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1.
Exp Hematol ; 86: 1-14, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32422232

RESUMO

The CD34 cell surface antigen is widely expressed in tissues on cells with progenitor-like properties and on mature vascular endothelia. In adult human bone marrow, CD34 marks hematopoietic stem and progenitor cells (HSPCs) starting from the bulk of hematopoietic stem cells with long-term repopulating potential (LT-HSCs) throughout expansion and differentiation of oligopotent and unipotent progenitors. CD34 protein surface expression is typically lost as cells mature into terminal effectors. Because of this expression pattern of HSPCs, CD34 has had a central role in the evaluation or selection of donor graft tissue in HSC transplant (HSCT). Given its clinical importance, it is surprising that the biological functions of CD34 are still poorly understood. This enigma is due, in part, to CD34's context-specific role as both a pro-adhesive and anti-adhesive molecule and its potential functional redundancy with other sialomucins. Moreover, there are also critical differences in the regulation of CD34 expression on HSPCs in humans and experimental mice. In this review, we highlight some of the more well-defined functions of CD34 in HSPCs with a focus on proposed functions most relevant to HSCT biology.


Assuntos
Antígenos CD34/metabolismo , Diferenciação Celular , Células-Tronco Hematopoéticas/metabolismo , Animais , Medula Óssea/metabolismo , Regulação da Expressão Gênica , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Humanos , Camundongos
2.
J Immunol ; 202(3): 956-965, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30617224

RESUMO

The cytokine IL-22 is rapidly induced at barrier surfaces where it regulates host-protective antimicrobial immunity and tissue repair but can also enhance disease severity in some chronic inflammatory settings. Using the chronic Salmonella gastroenteritis model, Ab-mediated neutralization of IL-22 impaired intestinal epithelial barrier integrity and, consequently, exaggerated expression of proinflammatory cytokines. As disease normally resolved, neutralization of IL-22 caused luminal narrowing of the cecum-a feature reminiscent of fibrotic strictures seen in Crohn disease patients. Corresponding to the exaggerated immunopathology caused by IL-22 suppression, Salmonella burdens in the gut were reduced. This enhanced inflammation and pathogen clearance was associated with alterations in gut microbiome composition, including the overgrowth of Bacteroides acidifaciens Our findings thus indicate that IL-22 plays a protective role by limiting infection-induced gut immunopathology but can also lead to persistent pathogen colonization.


Assuntos
Gastroenterite/imunologia , Microbioma Gastrointestinal , Interleucinas/imunologia , Salmonelose Animal/imunologia , Animais , Anticorpos Antibacterianos/imunologia , Anticorpos Neutralizantes/imunologia , Bacteroides , Ceco/imunologia , Ceco/patologia , Doença de Crohn/imunologia , Doença de Crohn/patologia , Citocinas/imunologia , Gastroenterite/microbiologia , Inflamação , Interleucinas/antagonistas & inibidores , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Camundongos , Camundongos Endogâmicos C57BL , Indução de Remissão , Salmonelose Animal/terapia , Salmonella typhimurium , Interleucina 22
3.
Dev Cell ; 37(1): 47-57, 2016 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-27046831

RESUMO

Intestinal tumorigenesis is a result of mutations in signaling pathways that control cellular proliferation, differentiation, and survival. Mutations in the Wnt/ß-catenin pathway are associated with the majority of intestinal cancers, while dysregulation of the Hippo/Yes-Associated Protein (YAP) pathway is an emerging regulator of intestinal tumorigenesis. In addition, these closely related pathways play a central role during intestinal regeneration. We have previously shown that methylation of the Hippo transducer YAP by the lysine methyltransferase SETD7 controls its subcellular localization and function. We now show that SETD7 is required for Wnt-driven intestinal tumorigenesis and regeneration. Mechanistically, SETD7 is part of a complex containing YAP, AXIN1, and ß-catenin, and SETD7-dependent methylation of YAP facilitates Wnt-induced nuclear accumulation of ß-catenin. Collectively, these results define a methyltransferase-dependent regulatory mechanism that links the Wnt/ß-catenin and Hippo/YAP pathways during intestinal regeneration and tumorigenesis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Transformação Celular Neoplásica/patologia , Neoplasias Intestinais/patologia , Fosfoproteínas/metabolismo , Proteínas Metiltransferases/metabolismo , Proteínas Wnt/genética , beta Catenina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteína Axina/genética , Células CACO-2 , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Células HEK293 , Histona-Lisina N-Metiltransferase , Humanos , Neoplasias Intestinais/genética , Intestinos/patologia , Células MCF-7 , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfoproteínas/genética , Proteínas Metiltransferases/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Via de Sinalização Wnt/fisiologia , Proteínas de Sinalização YAP , beta Catenina/genética
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