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1.
Gene ; 764: 145101, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32877747

RESUMO

India is the world's largest milk producing country because of massive contribution made by cattle and buffaloes. In the present investigation, comprehensive comparative profiling of transcriptomic landscape of milk somatic cells of Sahiwal cattle and Murrah buffaloes was carried out. Genes with highest transcript abundance in both species were enriched for biological processes such as lactation, immune response, cellular oxidant detoxification and response to hormones. Analysis of differential expression identified 377 significantly up-regulated and 847 significantly down-regulated genes with fold change >1.5 in Murrah buffaloes as compared to Sahiwal cattle (padj <0.05). Marked enrichment of innate and adaptive immune response related GO terms and higher expression of genes for various host defense peptides such as lysozyme, defensin ß and granzymes were evident in buffaloes. Genes related to ECM-receptor interaction, complement and coagulation cascades, cytokine-cytokine receptor interaction and keratinization pathway showed more abundant expression in cattle. Network analysis of the up-regulated genes delineated highly connected genes representing immunity and haematopoietic cell lineage (CBL, CD28, CD247, PECAM1 and ITGA4). For the down-regulated dataset, genes with highest interactions were KRT18, FGFR1, GPR183, ITGB3 and DKK3. Our results lend support to more robust immune mechanisms in buffaloes, possibly explaining lower susceptibility to mammary infections as compared to cattle.


Assuntos
Búfalos/imunologia , Bovinos/imunologia , Imunidade/genética , Transcriptoma/imunologia , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Búfalos/genética , Bovinos/genética , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Regulação para Baixo/imunologia , Feminino , Hematopoese/genética , Hematopoese/imunologia , Índia , Lactação/genética , Lactação/imunologia , Leite/citologia , Leite/imunologia , RNA-Seq , Transcriptoma/genética , Regulação para Cima/imunologia
2.
Mol Med Rep ; 22(6): 4485-4491, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33173966

RESUMO

In December 2019, an emergence of pneumonia was detected in patients infected with a novel coronavirus (CoV) in Wuhan (Hubei, China). The International Committee on Taxonomy of Viruses named the virus severe acute respiratory syndrome­CoV­2 and the disease CoV disease­19 (COVID­19). Patients with COVID­19 present with symptoms associated with respiratory system dysfunction and hematological changes, including lymphopenia, thrombocytopenia and coagulation disorders. However, to the best of our knowledge, the pathogenesis of COVID­19 remains unclear. Therefore, understanding the mechanisms underlying the hematological changes that manifest during COVID­19 may aid in the development of treatments and may improve patient prognosis.


Assuntos
Betacoronavirus , Infecções por Coronavirus/sangue , Pneumonia Viral/sangue , Anticorpos Antivirais/imunologia , Complexo Antígeno-Anticorpo/imunologia , Antivirais/farmacologia , Antivirais/uso terapêutico , Betacoronavirus/imunologia , Microambiente Celular , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/terapia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/prevenção & controle , Citocinas/sangue , Testes Diagnósticos de Rotina , Endotélio Vascular/patologia , Testes Hematológicos , Hematopoese/efeitos dos fármacos , Células-Tronco Hematopoéticas/patologia , Humanos , Hipoalbuminemia/etiologia , Fígado/fisiopatologia , Pulmão/fisiopatologia , Linfopenia/etiologia , Linfopenia/fisiopatologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/terapia , Traumatismo por Reperfusão/etiologia , Trombocitopenia/etiologia , Trombocitopenia/fisiopatologia , Trombofilia/etiologia
3.
Yi Chuan ; 42(8): 725-738, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32952109

RESUMO

Hematopoiesis is a complex, orderly and conserved developmental process, coordinated by multiple factors including transcription factors and signaling pathways. Dysregulation of any of these factors may cause developmental or functional defects in the blood system, leading to the pathogenesis of blood diseases. Zebrafish hematopoiesis and the underlying molecular mechanisms are highly conserved with those in mammals. The use of zebrafish to recapitulate abnormal changes in pathogenic factors can build models of related blood diseases, thus providing powerful tools for exploring the molecular mechanisms of pathogenesis and progression, visualization of tumorigenesis and high-throughput chemical screening. In this review, we summarize the zebrafish models of blood diseases and their applications. These disease models not only help to improve our understanding of the pathophysiology of the blood system and the molecular mechanisms on pathogeneses of blood diseases, but also provide new ideas for the treatment of clinically relevant hematological malignancies.


Assuntos
Doenças Hematológicas , Peixe-Zebra , Animais , Modelos Animais de Doenças , Doenças Hematológicas/genética , Neoplasias Hematológicas/fisiopatologia , Hematopoese/genética
4.
Proc Natl Acad Sci U S A ; 117(38): 23336-23338, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32900927

RESUMO

Colony-stimulating factor 1 receptor (CSF1R) inhibition has been proposed as a method for microglia depletion, with the assumption that it does not affect peripheral immune cells. Here, we show that CSF1R inhibition by PLX5622 indeed affects the myeloid and lymphoid compartments, causes long-term changes in bone marrow-derived macrophages by suppressing interleukin 1ß, CD68, and phagocytosis but not CD208, following exposure to endotoxin, and also reduces the population of resident and interstitial macrophages of peritoneum, lung, and liver but not spleen. Thus, small-molecule CSF1R inhibition is not restricted to microglia, causing strong effects on circulating and tissue macrophages that perdure long after cessation of the treatment. Given that peripheral monocytes repopulate the central nervous system after CSF1R inhibition, these changes have practical implications for relevant experimental data.


Assuntos
Hematopoese/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Microglia/efeitos dos fármacos , Compostos Orgânicos/farmacologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/imunologia , Feminino , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/imunologia , Fagocitose/efeitos dos fármacos , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/imunologia , Especificidade da Espécie
5.
Proc Natl Acad Sci U S A ; 117(38): 23626-23635, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32883883

RESUMO

Hematopoietic stem and progenitor cell (HSPC) formation and lineage differentiation involve gene expression programs orchestrated by transcription factors and epigenetic regulators. Genetic disruption of the chromatin remodeler chromodomain-helicase-DNA-binding protein 7 (CHD7) expanded phenotypic HSPCs, erythroid, and myeloid lineages in zebrafish and mouse embryos. CHD7 acts to suppress hematopoietic differentiation. Binding motifs for RUNX and other hematopoietic transcription factors are enriched at sites occupied by CHD7, and decreased RUNX1 occupancy correlated with loss of CHD7 localization. CHD7 physically interacts with RUNX1 and suppresses RUNX1-induced expansion of HSPCs during development through modulation of RUNX1 activity. Consequently, the RUNX1:CHD7 axis provides proper timing and function of HSPCs as they emerge during hematopoietic development or mature in adults, representing a distinct and evolutionarily conserved control mechanism to ensure accurate hematopoietic lineage differentiation.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core , Proteínas de Ligação a DNA , Hematopoese , Animais , Diferenciação Celular , Linhagem Celular , Subunidade alfa 2 de Fator de Ligação ao Core/química , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Células-Tronco Hematopoéticas , Humanos , Masculino , Camundongos , Baço/citologia , Peixe-Zebra
6.
PLoS One ; 15(9): e0235183, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32956421

RESUMO

Members of the broad complex, tram track, bric-a-brac and zinc finger (BTB-ZF) family of transcription factors, such as BCL-6, ZBTB20, and ZBTB32, regulate antigen-specific B cell differentiation, plasma cell longevity, and the duration of antibody production. We found that ZBTB38, a different member of the BTB-ZF family that binds methylated DNA at CpG motifs, is highly expressed by germinal center B cells and plasma cells. To define the functional role of ZBTB38 in B cell responses, we generated mice conditionally deficient in this transcription factor. Germinal center B cells lacking ZBTB38 dysregulated very few genes relative to wild-type and heterozygous littermate controls. Accordingly, mice with hematopoietic-specific deletion of Zbtb38 showed normal germinal center B cell numbers and antibody responses following immunization with hapten-protein conjugates. Memory B cells from these animals functioned normally in secondary recall responses. Despite expression of ZBTB38 in hematopoietic stem cells, progenitors and mature myeloid and lymphoid lineages were also present in normal numbers in mutant mice. These data demonstrate that ZBTB38 is dispensable for hematopoiesis and antibody responses. These conditional knockout mice may instead be useful in defining the functional importance of ZBTB38 in other cell types and contexts.


Assuntos
Formação de Anticorpos , Linfócitos B/imunologia , Proteínas Repressoras/imunologia , Animais , Linfócitos B/citologia , Deleção de Genes , Expressão Gênica , Hematopoese , Imunização , Camundongos , Camundongos Knockout , Proteínas Repressoras/genética
7.
Ann Hematol ; 99(11): 2529-2538, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32948913

RESUMO

INTRODUCTION: Since the 1970s outcome of aplastic anemia (AA) patients has improved significantly due to the introduction of immunosuppressive therapy (IST) and allogeneic hematopoietic transplantation (HCT). However, patients may suffer from persistent disease, relapse, clonal evolution, graft-versus-host disease and other late effects. Here, we analyse very long-term outcome of all AA patients at our institution comparing not only survival, but also response status and complications. METHODS: Patient charts of all 302 AA patients treated between 1973 and 2017 at the University Hospital Basel, Switzerland, were retrospectively analysed. RESULTS: First line treatment was IST in 226 (75%) and HCT in 76 (25%) patients. Overall survival at 30 years was similar in patients treated initially by HCT and IST (44% (±14%), and 40% (± 9%) respectively, with better results in more recent years. Partial and no response occurred more frequently after IST, relapse incidence after IST was 24 %, whereas non-engraftment and graft failure was documented in 15 patients (19 %) after HCT. Clonal evolution to myelodysplastic syndrome / acute myeloid leukemia was 16 % at 25 years in IST patients, 1.3 % in HCT patients, iron overload (18 versus 4 %, p = 0.002) and cardiovascular events (11 versus 1 %, p=0.011) occured significantly more often in IST than HCT treated patients. The majority of long-term survivors, 96% of those alive at 25 years, were in complete remission at last follow up, irrespective of the initial treatment modality. CONCLUSION: Very long term survivors after AA are those with stable hematopoietic recovery.


Assuntos
Anemia Aplástica , Hematopoese , Transplante de Células-Tronco Hematopoéticas , Imunossupressão , Recuperação de Função Fisiológica , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aloenxertos , Anemia Aplástica/mortalidade , Anemia Aplástica/terapia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
8.
Nat Commun ; 11(1): 4483, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32900993

RESUMO

The Drosophila lymph gland, the larval hematopoietic organ comprised of prohemocytes and mature hemocytes, has been a valuable model for understanding mechanisms underlying hematopoiesis and immunity. Three types of mature hemocytes have been characterized in the lymph gland: plasmatocytes, lamellocytes, and crystal cells, which are analogous to vertebrate myeloid cells, yet molecular underpinnings of the lymph gland hemocytes have been less investigated. Here, we use single-cell RNA sequencing to comprehensively analyze heterogeneity of developing hemocytes in the lymph gland, and discover previously undescribed hemocyte types including adipohemocytes, stem-like prohemocytes, and intermediate prohemocytes. Additionally, we identify the developmental trajectory of hemocytes during normal development as well as the emergence of the lamellocyte lineage following active cellular immunity caused by wasp infestation. Finally, we establish similarities and differences between embryonically derived- and larval lymph gland hemocytes. Altogether, our study provides detailed insights into the hemocyte development and cellular immune responses at single-cell resolution.


Assuntos
Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Hemócitos/citologia , Hemócitos/metabolismo , Transcriptoma , Animais , Animais Geneticamente Modificados , Diferenciação Celular/genética , Linhagem da Célula/genética , Drosophila melanogaster/metabolismo , Ectoparasitoses/genética , Ectoparasitoses/metabolismo , Ectoparasitoses/patologia , Perfilação da Expressão Gênica , Hematopoese/genética , Interações Hospedeiro-Parasita/genética , Interações Hospedeiro-Parasita/fisiologia , Tecido Linfoide/citologia , Tecido Linfoide/metabolismo , Tecido Linfoide/parasitologia , RNA-Seq , Análise de Célula Única , Vespas/patogenicidade
10.
Proc Natl Acad Sci U S A ; 117(34): 20729-20740, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32796104

RESUMO

Tissue-resident macrophages can originate from embryonic or adult hematopoiesis. They play important roles in a wide range of biological processes including tissue remodeling during organogenesis, organ homeostasis, repair following injury, and immune response to pathogens. Although the origins and tissue-specific functions of resident macrophages have been extensively studied in many other tissues, they are not well characterized in skeletal muscle. In the present study, we have characterized the ontogeny of skeletal muscle-resident macrophages by lineage tracing and bone marrow transplant experiments. We demonstrate that skeletal muscle-resident macrophages originate from both embryonic hematopoietic progenitors located within the yolk sac and fetal liver as well as definitive hematopoietic stem cells located within the bone marrow of adult mice. Single-cell-based transcriptome analyses revealed that skeletal muscle-resident macrophages are distinctive from resident macrophages in other tissues as they express a distinct complement of transcription factors and are composed of functionally diverse subsets correlating to their origins. Functionally, skeletal muscle-resident macrophages appear to maintain tissue homeostasis and promote muscle growth and regeneration.


Assuntos
Macrófagos/imunologia , Músculo Esquelético/imunologia , Animais , Medula Óssea/metabolismo , Transplante de Medula Óssea/métodos , Diferenciação Celular/genética , Linhagem da Célula/genética , Desenvolvimento Embrionário , Feminino , Heterogeneidade Genética , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Homeostase , Macrófagos/metabolismo , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia , Monócitos/metabolismo , Organogênese/genética
11.
Scand J Immunol ; 92(5): e12957, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32767789

RESUMO

Bone marrow haematopoietic stem and progenitor cells (HSPCs) express pattern recognition receptors such as Toll-like receptors (TLRs) to sense microbial products and activation of these innate immune receptors induces cytokine expression and redirects bone marrow haematopoiesis towards the increased production of myeloid cells. Secreted cytokines by HSPCs in response to TLR ligands can act in an autocrine or paracrine manner to regulate haematopoiesis. Moreover, tonic activation of HSPCs by microbiota-derived compounds might educate HSPCs to produce superior myeloid cells equipped with innate memory responses to combat pathogens. While haematopoietic stem cell activation through TLRs meets the increased demand for blood leucocytes to protect the host against infection, persistent exposure to inflammatory cytokines or microbial products might impair their function and even induce malignant transformation. This review highlights the potential outcomes of HSPCs in response to TLR ligands.


Assuntos
Células da Medula Óssea/imunologia , Células-Tronco Hematopoéticas/imunologia , Microbiota/imunologia , Células Mieloides/imunologia , Receptores de Reconhecimento de Padrão/imunologia , Animais , Células da Medula Óssea/metabolismo , Células da Medula Óssea/microbiologia , Citocinas/imunologia , Citocinas/metabolismo , Hematopoese/imunologia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/microbiologia , Humanos , Células Mieloides/metabolismo , Receptores de Reconhecimento de Padrão/metabolismo , Receptores Toll-Like/imunologia , Receptores Toll-Like/metabolismo
12.
Nat Commun ; 11(1): 4075, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796847

RESUMO

Hematopoietic ageing involves declining erythropoiesis and lymphopoiesis, leading to frequent anaemia and decreased adaptive immunity. How intrinsic changes to the hematopoietic stem cells (HSCs), an altered microenvironment and systemic factors contribute to this process is not fully understood. Here we use bone marrow stromal cells as sensors of age-associated changes to the bone marrow microenvironment, and observe up-regulation of IL-6 and TGFß signalling-induced gene expression in aged bone marrow stroma. Inhibition of TGFß signalling leads to reversal of age-associated HSC platelet lineage bias, increased generation of lymphoid progenitors and rebalanced HSC lineage output in transplantation assays. In contrast, decreased erythropoiesis is not an intrinsic property of aged HSCs, but associated with decreased levels and functionality of erythroid progenitor populations, defects ameliorated by TGFß-receptor and IL-6 inhibition, respectively. These results show that both HSC-intrinsic and -extrinsic mechanisms are involved in age-associated hematopoietic decline, and identify therapeutic targets that promote their reversal.


Assuntos
Envelhecimento/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Interleucina-6/metabolismo , Células-Tronco Mesenquimais/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Envelhecimento/genética , Animais , Medula Óssea , Ciclo Celular/fisiologia , Células Cultivadas , Modelos Animais de Doenças , Células Precursoras Eritroides , Eritropoese/genética , Eritropoese/fisiologia , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Hematopoese , Interleucina-6/genética , Linfopoese/genética , Linfopoese/fisiologia , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides , Transdução de Sinais , Nicho de Células-Tronco , Fator de Crescimento Transformador beta1/genética
13.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(4): 1349-1356, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32798425

RESUMO

OBJECTIVE: To investigate the effect of PDGFRα+ stromal cells derived SCF on hematopoiesis of adult mice. METHODS: Pdgfrα-CreER; R26-tdTomato mice model was constructed, and the proportion and distribution of PDGFRα+ cells in the liver, spleen, lung, kidney and bone marrow were analyzed by flow cytometry and confocal microscopy. Then the Pdgfrα-CreER; Scf flox/flox mice model was further constructed, the Scf in PDGFRα+ was knocked out specifically, the effect of Scf-knocked out in PDGFRα+ stromal cells in the propitiation of HSPCs in the bone marrow was analyzed by flow cytometry. The effect of SCF on the proportion on number of peripheral blood cells in mice was analyzed by whole blood analyzer. RESULTS: After Scf was knocked out in PDGFRα+ stromal cells, the propitiation and number of LKS- cell, LKS+ cell, HSC, MPP1, MKP, PreGM, PreMegE, and CFU-E in the bone marrow of mice was decreased, as well as in the number of red blood cells and hemoglobin concentration of peripheral blood. However, Scf knocked out from PDGFRα+ cells showed no effect on the hematopoiesis in spleen. CONCLUSION: specific knocked out of Scf in PDGFRα+ stromal cells in adult mice can decrease the proportion of HSPCs in the bone marrow and the number of red blood cells in peripheral blood, and finally lead to anemia in mice.


Assuntos
Receptor alfa de Fator de Crescimento Derivado de Plaquetas , Fator de Células-Tronco , Animais , Medula Óssea , Células da Medula Óssea , Hematopoese , Camundongos
14.
Ann Hematol ; 99(10): 2303-2313, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32856141

RESUMO

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease characterized by a deregulated complement system, chronic Coombs-negative, intravascular hemolysis, and a variable clinical course with substantial risk to develop thromboembolic events. We analyzed diagnostic and prognostic parameters as well as clinical endpoints in 59 adult patients suffering from PNH in 5 hematology centers in Austria (observation period: 1978-2015). Median follow-up time was 5.6 years. The median clone size at diagnosis amounted to 55% and was higher in patients with classical PNH (81%) compared to patients with PNH associated with aplastic anemia (AA) or myelodysplastic syndromes (MDS) (50%). The clone size also correlated with lactate dehydrogenase (LDH) levels. In one patient, anemia improved spontaneously and disappeared with complete normalization of LDH after 16 years. Seventeen patients received therapy with eculizumab. The rate of thromboembolic events was higher in the pre-eculizumab era compared with eculizumab-treated patients but did not correlate with the presence of age-related clonal hematopoiesis or any other clinical or laboratory parameters. Peripheral blood colony-forming progenitor cell counts were lower in PNH patients compared with healthy controls. Only two patients with classical PNH developed MDS. Overall, 7/59 patients died after 0.5-32 years. Causes of death were acute pulmonary hypertension, Budd-Chiari syndrome, and septicemia. Overall survival (OS) was mainly influenced by age and was similar to OS measured in an age-matched healthy Austrian control cohort. Together, compared with previous times, the clinical course and OS in PNH are favorable, which may be due to better diagnosis, early recognition, and eculizumab therapy.


Assuntos
Hemoglobinúria Paroxística/epidemiologia , Lesão Renal Aguda/sangue , Lesão Renal Aguda/etiologia , Adulto , Anemia Aplástica/epidemiologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Áustria/epidemiologia , Medula Óssea/patologia , Causas de Morte , Células Clonais/patologia , Ensaio de Unidades Formadoras de Colônias , Terapia Combinada , Inativadores do Complemento/uso terapêutico , Creatinina/sangue , Progressão da Doença , Feminino , Seguimentos , Hematopoese , Transplante de Células-Tronco Hematopoéticas , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/tratamento farmacológico , Hemoglobinúria Paroxística/terapia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/epidemiologia , Gravidez , Complicações Hematológicas na Gravidez/epidemiologia , Prognóstico , Tromboembolia/etiologia
15.
Gene ; 760: 145020, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32755656

RESUMO

Conserved sequences across species have always provided valuable insights to improve our understanding on the human genome's entity and the interplay among different loci. Lymphoma/leukemia related factor (LRF) is encoded by ZBTB7A gene and belongs to an evolutionarily conserved family of transcription factors, implicated in vital cellular functions. The present data, demonstrating the wide-spread and the high overlap of the LRF/ZBTB7A recognition sites with genomic segments identified as CpG islands in the human genome, suggest that its binding capacity strongly depends on a specific sequence-encoded feature within CpGs. We have previously shown that de-methylation of the CpG island 326 lying in the ZBTB7A gene promoter is associated with impaired pharmacological induction of fetal hemoglobin in ß-type hemoglobinopathies patients. Within this context we aimed to investigate the extent of the LRF/ZBTB7A conservation among primates and mouse genome, focusing our interest also on the CpG island flanking the gene's promoter region, in an effort to further establish its epigenetic regulatory role in human hematopoiesis and pharmacological involvement in hematopoietic disorders. Comparative analysis of the human ZBTB7A nucleotide and amino acid sequences and orthologous sequences among non-human primates and mouse, exhibited high conservation scores. Pathway analysis, clearly indicated that LRF/ZBTB7A influences conserved cellular processes. These data in conjunction with the high levels of expression foremost in hematopoietic tissues, highlighted LRF/ZBTB7A as an essential factor operating indisputably during hematopoiesis.


Assuntos
Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Doenças Hematológicas/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Animais , Sítios de Ligação/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Sequência Conservada/genética , Ilhas de CpG/genética , Bases de Dados Genéticas , Hemoglobina Fetal/genética , Hematopoese/genética , Humanos , Camundongos , Primatas/genética , Regiões Promotoras Genéticas/genética
16.
Medicine (Baltimore) ; 99(28): e20906, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664083

RESUMO

Osteoporosis (OP) is a metabolic bone disease that can cause structural changes in bone marrow cavity. Bone marrow is the hematopoietic organ of adults. Accumulating evidence has shown a close connection between bone marrow hematopoietic function and bone formation. Some studies have revealed that OP is associated with hematopoiesis. However, the relationship is not definite.This study aimed to evaluate the association between peripheral blood cell counts (white blood cells [WBC], red blood cells [RBC], platelets [PLT]), hemoglobin [HGB], and bone mineral density [BMD]) in a sample of Chinese postmenopausal women. This is a retrospective study involving 673 postmenopausal women cases. The BMD of lumbar spine and left hip joint were measured by dual-energy X-ray absorptiometry. The levels of blood cell counts and HGB were measured and analyzed.The study results showed the WBC, RBC, PLT, and HGB levels of postmenopausal women in the OP group were all higher than those in the non-osteoporosis group. Spearman linear trend analysis and partial correlation analysis demonstrated that BMD was negatively correlated with WBC, RBC, PLT, and HGB in postmenopausal women.Due to the differences between different countries and races, and there are few studies on the association of BMD with peripheral blood cell counts and HGB in Chinese Postmenopausal Women. Therefore, more large sample studies are needed.


Assuntos
Grupo com Ancestrais do Continente Asiático/etnologia , Contagem de Células Sanguíneas/métodos , Densidade Óssea/fisiologia , Hemoglobinas/análise , Pós-Menopausa/sangue , Absorciometria de Fóton/métodos , Idoso , Contagem de Células Sanguíneas/tendências , Doenças Ósseas Metabólicas/diagnóstico , Doenças Ósseas Metabólicas/epidemiologia , Doenças Ósseas Metabólicas/fisiopatologia , Estudos de Casos e Controles , Feminino , Hematopoese/fisiologia , Articulação do Quadril/diagnóstico por imagem , Articulação do Quadril/fisiopatologia , Humanos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/fisiopatologia , Pessoa de Meia-Idade , Osteogênese/fisiologia , Osteoporose/diagnóstico , Osteoporose/epidemiologia , Osteoporose/fisiopatologia , Estudos Retrospectivos
17.
PLoS Comput Biol ; 16(7): e1007620, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32701980

RESUMO

Myelosuppression is one of the most common and severe adverse events associated with anti-cancer therapies and can be a source of drug attrition. Current mathematical modeling methods for assessing cytopenia risk rely on indirect measurements of drug effects and primarily focus on single lineage responses to drugs. However, anti-cancer therapies have diverse mechanisms with varying degrees of effect across hematopoietic lineages. To improve predictive understanding of drug-induced myelosuppression, we developed a quantitative systems pharmacology (QSP) model of hematopoiesis in vitro for quantifying the effects of anti-cancer agents on multiple hematopoietic cell lineages. We calibrated the system parameters of the model to cell kinetics data without treatment and then validated the model by showing that the inferred mechanisms of anti-proliferation and/or cell-killing are consistent with the published mechanisms for three classes of drugs with different mechanisms of action. Using a set of compounds as a reference set, we then analyzed novel compounds to predict their mechanisms and magnitude of myelosuppression. Further, these quantitative mechanisms are valuable for the development of translational in vivo models to predict clinical cytopenia effects.


Assuntos
Antineoplásicos/farmacologia , Doenças Hematológicas/induzido quimicamente , Hematopoese/efeitos dos fármacos , Modelos Biológicos , Células Sanguíneas/efeitos dos fármacos , Células Cultivadas , Citocinas/farmacologia , Humanos , Concentração Inibidora 50 , Análise de Componente Principal , Células-Tronco/efeitos dos fármacos , Biologia de Sistemas
18.
Proc Natl Acad Sci U S A ; 117(29): 17041-17048, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32632001

RESUMO

A central task in developmental biology is to learn the sequence of fate decisions that leads to each mature cell type in a tissue or organism. Recently, clonal labeling of cells using DNA barcodes has emerged as a powerful approach for identifying cells that share a common ancestry of fate decisions. Here we explore the idea that stochasticity of cell fate choice during tissue development could be harnessed to read out lineage relationships after a single step of clonal barcoding. By considering a generalized multitype branching process, we determine the conditions under which the final distribution of barcodes over observed cell types encodes their bona fide lineage relationships. We then propose a method for inferring the order of fate decisions. Our theory predicts a set of symmetries of barcode covariance that serves as a consistency check for the validity of the method. We show that broken symmetries may be used to detect multiple paths of differentiation to the same cell types. We provide computational tools for general use. When applied to barcoding data in hematopoiesis, these tools reconstruct the classical hematopoietic hierarchy and detect couplings between monocytes and dendritic cells and between erythrocytes and basophils that suggest multiple pathways of differentiation for these lineages.


Assuntos
Linhagem da Célula , Código de Barras de DNA Taxonômico/métodos , Animais , Linhagem da Célula/genética , Linhagem da Célula/fisiologia , Árvores de Decisões , Células Dendríticas/citologia , Eritrócitos/citologia , Hematopoese/genética , Hematopoese/fisiologia , Leucócitos/citologia , Modelos Biológicos , Biologia de Sistemas
19.
Rinsho Ketsueki ; 61(6): 651-656, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32624539

RESUMO

Hematopoietic stem cells (HSCs) are maintained in steady state in the bone marrow (BM); these cells are capable of continuous self-renewal and have the potential for multilineage-differentiation into all blood cell lineages. The BM has long been considered as an immune-privilege organ with little immunological reactions. However, recent findings have revealed that immunological/hematopoietic challenges such as infection or inflammation induce broad spectrum of immune and inflammatory responses in BM. While these responses play a beneficial role to boost immune activation and blood production, chronic challenge might lead to BM pathology and dysregulation, including hematopoietic aplasia or neoplasia. We will introduce recent findings focused on hematopoietic activation induced by existing outside of our body or co-existing with us, and discuss to what degree and how function of HSCs and progenitors is regulated and altered by bacterial insult.


Assuntos
Hematopoese , Imunidade Inata , Medula Óssea , Diferenciação Celular , Células-Tronco Hematopoéticas
20.
Nat Commun ; 11(1): 3327, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620863

RESUMO

Gaucher disease is a lysosomal storage disorder caused by insufficient glucocerebrosidase activity. Its hallmark manifestations are attributed to infiltration and inflammation by macrophages. Current therapies for Gaucher disease include life-long intravenous administration of recombinant glucocerebrosidase and orally-available glucosylceramide synthase inhibitors. An alternative approach is to engineer the patient's own hematopoietic system to restore glucocerebrosidase expression, thereby replacing the affected cells, and constituting a potential one-time therapy for this disease. Here, we report an efficient CRISPR/Cas9-based approach that targets glucocerebrosidase expression cassettes with a monocyte/macrophage-specific element to the CCR5 safe-harbor locus in human hematopoietic stem and progenitor cells. The targeted cells generate glucocerebrosidase-expressing macrophages and maintain long-term repopulation and multi-lineage differentiation potential with serial transplantation. The combination of a safe-harbor and a lineage-specific promoter establishes a universal correction strategy and circumvents potential toxicity of ectopic glucocerebrosidase in the stem cells. Furthermore, it constitutes an adaptable platform for other lysosomal enzyme deficiencies.


Assuntos
Edição de Genes/métodos , Glucosilceramidase/metabolismo , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/enzimologia , Macrófagos/enzimologia , Monócitos/enzimologia , Animais , Diferenciação Celular/genética , Células Cultivadas , Doença de Gaucher/genética , Doença de Gaucher/terapia , Glucosilceramidase/genética , Células HEK293 , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Humanos , Macrófagos/metabolismo , Engenharia Metabólica , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Monócitos/metabolismo , Transplante Autólogo
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