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Results: 1 to 10 of 302

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Identification of a pro-angiogenic functional role for FSP1-positive fibroblast subtype in wound healing.
Saraswati S, Marrow SMW, Watch LA, Young PP
(2019) Nat Commun 10: 3027
MeSH Terms: Actins, Animals, Bone Marrow Transplantation, Calcium-Binding Proteins, Cell Differentiation, Disease Models, Animal, Fibroblasts, Fibrosis, Green Fluorescent Proteins, Human Umbilical Vein Endothelial Cells, Humans, Mice, Mice, Inbred C57BL, Mice, Transgenic, Myocardial Infarction, Myocardium, Neovascularization, Physiologic, S100 Calcium-Binding Protein A4, Transplantation Chimera, Wound Healing
Show Abstract · Added March 24, 2020
Fibrosis accompanying wound healing can drive the failure of many different organs. Activated fibroblasts are the principal determinants of post-injury pathological fibrosis along with physiological repair, making them a difficult therapeutic target. Although activated fibroblasts are phenotypically heterogeneous, they are not recognized as distinct functional entities. Using mice that express GFP under the FSP1 or αSMA promoter, we characterized two non-overlapping fibroblast subtypes from mouse hearts after myocardial infarction. Here, we report the identification of FSP1-GFP cells as a non-pericyte, non-hematopoietic fibroblast subpopulation with a predominant pro-angiogenic role, characterized by in vitro phenotypic/cellular/ultrastructural studies and in vivo granulation tissue formation assays combined with transcriptomics and proteomics. This work identifies a fibroblast subtype that is functionally distinct from the pro-fibrotic αSMA-expressing myofibroblast subtype. Our study has the potential to shift our focus towards viewing fibroblasts as molecularly and functionally heterogeneous and provides a paradigm to approach treatment for organ fibrosis.
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Haploidentical bone marrow transplantation improves cerebral hemodynamics in adults with sickle cell disease.
Jordan LC, Juttukonda MR, Kassim AA, DeBaun MR, Davis LT, Pruthi S, Patel NJ, Lee CA, Waddle SL, Donahue MJ
(2019) Am J Hematol 94: E155-E158
MeSH Terms: Adolescent, Adult, Allografts, Anemia, Sickle Cell, Bone Marrow Transplantation, Cerebrovascular Circulation, Female, Hemodynamics, Humans, Male
Added March 24, 2020
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Increased Ripk1-mediated bone marrow necroptosis leads to myelodysplasia and bone marrow failure in mice.
Wagner PN, Shi Q, Salisbury-Ruf CT, Zou J, Savona MR, Fedoriw Y, Zinkel SS
(2019) Blood 133: 107-120
MeSH Terms: Animals, BH3 Interacting Domain Death Agonist Protein, Bone Marrow, Bone Marrow Diseases, Cells, Cultured, Cytokines, Hematopoietic Stem Cells, Inflammation, Mice, Mice, Inbred C57BL, Mice, Knockout, Myelodysplastic Syndromes, Necrosis, Receptor-Interacting Protein Serine-Threonine Kinases, bcl-2 Homologous Antagonist-Killer Protein
Show Abstract · Added December 11, 2018
Hematopoiesis is a dynamic system that requires balanced cell division, differentiation, and death. The 2 major modes of programmed cell death, apoptosis and necroptosis, share molecular machinery but diverge in outcome with important implications for the microenvironment; apoptotic cells are removed in an immune silent process, whereas necroptotic cells leak cellular contents that incite inflammation. Given the importance of cytokine-directed cues for hematopoietic cell survival and differentiation, the impact on hematopoietic homeostasis of biasing cell death fate to necroptosis is substantial and poorly understood. Here, we present a mouse model with increased bone marrow necroptosis. Deletion of the proapoptotic Bcl-2 family members Bax and Bak inhibits bone marrow apoptosis. Further deletion of the BH3-only member Bid (to generate triple-knockout [TKO] mice) leads to unrestrained bone marrow necroptosis driven by increased Rip1 kinase (Ripk1). TKO mice display loss of progenitor cells, leading to increased cytokine production and increased stem cell proliferation and exhaustion and culminating in bone marrow failure. Genetically restoring Ripk1 to wild-type levels restores peripheral red cell counts as well as normal cytokine production. TKO bone marrow is hypercellular with abnormal differentiation, resembling the human disorder myelodysplastic syndrome (MDS), and we demonstrate increased necroptosis in MDS bone marrow. Finally, we show that Bid impacts necroptotic signaling through modulation of caspase-8-mediated Ripk1 degradation. Thus, we demonstrate that dysregulated necroptosis in hematopoiesis promotes bone marrow progenitor cell death that incites inflammation, impairs hematopoietic stem cells, and recapitulates the salient features of the bone marrow failure disorder MDS.
© 2019 by The American Society of Hematology.
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15 MeSH Terms
TGF-β promotes fibrosis after severe acute kidney injury by enhancing renal macrophage infiltration.
Chung S, Overstreet JM, Li Y, Wang Y, Niu A, Wang S, Fan X, Sasaki K, Jin GN, Khodo SN, Gewin L, Zhang MZ, Harris RC
(2018) JCI Insight 3:
MeSH Terms: Acute Kidney Injury, Animals, Bone Marrow Cells, Chemotactic Factors, Fibrosis, Kidney, Macrophages, Male, Mice, Mice, Transgenic, Monocytes, N-Formylmethionine Leucyl-Phenylalanine, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Transforming Growth Factor beta, Transforming Growth Factor beta1
Show Abstract · Added December 26, 2018
TGF-β signals through a receptor complex composed of 2 type I and 2 type II (TGF-βRII) subunits. We investigated the role of macrophage TGF-β signaling in fibrosis after AKI in mice with selective monocyte/macrophage TGF-βRII deletion (macrophage TGF-βRII-/- mice). Four weeks after injury, renal TGF-β1 expression and fibrosis were higher in WT mice than macrophage TGF-βRII-/- mice, which had decreased renal macrophages. The in vitro chemotactic response to f-Met-Leu-Phe was comparable between bone marrow-derived monocytes (BMMs) from WT and macrophage TGF-βRII-/- mice, but TGF-βRII-/- BMMs did not respond to TGF-β. We then implanted Matrigel plugs suffused with either f-Met-Leu-Phe or TGF-β1 into WT or macrophage TGF-βRII-/- mice. After 6 days, f-Met-Leu-Phe induced similar macrophage infiltration into the Matrigel plugs of WT and macrophage TGF-βRII-/- mice, but TGF-β induced infiltration only in WT mice. We further determined the number of labeled WT or TGF-βRII-/- BMMs infiltrating into WT kidneys 20 days after ischemic injury. There were more labeled WT BMMs than TGF-βRII-/- BMMs. Therefore, macrophage TGF-βRII deletion protects against the development of tubulointerstitial fibrosis following severe ischemic renal injury. Chemoattraction of macrophages to the injured kidney through a TGF-β/TGF-βRII axis is a heretofore undescribed mechanism by which TGF-β can mediate renal fibrosis during progressive renal injury.
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16 MeSH Terms
Enrichment and detection of bone disseminated tumor cells in models of low tumor burden.
Sowder ME, Johnson RW
(2018) Sci Rep 8: 14299
MeSH Terms: Animals, Antigens, CD, Bone Marrow, Bone and Bones, Estradiol, Humans, MCF-7 Cells, Mice, Inbred BALB C, Mice, Nude, Models, Biological, Neoplasms, Osteolysis, Time Factors, Tumor Burden
Show Abstract · Added March 26, 2019
Breast cancer cells frequently home to the bone, but the mechanisms controlling tumor colonization of the bone marrow remain unclear. We report significant enrichment of bone-disseminated estrogen receptor positive human MCF7 cells by 17 β-estradiol (E2) following intracardiac inoculation. Using flow cytometric and quantitative PCR approaches, tumor cells were detected in >80% of MCF7 tumor-inoculated mice, regardless of E2, suggesting that E2 is not required for MCF7 dissemination to the bone marrow. Furthermore, we propose two additional models in which to study prolonged latency periods by bone-disseminated tumor cells: murine D2.0R and human SUM159 breast carcinoma cells. Tumor cells were detected in bone marrow of up to 100% of D2.0R and SUM159-inoculated mice depending on the detection method. These findings establish novel models of bone colonization in which to study mechanisms underlying tumor cell seeding to the marrow and prolonged latency, and provide highly sensitive methods to detect these rare events.
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14 MeSH Terms
Loss of CXCR4 in Myeloid Cells Enhances Antitumor Immunity and Reduces Melanoma Growth through NK Cell and FASL Mechanisms.
Yang J, Kumar A, Vilgelm AE, Chen SC, Ayers GD, Novitskiy SV, Joyce S, Richmond A
(2018) Cancer Immunol Res 6: 1186-1198
MeSH Terms: Animals, Bone Marrow Transplantation, Cell Line, Tumor, Cytotoxicity, Immunologic, Fas Ligand Protein, Interleukin-18, Killer Cells, Natural, Macrophages, Melanoma, Experimental, Mice, Inbred C57BL, Mice, Transgenic, Neutrophils, Receptors, CXCR4
Show Abstract · Added December 20, 2018
The chemokine receptor, CXCR4, is involved in cancer growth, invasion, and metastasis. Several promising CXCR4 antagonists have been shown to halt tumor metastasis in preclinical studies, and clinical trials evaluating the effectiveness of these agents in patients with cancer are ongoing. However, the impact of targeting CXCR4 specifically on immune cells is not clear. Here, we demonstrate that genetic deletion of CXCR4 in myeloid cells (CXCR4) enhances the antitumor immune response, resulting in significantly reduced melanoma tumor growth. Moreover, CXCR4 mice exhibited slowed tumor progression compared with CXCR4 mice in an inducible melanocyte mouse model. The percentage of Fas ligand (FasL)-expressing myeloid cells was reduced in CXCR4 mice as compared with myeloid cells from CXCR4 mice. In contrast, there was an increased percentage of natural killer (NK) cells expressing FasL in tumors growing in CXCR4 mice. NK cells from CXCR4 mice also exhibited increased tumor cell killing capacity , based on clearance of NK-sensitive Yac-1 cells. NK cell-mediated killing of Yac-1 cells occurred in a FasL-dependent manner, which was partially dependent upon the presence of CXCR4 neutrophils. Furthermore, enhanced NK cell activity in CXCR4 mice was also associated with increased production of IL18 by specific leukocyte subpopulations. These data suggest that CXCR4-mediated signals from myeloid cells suppress NK cell-mediated tumor surveillance and thereby enhance tumor growth. Systemic delivery of a peptide antagonist of CXCR4 to tumor-bearing CXCR4 mice resulted in enhanced NK-cell activation and reduced tumor growth, supporting potential clinical implications for CXCR4 antagonism in some cancers. .
©2018 American Association for Cancer Research.
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13 MeSH Terms
Systemic Sclerosis as an Indication for Autologous Hematopoietic Cell Transplantation: Position Statement from the American Society for Blood and Marrow Transplantation.
Sullivan KM, Majhail NS, Bredeson C, Carpenter PA, Chatterjee S, Crofford LJ, Georges GE, Nash RA, Pasquini MC, Sarantopoulos S, Storek J, Savani B, St Clair EW
(2018) Biol Blood Marrow Transplant 24: 1961-1964
MeSH Terms: Autografts, Bone Marrow Transplantation, Cyclophosphamide, Hematopoietic Stem Cell Transplantation, Humans, Randomized Controlled Trials as Topic, Scleroderma, Systemic, Societies, Medical, United States
Show Abstract · Added March 25, 2020
Systemic sclerosis is a progressive inflammatory disease that is frequently fatal and has limited treatment options. High-dose chemotherapy with autologous hematopoietic cell transplantation (AHCT) has been evaluated as treatment for this disease in observational studies, multicenter randomized controlled clinical trials, and meta-analyses. On behalf of the American Society for Blood and Marrow Transplantation (ASBMT), a panel of experts in transplantation and rheumatology was convened to review available evidence and make a recommendation on AHCT as an indication for systemic sclerosis. Three randomized trials have compared the efficacy of AHCT with cyclophosphamide only, and all demonstrated benefit for the AHCT arm for their primary endpoint (improvement in the American Scleroderma Stem Cell versus Immune Suppression Trial, event-free survival in Autologous Stem Cell Transplantation International Scleroderma trial, and change in global rank composite score in Scleroderma: Cyclophosphamide or Transplantation trial). AHCT recipients also had better overall survival and a lower rate of disease progression. These findings have been confirmed in subsequent meta-analyses. Based on this high-quality evidence, the ASBMT recommends systemic sclerosis should be considered as a "standard of care" indication for AHCT. Close collaboration between rheumatologists and transplant clinicians is critical for optimizing patient selection and patient outcomes. Transplant centers in the United States are strongly encouraged to report patient and outcomes data to the Center for International Blood and Marrow Transplant Research on their patients receiving AHCT for this indication.
Copyright © 2018 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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Discovery of human cell selective effector molecules using single cell multiplexed activity metabolomics.
Earl DC, Ferrell PB, Leelatian N, Froese JT, Reisman BJ, Irish JM, Bachmann BO
(2018) Nat Commun 9: 39
MeSH Terms: Aged, Bone Marrow, Cell Extracts, Chromatography, Liquid, DNA Damage, Female, Flow Cytometry, Humans, Leukemia, Leukemia, Myeloid, Acute, Lymphocytes, Male, Mass Spectrometry, Metabolome, Metabolomics, Monocytes, Signal Transduction, Streptomyces, Tumor Cells, Cultured, Young Adult
Show Abstract · Added January 4, 2018
Discovering bioactive metabolites within a metabolome is challenging because there is generally little foreknowledge of metabolite molecular and cell-targeting activities. Here, single-cell response profiles and primary human tissue comprise a response platform used to discover novel microbial metabolites with cell-type-selective effector properties in untargeted metabolomic inventories. Metabolites display diverse effector mechanisms, including targeting protein synthesis, cell cycle status, DNA damage repair, necrosis, apoptosis, or phosphoprotein signaling. Arrayed metabolites are tested against acute myeloid leukemia patient bone marrow and molecules that specifically targeted blast cells or nonleukemic immune cell subsets within the same tissue biopsy are revealed. Cell-targeting polyketides are identified in extracts from biosynthetically prolific bacteria, including a previously unreported leukemia blast-targeting anthracycline and a polyene macrolactam that alternates between targeting blasts or nonmalignant cells by way of light-triggered photochemical isomerization. High-resolution cell profiling with mass cytometry confirms response mechanisms and is used to validate initial observations.
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20 MeSH Terms
Hallmarks of Bone Metastasis.
Johnson RW, Suva LJ
(2018) Calcif Tissue Int 102: 141-151
MeSH Terms: Animals, Bone Marrow Cells, Bone Neoplasms, Bone and Bones, Breast Neoplasms, Female, Humans, Mice, Osteoblasts, Osteoclasts, Osteolysis
Show Abstract · Added March 26, 2019
Breast cancer bone metastasis develops as the result of a series of complex interactions between tumor cells, bone marrow cells, and resident bone cells. The net effect of these interactions are the disruption of normal bone homeostasis, often with significantly increased osteoclast and osteoblast activity, which has provided a rational target for controlling tumor progression, with little or no emphasis on tumor eradication. Indeed, the clinical course of metastatic breast cancer is relatively long, with patients likely to experience sequential skeletal-related events (SREs), often over lengthy periods of time, even up to decades. These SREs include bone pain, fractures, and spinal cord compression, all of which may profoundly impair a patient's quality-of-life. Our understanding of the contributions of the host bone and bone marrow cells to the control of tumor progression has grown over the years, yet the focus of virtually all available treatments remains on the control of resident bone cells, primarily osteoclasts. In this perspective, our focus is to move away from the current emphasis on the control of bone cells and focus our attention on the hallmarks of bone metastatic tumor cells and how these differ from primary tumor cells and normal host cells. In our opinion, there remains a largely unmet medical need to develop and utilize therapies that impede metastatic tumor cells while sparing normal host bone and bone marrow cells. This perspective examines the impact of metastatic tumor cells on the bone microenvironment and proposes potential new directions for uncovering the important mechanisms driving metastatic progression in bone based on the hallmarks of bone metastasis.
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Hypoxia and Bone Metastatic Disease.
Johnson RW, Sowder ME, Giaccia AJ
(2017) Curr Osteoporos Rep 15: 231-238
MeSH Terms: Bone Marrow, Bone Neoplasms, Bone and Bones, Breast Neoplasms, Female, Humans, Hypoxia, Hypoxia-Inducible Factor 1, Neoplasm Metastasis, Signal Transduction
Show Abstract · Added March 26, 2019
PURPOSE OF REVIEW - This review highlights our current knowledge of oxygen tensions in the bone marrow, and how low oxygen tensions (hypoxia) regulate tumor metastasis to and colonization of the bone marrow.
RECENT FINDINGS - The bone marrow is a relatively hypoxic microenvironment, but oxygen tensions fluctuate throughout the marrow cavity and across the endosteal and periosteal surfaces. Recent advances in imaging have made it possible to better characterize these fluctuations in bone oxygenation, but technical challenges remain. We have compiled evidence from multiple groups that suggests that hypoxia or hypoxia inducible factor (HIF) signaling may induce spontaneous metastasis to the bone and promote tumor colonization of bone, particularly in the case of breast cancer dissemination to the bone marrow. We are beginning to understand oxygenation patterns within the bone compartment and the role for hypoxia and HIF signaling in tumor cell dissemination to the bone marrow, but further studies are warranted.
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