneration could be beneficial in a variety of clinical settings, such as stimulating recovery of the hematopoietic system after bone marrow transplantation. Prostaglandin PGE2, a lipid signaling molecule that supports expansion of several types of tissue stem cells, is a candidate therapeutic target for promoting tissue regeneration in vivo. Here, we show that inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme, potentiates tissue regeneration in multiple organs in mice. In a chemical screen, we identify a small-molecule inhibitor of 15-PGDH (SW033291) that increases prostaglandin PGE2 levels in bone marrow and other tissues. SW033291 accelerates hematopoietic recovery in mice receiving a bone marrow transplant. The same compound also promotes tissue regeneration in mouse models of colon and liver injury. Tissues from 15-PGDH knockout mice demonstrate similar increased regenerative capacity. Thus, 15-PGDH inhibition may be a valuable therapeutic strategy for tissue regeneration in diverse clinical contexts.
Copyright © 2015, American Association for the Advancement of Science.
1 Communities
0 Members
0 Resources
14 MeSH Terms
Macrophage SR-BI mediates efferocytosis via Src/PI3K/Rac1 signaling and reduces atherosclerotic lesion necrosis.
Tao H, Yancey PG, Babaev VR, Blakemore JL, Zhang Y, Ding L, Fazio S, Linton MF
(2015) J Lipid Res 56: 1449-60
MeSH Terms: Animals, Apoptosis, Atherosclerosis, CD36 Antigens, Cell Survival, Collagen, Gene Deletion, Hematopoiesis, Macrophages, Mice, Mice, Inbred C57BL, Necrosis, Phagocytosis, Phagosomes, Phosphatidylinositol 3-Kinases, Phosphatidylserines, Protein Transport, Signal Transduction, rac1 GTP-Binding Protein, src-Family Kinases
Show Abstract · Added April 10, 2018
Macrophage apoptosis and efferocytosis are key determinants of atherosclerotic plaque inflammation and necrosis. Bone marrow transplantation studies in ApoE- and LDLR-deficient mice revealed that hematopoietic scavenger receptor class B type I (SR-BI) deficiency results in severely defective efferocytosis in mouse atherosclerotic lesions, resulting in a 17-fold higher ratio of free to macrophage-associated dead cells in lesions containing SR-BI(-/-) cells, 5-fold more necrosis, 65.2% less lesional collagen content, nearly 7-fold higher dead cell accumulation, and 2-fold larger lesion area. Hematopoietic SR-BI deletion elicited a maladaptive inflammatory response [higher interleukin (IL)-1β, IL-6, and TNF-α lower IL-10 and transforming growth factor β]. Efferocytosis of apoptotic thymocytes was reduced by 64% in SR-BI(-/-) versus WT macrophages, both in vitro and in vivo. In response to apoptotic cells, macrophage SR-BI bound with phosphatidylserine and induced Src phosphorylation and cell membrane recruitment, which led to downstream activation of phosphoinositide 3-kinase (PI3K) and Ras-related C3 botulinum toxin substrate 1 (Rac1) for engulfment and clearance of apoptotic cells, as inhibition of Src decreased PI3K, Rac1-GTP, and efferocytosis in WT cells. Pharmacological inhibition of Rac1 reduced macrophage efferocytosis in a SR-BI-dependent fashion, and activation of Rac1 corrected the defective efferocytosis in SR-BI(-/-) macrophages. Thus, deficiency of macrophage SR-BI promotes defective efferocytosis signaling via the Src/PI3K/Rac1 pathway, resulting in increased plaque size, necrosis, and inflammation.
Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.
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1 Members
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MeSH Terms
Hhex is Required at Multiple Stages of Adult Hematopoietic Stem and Progenitor Cell Differentiation.
Goodings C, Smith E, Mathias E, Elliott N, Cleveland SM, Tripathi RM, Layer JH, Chen X, Guo Y, Shyr Y, Hamid R, Du Y, Davé UP
(2015) Stem Cells 33: 2628-41
MeSH Terms: Animals, Cell Differentiation, Hematopoiesis, Hematopoietic Stem Cells, Homeodomain Proteins, Mice, Mice, Knockout, Precursor Cells, B-Lymphoid, Precursor Cells, T-Lymphoid, Transcription Factors
Show Abstract · Added February 22, 2016
Hhex encodes a homeodomain transcription factor that is widely expressed in hematopoietic stem and progenitor cell populations. Its enforced expression induces T-cell leukemia and we have implicated it as an important oncogene in early T-cell precursor leukemias where it is immediately downstream of an LMO2-associated protein complex. Conventional Hhex knockouts cause embryonic lethality precluding analysis of adult hematopoiesis. Thus, we induced highly efficient conditional knockout (cKO) using vav-Cre transgenic mice. Hhex cKO mice were viable and born at normal litter sizes. At steady state, we observed a defect in B-cell development that we localized to the earliest B-cell precursor, the pro-B-cell stage. Most remarkably, bone marrow transplantation using Hhex cKO donor cells revealed a more profound defect in all hematopoietic lineages. In contrast, sublethal irradiation resulted in normal myeloid cell repopulation of the bone marrow but markedly impaired repopulation of T- and B-cell compartments. We noted that Hhex cKO stem and progenitor cell populations were skewed in their distribution and showed enhanced proliferation compared to WT cells. Our results implicate Hhex in the maintenance of LT-HSCs and in lineage allocation from multipotent progenitors especially in stress hematopoiesis.
© 2015 AlphaMed Press.
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1 Members
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10 MeSH Terms
Macrophage deficiency of Akt2 reduces atherosclerosis in Ldlr null mice.
Babaev VR, Hebron KE, Wiese CB, Toth CL, Ding L, Zhang Y, May JM, Fazio S, Vickers KC, Linton MF
(2014) J Lipid Res 55: 2296-308
MeSH Terms: Animals, Antigens, Ly, Atherosclerosis, Cell Movement, Female, Gene Expression Regulation, Gene Knockout Techniques, Hematopoiesis, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Monocytes, Phenotype, Proto-Oncogene Proteins c-akt, Receptors, CCR2, Receptors, LDL
Show Abstract · Added February 12, 2015
Macrophages play crucial roles in the formation of atherosclerotic lesions. Akt, a serine/threonine protein kinase B, is vital for cell proliferation, migration, and survival. Macrophages express three Akt isoforms, Akt1, Akt2, and Akt3, but the roles of Akt1 and Akt2 in atherosclerosis in vivo remain unclear. To dissect the impact of macrophage Akt1 and Akt2 on early atherosclerosis, we generated mice with hematopoietic deficiency of Akt1 or Akt2. After 8 weeks on Western diet, Ldlr(-/-) mice reconstituted with Akt1(-/-) fetal liver cells (Akt1(-/-)→Ldlr(-/-)) had similar atherosclerotic lesion areas compared with control mice transplanted with WT cells (WT→Ldlr(-/-)). In contrast, Akt2(-/-)→Ldlr(-/-) mice had dramatically reduced atherosclerotic lesions compared with WT→Ldlr(-/-) mice of both genders. Similarly, in the setting of advanced atherosclerotic lesions, Akt2(-/-)→Ldlr(-/-) mice had smaller aortic lesions compared with WT→Ldlr(-/-) and Akt1(-/-)→Ldlr(-/-) mice. Importantly, Akt2(-/-)→Ldlr(-/-) mice had reduced numbers of proinflammatory blood monocytes expressing Ly-6C(hi) and chemokine C-C motif receptor 2. Peritoneal macrophages isolated from Akt2(-/-) mice were skewed toward an M2 phenotype and showed decreased expression of proinflammatory genes and reduced cell migration. Our data demonstrate that loss of Akt2 suppresses the ability of macrophages to undergo M1 polarization reducing both early and advanced atherosclerosis.
Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.
0 Communities
2 Members
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18 MeSH Terms
Requirement for ssbp2 in hematopoietic stem cell maintenance and stress response.
Li J, Kurasawa Y, Wang Y, Clise-Dwyer K, Klumpp SA, Liang H, Tailor RC, Raymond AC, Estrov Z, Brandt SJ, Davis RE, Zweidler-McKay P, Amin HM, Nagarajan L
(2014) J Immunol 193: 4654-62
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Bone Marrow, Bone Marrow Transplantation, Cell Differentiation, DNA-Binding Proteins, Gene Expression, Hematopoiesis, Hematopoietic Stem Cells, Homeostasis, Immunophenotyping, Mice, Mice, Knockout, Phenotype, Receptor, Notch1, Stress, Physiological
Show Abstract · Added February 14, 2015
Transcriptional mechanisms governing hematopoietic stem cell (HSC) quiescence, self-renewal, and differentiation are not fully understood. Sequence-specific ssDNA-binding protein 2 (SSBP2) is a candidate acute myelogenous leukemia (AML) suppressor gene located at chromosome 5q14. SSBP2 binds the transcriptional adaptor protein Lim domain-binding protein 1 (LDB1) and enhances LDB1 stability to regulate gene expression. Notably, Ldb1 is essential for HSC specification during early development and maintenance in adults. We previously reported shortened lifespan and greater susceptibility to B cell lymphomas and carcinomas in Ssbp2(-/-) mice. However, whether Ssbp2 plays a regulatory role in normal HSC function and leukemogenesis is unknown. In this study, we provide several lines of evidence to demonstrate a requirement for Ssbp2 in the function and transcriptional program of hematopoietic stem and progenitor cells (HSPCs) in vivo. We found that hematopoietic tissues were hypoplastic in Ssbp2(-/-) mice, and the frequency of lymphoid-primed multipotent progenitor cells in bone marrow was reduced. Other significant features of these mice were delayed recovery from 5-fluorouracil treatment and diminished multilineage reconstitution in lethally irradiated bone marrow recipients. Dramatic reduction of Notch1 transcripts and increased expression of transcripts encoding the transcription factor E2a and its downstream target Cdkn1a also distinguished Ssbp2(-/-) HSPCs from wild-type HSPCs. Finally, a tendency toward coordinated expression of SSBP2 and the AML suppressor NOTCH1 in a subset of the Cancer Genome Atlas AML cases suggested a role for SSBP2 in AML pathogenesis. Collectively, our results uncovered a critical regulatory function for SSBP2 in HSPC gene expression and function.
Copyright © 2014 by The American Association of Immunologists, Inc.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Genetic interaction between mutations in c-Myb and the KIX domains of CBP and p300 affects multiple blood cell lineages and influences both gene activation and repression.
Kasper LH, Fukuyama T, Lerach S, Chang Y, Xu W, Wu S, Boyd KL, Brindle PK
(2013) PLoS One 8: e82684
MeSH Terms: Animals, Blood Cells, CREB-Binding Protein, Cells, Cultured, E1A-Associated p300 Protein, Epistasis, Genetic, Hematopoiesis, Mice, Mice, Knockout, Protein Structure, Tertiary, Proto-Oncogene Proteins c-myb
Show Abstract · Added March 20, 2014
Adult blood cell production or definitive hematopoiesis requires the transcription factor c-Myb. The closely related KAT3 histone acetyltransferases CBP (CREBBP) and p300 (EP300) bind c-Myb through their KIX domains and mice homozygous for a p300 KIX domain mutation exhibit multiple blood defects. Perplexingly, mice homozygous for the same KIX domain mutation in CBP have normal blood. Here we test the hypothesis that the CBP KIX domain contributes subordinately to hematopoiesis via a genetic interaction with c-Myb. We assessed hematopoiesis in mice bearing compound mutations of c-Myb and/or the KIX domains of CBP and p300, and measured the effect of KIX domain mutations on c-Myb-dependent gene expression. We found that in the context of a p300 KIX mutation, the CBP KIX domain mutation affects platelets, B cells, T cells, and red cells. Gene interaction (epistasis) analysis provides mechanistic evidence that blood defects in KIX mutant mice are consistent with reduced c-Myb and KIX interaction. Lastly, we demonstrated that the CBP and p300 KIX domains contribute to both c-Myb-dependent gene activation and repression. Together these results suggest that the KIX domains of CBP, and especially p300, are principal mediators of c-Myb-dependent gene activation and repression that is required for definitive hematopoiesis.
1 Communities
1 Members
0 Resources
11 MeSH Terms