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[PMID]: 28916711 [Au] Autor: Huang P; Keller CA; Giardine B; Grevet JD; Davies JOJ; Hughes JR; Kurita R; Nakamura Y; Hardison RC; Blobel GA [Ad] Endereço: Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. [Ti] Título: Comparative analysis of three-dimensional chromosomal architecture identifies a novel fetal hemoglobin regulatory element. [So] Source: Genes Dev;31(16):1704-1713, 2017 Aug 15. [Is] ISSN: 1549-5477 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Chromatin structure is tightly intertwined with transcription regulation. Here we compared the chromosomal architectures of fetal and adult human erythroblasts and found that, globally, chromatin structures and compartments A/B are highly similar at both developmental stages. At a finer scale, we detected distinct folding patterns at the developmentally controlled ß-globin locus. Specifically, new fetal stage-specific contacts were uncovered between a region separating the fetal (γ) and adult (δ and ß) globin genes (encompassing the and noncoding genes) and two distal chromosomal sites (HS5 and 3'HS1) that flank the locus. In contrast, in adult cells, the - region contacts the embryonic ε-globin gene, physically separating the fetal globin genes from the enhancer (locus control region [LCR]). Deletion of the region in adult cells alters contact landscapes in ways more closely resembling those of fetal cells, including increased LCR-γ-globin contacts. These changes are accompanied by strong increases in γ-globin transcription. Notably, the effects of removal on chromatin architecture and gene expression closely mimic those of deleting the fetal globin repressor BCL11A, implicating BCL11A in the function of the region. Our results uncover a new critical regulatory region as a potential target for therapeutic genome editing for hemoglobinopathies and highlight the power of chromosome conformation analysis in discovering new control elements. [Mh] Termos MeSH primário: Cromatina/química Eritroblastos/metabolismo Regulação da Expressão Gênica no Desenvolvimento Elementos Reguladores de Transcrição Globinas beta/genética [Mh] Termos MeSH secundário: Adulto Proteínas de Transporte/genética Feto Inativação Gênica Seres Humanos Região de Controle de Locus Gênico Proteínas Nucleares/genética Pseudogenes Transcriptoma gama-Globinas/genética [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE [Nm] Nome de substância: 0 (BCL11A protein, human); 0 (Carrier Proteins); 0 (Chromatin); 0 (Nuclear Proteins); 0 (beta-Globins); 0 (gamma-Globins) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171029 [Lr] Data última revisão: 171029 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170917 [St] Status: MEDLINE [do] DOI: 10.1101/gad.303461.117

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[PMID]: 28784691 [Au] Autor: Lam WKJ; Gai W; Sun K; Wong RSM; Chan RWY; Jiang P; Chan NPH; Hui WWI; Chan AWH; Szeto CC; Ng SC; Law MF; Chan KCA; Chiu RWK; Lo YMD [Ad] Endereço: Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China. [Ti] Título: DNA of Erythroid Origin Is Present in Human Plasma and Informs the Types of Anemia. [So] Source: Clin Chem;63(10):1614-1623, 2017 Oct. [Is] ISSN: 1530-8561 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: There is much interest in the tissue of origin of circulating DNA in plasma. Data generated using DNA methylation markers have suggested that hematopoietic cells of white cell lineages are important contributors to the circulating DNA pool. However, it is not known whether cells of the erythroid lineage would also release DNA into the plasma. METHODS: Using high-resolution methylation profiles of erythroblasts and other tissue types, 3 genomic loci were found to be hypomethylated in erythroblasts but hypermethylated in other cell types. We developed digital PCR assays for measuring erythroid DNA using the differentially methylated region for each locus. RESULTS: Based on the methylation marker in the ferrochelatase gene, erythroid DNA represented a median of 30.1% of the plasma DNA of healthy subjects. In subjects with anemia of different etiologies, quantitative analysis of circulating erythroid DNA could reflect the erythropoietic activity in the bone marrow. For patients with reduced erythropoietic activity, as exemplified by aplastic anemia, the percentage of circulating erythroid DNA was decreased. For patients with increased but ineffective erythropoiesis, as exemplified by ß-thalassemia major, the percentage was increased. In addition, the plasma concentration of erythroid DNA was found to correlate with treatment response in aplastic anemia and iron deficiency anemia. Plasma DNA analysis using digital PCR assays targeting the other 2 differentially methylated regions showed similar findings. CONCLUSIONS: Erythroid DNA is a hitherto unrecognized major component of the circulating DNA pool and is a noninvasive biomarker for differential diagnosis and monitoring of anemia. [Mh] Termos MeSH primário: Anemia/sangue Anemia/genética Metilação de DNA DNA/sangue DNA/genética Eritroblastos/patologia [Mh] Termos MeSH secundário: Anemia/diagnóstico Anemia/patologia Anemia Aplástica/sangue Anemia Aplástica/diagnóstico Anemia Aplástica/genética Anemia Aplástica/patologia Anemia Ferropriva/sangue Anemia Ferropriva/diagnóstico Anemia Ferropriva/genética Anemia Ferropriva/patologia Diagnóstico Diferencial Eritroblastos/metabolismo Eritropoese Ferroquelatase/genética Seres Humanos Síndromes Mielodisplásicas/sangue Síndromes Mielodisplásicas/diagnóstico Síndromes Mielodisplásicas/genética Síndromes Mielodisplásicas/patologia Talassemia beta/sangue Talassemia beta/diagnóstico Talassemia beta/genética Talassemia beta/patologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 9007-49-2 (DNA); EC 4.99.1.1 (Ferrochelatase) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171013 [Lr] Data última revisão: 171013 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170809 [St] Status: MEDLINE [do] DOI: 10.1373/clinchem.2017.272401

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[PMID]: 28776729 [Au] Autor: Dai Y; Chen T; Ijaz H; Cho EH; Steinberg MH [Ad] Endereço: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, 02118. [Ti] Título: SIRT1 activates the expression of fetal hemoglobin genes. [So] Source: Am J Hematol;92(11):1177-1186, 2017 Nov. [Is] ISSN: 1096-8652 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: High fetal hemoglobin (HbF, α γ ) levels ameliorate the clinical manifestations of sickle cell disease and ß thalassemia. The mechanisms that repress HbF expression and silence γ-globin genes in adults are incompletely characterized and only a single HbF inducer, hydroxyurea, is approved for treatment, and only in patients with sickle cell disease. We identified SIRT1, a protein deacetylase, as a new inducer of γ-globin. SIRT1 knockdown decreased, while SIRT1 ectopic expression upregulated γ-globin gene (HBG) expression in primary human erythroid cells and in K562 cells. The small molecule SIRT1 activators SRT2104 and SRT1720 enhanced HBG expression in cord blood human erythroblasts and reactivated silenced HBG in adult human erythroblasts. Furthermore, SIRT1 binds in the ß-globin gene cluster locus control region (LCR) and HBG promoters, promotes the looping of the LCR to HBG promoter, and increases the binding of RNA polymerase II and H4K16Ac in the HBG promoter. SIRT1 suppressed the expression of the HBG suppressors BCL11A, KLF1, HDAC1 and HDAC2. Lastly, SIRT1 did not change the proliferation of human erythroid progenitor cells or the expression of differentiation marker CD235a. These data suggest that SIRT1 activates HBG expression through facilitating LCR looping to the HBG promoter, inhibiting the expression of transcriptional suppressors of HBG, and indirectly increasing histone acetylation in the HBG promoter. SIRT1 is a potential therapeutic target for γ-globin gene induction, and small molecule SIRT1 activators might serve as a lead compound for the development of new HbF inducers. [Mh] Termos MeSH primário: Hemoglobina Fetal/genética Regulação da Expressão Gênica Sirtuína 1/metabolismo Ativação Transcricional gama-Globinas/genética [Mh] Termos MeSH secundário: Diferenciação Celular/genética Proliferação Celular/genética Expressão Ectópica do Gene Eritroblastos/metabolismo Células Precursoras Eritroides/metabolismo Eritropoese/genética Hemoglobina Fetal/metabolismo Técnicas de Silenciamento de Genes Inativação Gênica Seres Humanos Células K562 Região de Controle de Locus Gênico Especificidade de Órgãos/genética Regiões Promotoras Genéticas Ligação Proteica RNA Mensageiro/genética RNA Mensageiro/metabolismo Sirtuína 1/genética gama-Globinas/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (RNA, Messenger); 0 (gamma-Globins); 9034-63-3 (Fetal Hemoglobin); EC 3.5.1.- (Sirtuin 1) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171101 [Lr] Data última revisão: 171101 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170805 [St] Status: MEDLINE [do] DOI: 10.1002/ajh.24879

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[PMID]: 28729432 [Au] Autor: Nowak RB; Papoin J; Gokhin DS; Casu C; Rivella S; Lipton JM; Blanc L; Fowler VM [Ad] Endereço: Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA. [Ti] Título: Tropomodulin 1 controls erythroblast enucleation via regulation of F-actin in the enucleosome. [So] Source: Blood;130(9):1144-1155, 2017 Aug 31. [Is] ISSN: 1528-0020 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Biogenesis of mammalian red blood cells requires nuclear expulsion by orthochromatic erythoblasts late in terminal differentiation (enucleation), but the mechanism is largely unexplained. Here, we employed high-resolution confocal microscopy to analyze nuclear morphology and F-actin rearrangements during the initiation, progression, and completion of mouse and human erythroblast enucleation in vivo. Mouse erythroblast nuclei acquire a dumbbell-shaped morphology during enucleation, whereas human bone marrow erythroblast nuclei unexpectedly retain their spherical morphology. These morphological differences are linked to differential expression of Lamin isoforms, with primary mouse erythroblasts expressing only Lamin B and primary human erythroblasts only Lamin A/C. We did not consistently identify a continuous F-actin ring at the cell surface constriction in mouse erythroblasts, nor at the membrane protein-sorting boundary in human erythroblasts, which do not have a constriction, arguing against a contractile ring-based nuclear expulsion mechanism. However, both mouse and human erythroblasts contain an F-actin structure at the rear of the translocating nucleus, enriched in tropomodulin 1 (Tmod1) and nonmuscle myosin IIB. We investigated Tmod1 function in mouse and human erythroblasts both in vivo and in vitro and found that absence of Tmod1 leads to enucleation defects in mouse fetal liver erythroblasts, and in CD34 hematopoietic stem and progenitor cells, with increased F-actin in the structure at the rear of the nucleus. This novel structure, the "enucleosome," may mediate common cytoskeletal mechanisms underlying erythroblast enucleation, notwithstanding the morphological heterogeneity of enucleation across species. [Mh] Termos MeSH primário: Actinas/metabolismo Núcleo Celular/metabolismo Eritroblastos/metabolismo Tropomodulina/metabolismo [Mh] Termos MeSH secundário: Animais Medula Óssea/metabolismo Diferenciação Celular Forma do Núcleo Celular Polaridade Celular Feto/metabolismo Técnicas de Silenciamento de Genes Laminas/metabolismo Fígado/embriologia Camundongos Endogâmicos C57BL Miosina não Muscular Tipo IIB/metabolismo Isoformas de Proteínas/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Actins); 0 (Lamins); 0 (Protein Isoforms); 0 (Tropomodulin); EC 3.6.1.- (Nonmuscle Myosin Type IIB) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170925 [Lr] Data última revisão: 170925 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170722 [St] Status: MEDLINE [do] DOI: 10.1182/blood-2017-05-787051

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[PMID]: 28714864 [Au] Autor: Lessard S; Gatof ES; Beaudoin M; Schupp PG; Sher F; Ali A; Prehar S; Kurita R; Nakamura Y; Baena E; Ledoux J; Oceandy D; Bauer DE; Lettre G [Ad] Endereço: Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada. [Ti] Título: An erythroid-specific ATP2B4 enhancer mediates red blood cell hydration and malaria susceptibility. [So] Source: J Clin Invest;127(8):3065-3074, 2017 Aug 01. [Is] ISSN: 1558-8238 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The lack of mechanistic explanations for many genotype-phenotype associations identified by GWAS precludes thorough assessment of their impact on human health. Here, we conducted an expression quantitative trait locus (eQTL) mapping analysis in erythroblasts and found erythroid-specific eQTLs for ATP2B4, the main calcium ATPase of red blood cells (rbc). The same SNPs were previously associated with mean corpuscular hemoglobin concentration (MCHC) and susceptibility to severe malaria infection. We showed that Atp2b4-/- mice demonstrate increased MCHC, confirming ATP2B4 as the causal gene at this GWAS locus. Using CRISPR-Cas9, we fine mapped the genetic signal to an erythroid-specific enhancer of ATP2B4. Erythroid cells with a deletion of the ATP2B4 enhancer had abnormally high intracellular calcium levels. These results illustrate the power of combined transcriptomic, epigenomic, and genome-editing approaches in characterizing noncoding regulatory elements in phenotype-relevant cells. Our study supports ATP2B4 as a potential target for modulating rbc hydration in erythroid disorders and malaria infection. [Mh] Termos MeSH primário: ATPases Transportadoras de Cálcio/genética Eritrócitos/citologia Predisposição Genética para Doença Malária/genética ATPases Transportadoras de Cálcio da Membrana Plasmática/genética [Mh] Termos MeSH secundário: Animais Sistemas CRISPR-Cas Cálcio/metabolismo ATPases Transportadoras de Cálcio/metabolismo Mapeamento Cromossômico Elementos Facilitadores Genéticos Epigenômica Eritroblastos/metabolismo Perfilação da Expressão Gênica Redes Reguladoras de Genes Estudo de Associação Genômica Ampla Células HEK293 Seres Humanos Malária/metabolismo Masculino Camundongos Camundongos Transgênicos Fenótipo ATPases Transportadoras de Cálcio da Membrana Plasmática/metabolismo Polimorfismo de Nucleotídeo Único Locos de Características Quantitativas [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: EC 3.6.1.8 (ATP2B4 protein, human); EC 3.6.3.8 (Calcium-Transporting ATPases); EC 3.6.3.8 (PMCA4 protein, mouse); EC 3.6.3.8 (Plasma Membrane Calcium-Transporting ATPases); SY7Q814VUP (Calcium) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171101 [Lr] Data última revisão: 171101 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170718 [St] Status: MEDLINE

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[PMID]: 28694332 [Au] Autor: Peraki I; Palis J; Mavrothalassitis G [Ad] Endereço: Medical School, University of Crete, Heraklion, Crete, Greece. [Ti] Título: The Ets2 Repressor Factor (Erf) Is Required for Effective Primitive and Definitive Hematopoiesis. [So] Source: Mol Cell Biol;37(19), 2017 Oct 01. [Is] ISSN: 1098-5549 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: is a gene for a ubiquitously expressed Ets DNA-binding domain-containing transcriptional repressor. haploinsufficiency causes craniosynostosis in humans and mice, while its absence in mice leads to failed chorioallantoic fusion and death at embryonic day 10.5 (E10.5). In this study, we show that is required in all three waves of embryonic hematopoiesis. Mice lacking in the embryo proper exhibited severe anemia and died around embryonic day 14.5. epiblast-specific knockout embryos had reduced numbers of circulating blood cells from E9.5 onwards, with the development of severe anemia by E14.5. Elimination of resulted in both reduced and more immature primitive erythroblasts at E9.5 to E10.5. Reduced definitive erythroid colony-forming activity was found in the bloodstream of E10.5 embryos and in the fetal liver at E11.5 to E13.5. Finally, elimination of resulted in impaired repopulation ability, indicating that Erf is necessary for hematopoietic stem cell maintenance or differentiation. We conclude that Erf is required for both primitive and erythromyeloid progenitor waves of hematopoietic stem cell (HSC)-independent hematopoiesis as well as for the normal function of HSCs. [Mh] Termos MeSH primário: Desenvolvimento Embrionário Eritroblastos/citologia Células-Tronco Hematopoéticas/citologia Proteínas Repressoras/genética Proteínas Repressoras/metabolismo [Mh] Termos MeSH secundário: Anemia/genética Animais Diferenciação Celular Linhagem da Célula Proliferação Celular Embrião de Mamíferos/citologia Embrião de Mamíferos/embriologia Embrião de Mamíferos/metabolismo Eritroblastos/metabolismo Técnicas de Inativação de Genes Hematopoese Células-Tronco Hematopoéticas/metabolismo Seres Humanos Camundongos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Erf protein, mouse); 0 (Repressor Proteins) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171003 [Lr] Data última revisão: 171003 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170712 [St] Status: MEDLINE

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[PMID]: 28570892 [Au] Autor: Montalvão MF; de Souza JM; Guimarães ATB; de Menezes IPP; Castro ALDS; Rodrigues ASL; Malafaia G [Ad] Endereço: Laboratório de Pesquisas Biológicas, Instituto Federal Goiano - Campus Urutaí, GO, Brazil. [Ti] Título: The genotoxicity and cytotoxicity of tannery effluent in bullfrog (Lithobates catesbeianus). [So] Source: Chemosphere;183:491-502, 2017 Sep. [Is] ISSN: 1879-1298 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Some of the most polluting activities occur in bovine skin processing. Tannery generates effluents containing high concentrations of heavy metals and organic compounds. The phases composing the leather production process generate a large volume of tannery effluents that are often discarded in aquatic environments without any previous treatment. However, the effect these xenobiotics have on adult representatives belonging to the class Amphibia remains unknown. Thus, the aim of the present study is to assess the geno- and cytotoxic effects of tannery effluent on adult male bullfrogs (Lithobates castesbeianus) exposed to it. Accordingly, the animals were divided into the following groups: negative control (tannery effluent-free water), positive control (cyclophosphamide), and effluent (water added with 5% tannery effluent). The animals were euthanized for blood collection, and erythrocyte analyses were conducted after 35 and 90 days of exposure. The micronuclei (MN) frequency and the frequency of other nuclear abnormalities in each of the animals in the experimental groups were assessed in 2000 erythrocytes. According to the present results, the exposure to tannery effluents increased MN frequency as well as other nuclear abnormalities (i.e., lobed nuclei, binucleated cell, kidney-shaped nuclei, notched nuclei, and apoptotic cell) in the erythrocytes of animals in the effluent group and in the positive control group after 35 and 90 exposure days. Thus, the current study corroborated the hypothesis that the tannery effluent has aneugenic and clastogenic potential in adult male bullfrogs (L. castesbeianus). The present study is the first to report such effect. [Mh] Termos MeSH primário: Eritrócitos/efeitos dos fármacos Metais Pesados/toxicidade Micronúcleos com Defeito Cromossômico/induzido quimicamente Mutagênicos/toxicidade Curtume Poluentes Químicos da Água/toxicidade [Mh] Termos MeSH secundário: Animais Dano ao DNA Relação Dose-Resposta a Droga Eritroblastos/química Eritroblastos/efeitos dos fármacos Eritroblastos/patologia Eritrócitos/química Eritrócitos/patologia Eritrócitos Anormais/química Eritrócitos Anormais/efeitos dos fármacos Eritrócitos Anormais/patologia Resíduos Industriais/análise Masculino Metais Pesados/análise Testes para Micronúcleos Estrutura Molecular Mutagênicos/análise Rana catesbeiana Fatores de Tempo Poluentes Químicos da Água/análise [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Industrial Waste); 0 (Metals, Heavy); 0 (Mutagens); 0 (Water Pollutants, Chemical) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170915 [Lr] Data última revisão: 170915 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170602 [St] Status: MEDLINE

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[PMID]: 28553950 [Au] Autor: Duchene J; Novitzky-Basso I; Thiriot A; Casanova-Acebes M; Bianchini M; Etheridge SL; Hub E; Nitz K; Artinger K; Eller K; Caamaño J; Rülicke T; Moss P; Megens RTA; von Andrian UH; Hidalgo A; Weber C; Rot A [Ad] Endereço: Institute for Cardiovascular Prevention, Ludwig-Maximilians University (LMU), Munich, Germany. [Ti] Título: Atypical chemokine receptor 1 on nucleated erythroid cells regulates hematopoiesis. [So] Source: Nat Immunol;18(7):753-761, 2017 Jul. [Is] ISSN: 1529-2916 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Healthy individuals of African ancestry have neutropenia that has been linked with the variant rs2814778(G) of the gene encoding atypical chemokine receptor 1 (ACKR1). This polymorphism selectively abolishes the expression of ACKR1 in erythroid cells, causing a Duffy-negative phenotype. Here we describe an unexpected fundamental role for ACKR1 in hematopoiesis and provide the mechanism that links its absence with neutropenia. Nucleated erythroid cells had high expression of ACKR1, which facilitated their direct contact with hematopoietic stem cells. The absence of erythroid ACKR1 altered mouse hematopoiesis including stem and progenitor cells, which ultimately gave rise to phenotypically distinct neutrophils that readily left the circulation, causing neutropenia. Individuals with a Duffy-negative phenotype developed a distinct profile of neutrophil effector molecules that closely reflected the one observed in the ACKR1-deficient mice. Thus, alternative physiological patterns of hematopoiesis and bone marrow cell outputs depend on the expression of ACKR1 in the erythroid lineage, findings with major implications for the selection advantages that have resulted in the paramount fixation of the ACKR1 rs2814778(G) polymorphism in Africa. [Mh] Termos MeSH primário: Sistema do Grupo Sanguíneo Duffy/metabolismo Eritroblastos/metabolismo Hematopoese/genética Células-Tronco Hematopoéticas/metabolismo Neutropenia/genética Neutrófilos/metabolismo Receptores de Superfície Celular/metabolismo [Mh] Termos MeSH secundário: Grupo com Ancestrais do Continente Africano/genética Animais Medula Óssea/patologia Células da Medula Óssea/metabolismo Proliferação Celular Sistema do Grupo Sanguíneo Duffy/genética Citometria de Fluxo Imunofluorescência Células-Tronco Hematopoéticas/citologia Seres Humanos Camundongos Microscopia Confocal Neutrófilos/citologia Receptores de Superfície Celular/genética Receptores de Quimiocinas/genética Receptores de Quimiocinas/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (DARC protein, human); 0 (Dfy protein, mouse); 0 (Duffy Blood-Group System); 0 (Receptors, Cell Surface); 0 (Receptors, Chemokine) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170828 [Lr] Data última revisão: 170828 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170530 [St] Status: MEDLINE [do] DOI: 10.1038/ni.3763

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[PMID]: 28381471 [Au] Autor: Zhang L; Jambusaria A; Hong Z; Marsboom G; Toth PT; Herbert BS; Malik AB; Rehman J [Ad] Endereço: From Department of Pharmacology (L.Z., A.J., Z.H., G.M., P.T.T., A.B.M., J.R.), Department of Medicine, Division of Cardiology (J.R.), The University of Illinois College of Medicine, Chicago; and Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis (B.-S. [Ti] Título: SOX17 Regulates Conversion of Human Fibroblasts Into Endothelial Cells and Erythroblasts by Dedifferentiation Into CD34 Progenitor Cells. [So] Source: Circulation;135(25):2505-2523, 2017 Jun 20. [Is] ISSN: 1524-4539 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: The mechanisms underlying the dedifferentiation and lineage conversion of adult human fibroblasts into functional endothelial cells have not yet been fully defined. Furthermore, it is not known whether fibroblast dedifferentiation recapitulates the generation of multipotent progenitors during embryonic development, which give rise to endothelial and hematopoietic cell lineages. Here we established the role of the developmental transcription factor SOX17 in regulating the bilineage conversion of fibroblasts by the generation of intermediate progenitors. METHODS: CD34 progenitors were generated after the dedifferentiation of human adult dermal fibroblasts by overexpression of pluripotency transcription factors. Sorted CD34 cells were transdifferentiated into induced endothelial cells and induced erythroblasts using lineage-specific growth factors. The therapeutic potential of the generated cells was assessed in an experimental model of myocardial infarction. RESULTS: Induced endothelial cells expressed specific endothelial cell surface markers and also exhibited the capacity for cell proliferation and neovascularization. Induced erythroblasts expressed erythroid surface markers and formed erythroid colonies. Endothelial lineage conversion was dependent on the upregulation of the developmental transcription factor SOX17, whereas suppression of SOX17 instead directed the cells toward an erythroid fate. Implantation of these human bipotential CD34 progenitors into nonobese diabetic/severe combined immunodeficiency (NOD-SCID) mice resulted in the formation of microvessels derived from human fibroblasts perfused with mouse and human erythrocytes. Endothelial cells generated from human fibroblasts also showed upregulation of telomerase. Cell implantation markedly improved vascularity and cardiac function after myocardial infarction without any evidence of teratoma formation. CONCLUSIONS: Dedifferentiation of fibroblasts to intermediate CD34 progenitors gives rise to endothelial cells and erythroblasts in a SOX17-dependent manner. These findings identify the intermediate CD34 progenitor state as a critical bifurcation point, which can be tuned to generate functional blood vessels or erythrocytes and salvage ischemic tissue. [Mh] Termos MeSH primário: Antígenos CD34/fisiologia Desdiferenciação Celular/fisiologia Células Endoteliais/fisiologia Eritroblastos/fisiologia Fibroblastos/fisiologia Fatores de Transcrição SOXF/fisiologia Células-Tronco/fisiologia [Mh] Termos MeSH secundário: Animais Células Cultivadas Seres Humanos Recém-Nascido Camundongos Camundongos Endogâmicos NOD Camundongos SCID [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antigens, CD34); 0 (SOX17 protein, human); 0 (SOXF Transcription Factors) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170829 [Lr] Data última revisão: 170829 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170407 [St] Status: MEDLINE [do] DOI: 10.1161/CIRCULATIONAHA.116.025722

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[PMID]: 28370131 [Au] Autor: Cooling L; Roxbury K; Hoffmann S; DeBusscher J; Kota U; Goldstein S; Davenport R [Ad] Endereço: Department of Pathology, University of Michigan, Ann Arbor, Michigan. [Ti] Título: Use of allogeneic apheresis stem cell products as an interlaboratory proficiency challenge. [So] Source: Transfusion;57(6):1543-1554, 2017 Jun. [Is] ISSN: 1537-2995 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: AABB Standards requires that laboratories participate in a proficiency test (PT) program for critical analytes. Institutions can purchase commercial PT materials; however, PT can also be performed through interlaboratory exchange. We investigated the utility of allogeneic hematopoietic progenitor cell apheresis (HPC-A) products as an interlaboratory PT challenge for total nucleated cell count (TNC) and CD34 assessment. STUDY DESIGN AND METHODS: Three-year retrospective and comparative review of unrelated allogeneic HPC-A products received by the University of Michigan between January 2011 and December 2013. Internal TNC and CD34 count were compared to the external collecting facility by paired t test and linear regression. The absolute and percent difference between external and internal counts and 95% limits of agreeability (95% LA) were determined. Results were analyzed relative to donor center location (international, domestic), time zone (domestic), and calendar year. RESULTS: There was a strong correlation between internal and external TNC, regardless of donor center location or year. For CD34, there was a good correlation between centers (R = 0.88-0.91; slope = 0.95-0.98x) with a median difference of -1% (95% LA, -50%, +47%). This was considerably better than commercial PT challenges, which showed a persistent negative bias for absolute CD34 and CD3 counts. CONCLUSION: Allogeneic HPC-A products represent an interlaboratory PT exchange for all critical analytes, including TNC and CD34 count, cell viability, and sterility. Allogeneic HPC-A products, which are fresh and transported under validated conditions, are less subject to preanalytical variables that may impact commercial PT samples such as aliquoting and sample homogeneity, commercial additives, and sample stability during manufacturing and transport. [Mh] Termos MeSH primário: Remoção de Componentes Sanguíneos Células-Tronco/citologia [Mh] Termos MeSH secundário: Adulto Aloenxertos Antígenos CD34/imunologia Sobrevivência Celular/fisiologia Eritroblastos/metabolismo Feminino Células-Tronco Hematopoéticas/citologia Células-Tronco Hematopoéticas/metabolismo Seres Humanos Masculino Meia-Idade Estudos Retrospectivos Células-Tronco/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antigens, CD34) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170919 [Lr] Data última revisão: 170919 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170404 [St] Status: MEDLINE [do] DOI: 10.1111/trf.14107

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