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1.
J Exp Med ; 218(7)2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34129017

RESUMO

With a growing aged population, there is an imminent need to develop new therapeutic strategies to ameliorate disorders of hematopoietic aging, including clonal hematopoiesis and myelodysplastic syndrome (MDS). Cell-intrinsic dysregulation of innate immune- and inflammatory-related pathways as well as systemic inflammation have been implicated in hematopoietic defects associated with aging, clonal hematopoiesis, and MDS. Here, we review and discuss the role of dysregulated innate immune and inflammatory signaling that contribute to the competitive advantage and clonal dominance of preleukemic and MDS-derived hematopoietic cells. We also propose how emerging concepts will further reveal critical biology and novel therapeutic opportunities.


Assuntos
Envelhecimento/imunologia , Hematopoese/imunologia , Células-Tronco Hematopoéticas/imunologia , Imunidade Inata/imunologia , Inflamação/imunologia , Síndromes Mielodisplásicas/imunologia , Animais , Hematopoiese Clonal/imunologia , Humanos , Transdução de Sinais/imunologia
2.
J Cancer Res Ther ; 17(2): 547-550, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34121706

RESUMO

Purpose: Health emergency due to COVID-19 started in Uruguay on March 13, 2020; our mastology unit tried to ensure adequate oncological care, and protect patients from the virus infection and complications. Objective: To assess the health care activities in the "peak" of the pandemic during 3 months. Materials and Methods: we collected data from the electronic health record. Results: There were a total of 293 medical appointments from 131 patients (221 face-to-face), that decreased by 16.7% compared to the same period in 2019 (352 appointments). The medical appointments were scheduled to evaluate the continuity of systemic treatment or modifications (95 patients; 72.5%), follow-up (17; 12.9%), first-time consultation (12; 9.1%), and assess paraclinical studies (7; 5.3%). The patients were on hormone therapy (81 patients; 74%), chemotherapy (CT) (21; 19%), and anti-HER2 therapies (9; 8%). New twenty treatments were initiated. Of the 14 patients that were on adjuvant/neoadjuvant CT, 9 (64.3%) continued with the same regimen with the addition of prophylactic granulocyte-colony-stimulating factors (G-CSF), and 5 (35.7%), who were receiving weekly paclitaxel, continued the treatment with no changes. Of the seven patients that were on palliative CT, 2 (28.5%) continued the treatment with the addition of G-CSF, 3 (42.8%) continued with weekly capecitabine or paclitaxel with no treatment changes, and 2 (28.5%) changed their treatment regimen (a less myelosuppressive regimen was selected for one and due to progression of the disease in the other patient). The ninety patients who were receiving adjuvant, neoadjuvant, or palliative criteria hormone therapy and/or anti-HER2 therapies, continued the treatment with no changes. Conclusions: The evidence suggests that, although medical appointments decreased by approximately 17%, we could maintain healthcare activities, continued most of the treatments while the most modified was CT with G-CSF to avoid myelosuppression.


Assuntos
Neoplasias da Mama/tratamento farmacológico , COVID-19/epidemiologia , Continuidade da Assistência ao Paciente/estatística & dados numéricos , Atenção à Saúde/estatística & dados numéricos , Oncologia/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Medula Óssea/efeitos dos fármacos , Neoplasias da Mama/complicações , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/transmissão , Controle de Doenças Transmissíveis/normas , Continuidade da Assistência ao Paciente/organização & administração , Atenção à Saúde/organização & administração , Atenção à Saúde/normas , Registros Eletrônicos de Saúde/estatística & dados numéricos , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Hematopoese/efeitos dos fármacos , Hematopoese/imunologia , Humanos , Oncologia/organização & administração , Oncologia/normas , Pessoa de Meia-Idade , Pandemias/prevenção & controle , Encaminhamento e Consulta/normas , Encaminhamento e Consulta/estatística & dados numéricos , Estudos Retrospectivos , Telemedicina/organização & administração , Telemedicina/normas , Telemedicina/estatística & dados numéricos , Triagem/organização & administração , Triagem/normas , Uruguai/epidemiologia
3.
Front Immunol ; 12: 661900, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34054827

RESUMO

TNF is a multifunctional cytokine with its key functions attributed to inflammation, secondary lymphoid tissue organogenesis and immune regulation. However, it is also a physiological regulator of hematopoiesis and is involved in development and homeostatic maintenance of various organs and tissues. Somewhat unexpectedly, the most important practical application of TNF biology in medicine is anti-TNF therapy in several autoimmune diseases. With increased number of patients undergoing treatment with TNF inhibitors and concerns regarding possible adverse effects of systemic cytokine blockade, the interest in using humanized mouse models to study the efficacy and safety of TNF-targeting biologics in vivo is justified. This Perspective discusses the main functions of TNF and its two receptors, TNFR1 and TNFR2, in steady state, as well as in emergency hematopoiesis. It also provides a comparative overview of existing mouse lines with humanization of TNF/TNFR system. These genetically engineered mice allow us to study TNF signaling cascades in the hematopoietic compartment in the context of various experimental disease models and for evaluating the effects of various human TNF inhibitors on hematopoiesis and other physiological processes.


Assuntos
Hematopoese/efeitos dos fármacos , Hematopoese/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia , Animais , Células Cultivadas , Humanos , Inflamação/imunologia , Camundongos , Camundongos Transgênicos , Receptores Tipo I de Fatores de Necrose Tumoral/antagonistas & inibidores , Receptores Tipo II do Fator de Necrose Tumoral/antagonistas & inibidores , Transdução de Sinais
4.
Front Immunol ; 12: 643852, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33692812

RESUMO

Since the late 1980s, mice have been repopulated with human hematopoietic cells to study the fundamental biology of human hematopoiesis and immunity, as well as a broad range of human diseases in vivo. Multiple mouse recipient strains have been developed and protocols optimized to efficiently generate these "humanized" mice. Here, we review three guiding principles that have been applied to the development of the currently available models: (1) establishing tolerance of the mouse host for the human graft; (2) opening hematopoietic niches so that they can be occupied by human cells; and (3) providing necessary support for human hematopoiesis. We then discuss four remaining challenges: (1) human hematopoietic lineages that poorly develop in mice; (2) limited antigen-specific adaptive immunity; (3) absent tolerance of the human immune system for its mouse host; and (4) sub-functional interactions between human immune effectors and target mouse tissues. While major advances are still needed, the current models can already be used to answer specific, clinically-relevant questions and hopefully inform the development of new, life-saving therapies.


Assuntos
Imunidade Adaptativa , Modelos Animais de Doenças , Hematopoese/imunologia , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/imunologia , Animais , Xenoenxertos , Humanos , Camundongos
5.
Cell Death Dis ; 12(1): 28, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33414459

RESUMO

The IκB kinase complex, consisting of IKK1, IKK2 and the regulatory subunit NEMO, is required for NF-κB signalling following the activation of several cell surface receptors, such as members of the Tumour Necrosis Factor Receptor superfamily and the Interleukin-1 Receptor. This is critical for haematopoietic cell proliferation, differentiation, survival and immune responses. To determine the role of IKK in the regulation of haematopoiesis, we used the Rosa26Cre-ERT2 Cre/lox recombination system to achieve targeted, haematopoietic cell-restricted deletion of the genes for IKK1 or IKK2 in vivo. We found that the IKK complex plays a critical role in haematopoietic cell development and function. Deletion of IKK2, but not loss of IKK1, in haematopoietic cells led to an expansion of CD11b/Gr-1-positive myeloid cells (neutrophilia), severe anaemia and thrombocytosis, with reduced numbers of long-term haematopoietic stem cells (LT-HSCs), short-term haematopoietic stem cells (ST-HSCs) and multipotential progenitor cells (MPPs), increased circulating interleukin-6 (IL-6) and severe gastrointestinal inflammation. These findings identify distinct functions for the two IKK catalytic subunits, IKK1 and IKK2, in the haematopoietic system.


Assuntos
Gastrite/imunologia , Hematopoese/imunologia , Quinase I-kappa B/imunologia , Interleucina-6/imunologia , Células-Tronco/imunologia , Animais , Diferenciação Celular , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/imunologia , Células-Tronco/citologia
6.
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
7.
Elife ; 92020 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-33372660

RESUMO

Studies in different animal model systems have revealed the impact of odors on immune cells; however, any understanding on why and how odors control cellular immunity remained unclear. We find that Drosophila employ an olfactory-immune cross-talk to tune a specific cell type, the lamellocytes, from hematopoietic-progenitor cells. We show that neuronally released GABA derived upon olfactory stimulation is utilized by blood-progenitor cells as a metabolite and through its catabolism, these cells stabilize Sima/HIFα protein. Sima capacitates blood-progenitor cells with the ability to initiate lamellocyte differentiation. This systemic axis becomes relevant for larvae dwelling in wasp-infested environments where chances of infection are high. By co-opting the olfactory route, the preconditioned animals elevate their systemic GABA levels leading to the upregulation of blood-progenitor cell Sima expression. This elevates their immune-potential and primes them to respond rapidly when infected with parasitic wasps. The present work highlights the importance of the olfaction in immunity and shows how odor detection during animal development is utilized to establish a long-range axis in the control of blood-progenitor competency and immune-priming.


Assuntos
Fenômenos Bioquímicos/imunologia , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Células-Tronco Hematopoéticas/citologia , Hemócitos/citologia , Animais , Drosophila/imunologia , Drosophila/metabolismo , Proteínas de Drosophila/imunologia , Drosophila melanogaster/imunologia , Hematopoese/imunologia , Larva/metabolismo , Vespas/imunologia
8.
Front Immunol ; 11: 573915, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33329537

RESUMO

Cytosolic DNA sensing is a fundamental mechanism by which organisms handle various stresses, including infection and genotoxicity. The hematopoietic system is sensitive to stresses, and hematopoietic changes are often rapid and the first response to stresses. Based on the transcriptome database, cytosolic DNA sensing pathways are widely expressed in the hematopoietic system, and components of these pathways may be expressed at even higher levels in hematopoietic stem and progenitor cells (HSPCs) than in their certain progeny immune cells. Recent studies have described a previously unrecognized role for cytosolic DNA sensing pathways in the regulation of hematopoiesis under both homeostatic and stress conditions. In particular, the recently discovered cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a critical modulator of hematopoiesis. Perturbation of the cGAS-STING pathway in HSPCs may be involved in the pathogenesis of hematopoietic disorders, autoimmune diseases, and inflammation-related diseases and may be candidate therapeutic targets. In this review, we focus on the recent findings of the cGAS-STING pathway in the regulation of hematopoiesis, and its physiopathological significance including its implications in diseases and therapeutic potential.


Assuntos
Hematopoese/imunologia , Proteínas de Membrana/metabolismo , Nucleotidiltransferases/metabolismo , Citosol/imunologia , Citosol/metabolismo , DNA/imunologia , DNA/metabolismo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/imunologia , Humanos , Imunidade Inata , Inflamação , Transdução de Sinais
9.
Trends Immunol ; 41(12): 1116-1127, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33162327

RESUMO

Hematopoiesis is a complex process through which immature bone marrow precursor cells mature into all types of blood cells. Although the association of hematopoietic lineage bias (including anemia and neutrophilia) with chronic inflammatory diseases has long been appreciated, the causes involved are obscure. Recently, cytosolic multiprotein inflammasome complexes were shown to activate inflammatory and immune responses, and directly regulate hematopoiesis in zebrafish models; this was deemed to occur via cleavage and inactivation of the master erythroid transcription factor GATA1. Herein summarized are the zebrafish models that are currently available to study this unappreciated role of inflammasome-mediated regulation of hematopoiesis. Novel putative therapeutic strategies, for the treatment of hematopoietic alterations associated with chronic inflammatory diseases in humans, are also proposed.


Assuntos
Hematopoese , Inflamassomos , Modelos Animais , Peixe-Zebra , Animais , Hematopoese/genética , Hematopoese/imunologia , Humanos , Inflamassomos/metabolismo , Pesquisa/tendências , Peixe-Zebra/genética , Peixe-Zebra/imunologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/imunologia
10.
Fish Shellfish Immunol ; 107(Pt A): 95-103, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32966893

RESUMO

Gastropod hematopoiesis occurs at specialized tissues in some species, but the evidence also suggests that hemocyte generation is maybe widespread in the connective tissues or the blood system in others. In Ampullariidae (Caenogastropoda), both the kidney and the lung contain putative hematopoietic cells, which react to immune challenges. In the current study, we wanted to explore if hematopoiesis occurs in the blood of Pomacea canaliculata. Thus, we obtained circulating hemocytes from donor animals and tested their ability to proliferate in the blood of conspecific recipients. We tracked cell proliferation by labeling the donors' hemocytes with the fluorescent cell proliferation marker carboxyfluorescein diacetate succinimidyl ester (CFSE). Transferred CFSE-labeled hemocytes survived and proliferated into the recipients' circulation for at least 17 days. We also determined the cell cycle status of circulating hemocytes by using the propidium iodide (PI) and acridine orange (AO) staining methods. Flow cytometry analyses showed that most PI-stained hemocytes were in the G1 phase (~96%), while a lower proportion of cells were through the G2/S-M transition (~4%). When we instead used AO-staining, we further distinguished a subpopulation of cells (~5%) of low size, complexity-granularity, and RNA content. We regarded this subpopulation as quiescent cells. In separate experimental sets, we complemented these findings by assessing in circulating hemocytes two evolutionary conserved features of quiescent, undifferentiated cells. First, we used JC-1 staining to determine the mitochondrial membrane potential (Ψm) of circulating hemocytes, which is expected to be low in quiescent cells. Most hemocytes (~87%) showed high aggregation of JC-1, which indicates a high Ψm. Besides that, a small hemocyte subpopulation (~11%) showed low aggregation of the dye, thus indicating a low Ψm. It is known that the transition from a quiescent to a proliferating state associates with an increase of the Ψm. The specificity of these changes was here controlled by membrane depolarization with the Ψm disruptor CCCP. Second, we stained hemocytes with Hoechst33342 dye to determine the efflux activity of ABC transporters, which participate in the multixenobiotic resistance system characteristic of undifferentiated cells. Most hemocytes (>99%) showed a low dye-efflux activity, but a small proportion of cells (0.06-0.12%) showed a high dye-efflux activity, which was significantly inhibited by 100 and 500 µM verapamil, and thus is indicative of an undifferentiated subpopulation of circulating hemocytes. Taken together, our results suggest that, among circulating hemocytes, there are cells with the ability to proliferate or to stay in a quiescent state and behave as progenitor cells later, either in the circulation or the hematopoietic tissues/organs.


Assuntos
Hematopoese/imunologia , Hemócitos/imunologia , Caramujos/imunologia , Animais , Contagem de Células , Citometria de Fluxo , Espécies Introduzidas
11.
Exp Hematol ; 90: 18-29, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32910997

RESUMO

Forkhead-associated (FHA) domain-containing proteins are widely expressed across eubacteria and in eukaryotes. FHA domains contain phosphopeptide recognition motifs, which operate in a variety of phosphorylation-dependent and -independent biological processes, including the DNA damage response, signal transduction, and regulation of the cell cycle. More recently, two FHA domain-containing proteins were discovered in mammalian cells as tumor necrosis factor receptor-associated factor (TRAF)-interacting proteins: TIFA and TIFAB. TIFA and TIFAB are important modifiers of the innate immune signaling through their regulation of TRAF proteins. Recent studies have also revealed distinct roles for TIFA and TIFAB in the context of immune cell function, chronic inflammation, hematopoiesis, and hematologic disorders. Collectively, these studies indicate the important role of TIFA- and TIFAB-dependent signaling in hematopoietic cells and their dysregulation in several human diseases. In this review, we summarize the molecular mechanisms and biological role of these FHA-domain homologues, placing them into the context of human disease.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Doenças Hematológicas/imunologia , Hematopoese/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Transdução de Sinais/imunologia , Animais , Humanos , Inflamação/imunologia , Inflamação/patologia
12.
Immunity ; 53(3): 658-671.e6, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32937153

RESUMO

Identifying signals in the tumor microenvironment (TME) that shape CD8+ T cell phenotype can inform novel therapeutic approaches for cancer. Here, we identified a gradient of increasing glucocorticoid receptor (GR) expression and signaling from naïve to dysfunctional CD8+ tumor-infiltrating lymphocytes (TILs). Conditional deletion of the GR in CD8+ TILs improved effector differentiation, reduced expression of the transcription factor TCF-1, and inhibited the dysfunctional phenotype, culminating in tumor growth inhibition. GR signaling transactivated the expression of multiple checkpoint receptors and promoted the induction of dysfunction-associated genes upon T cell activation. In the TME, monocyte-macrophage lineage cells produced glucocorticoids and genetic ablation of steroidogenesis in these cells as well as localized pharmacologic inhibition of glucocorticoid biosynthesis improved tumor growth control. Active glucocorticoid signaling associated with failure to respond to checkpoint blockade in both preclinical models and melanoma patients. Thus, endogenous steroid hormone signaling in CD8+ TILs promotes dysfunction, with important implications for cancer immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Glucocorticoides/metabolismo , Macrófagos/metabolismo , Melanoma Experimental/patologia , Microambiente Tumoral/imunologia , Animais , Linfócitos T CD8-Positivos/citologia , Linhagem Celular Tumoral , Hematopoese/imunologia , Fator 1-alfa Nuclear de Hepatócito/biossíntese , Inibidores de Checkpoint Imunológico , Ativação Linfocitária/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais/imunologia
13.
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
14.
Int J Mol Sci ; 21(15)2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-32751628

RESUMO

There is growing interest in the contribution of the marrow niche to the pathogenesis of bone marrow failure syndromes, i.e., aplastic anemia (AA) and myelodysplastic syndromes (MDSs). In particular, mesenchymal stem cells (MSCs) are multipotent cells that contribute to the organization and function of the hematopoietic niche through their repopulating and supporting abilities, as well as immunomodulatory properties. The latter are of great interest in MDSs and, particularly, AA, where an immune attack against hematopoietic stem cells is the key pathogenic player. We, therefore, conducted Medline research, including all available evidence from the last 10 years concerning the role of MSCs in these two diseases. The data presented show that MSCs display morphologic, functional, and genetic alterations in AA and MDSs and contribute to immune imbalance, ineffective hematopoiesis, and leukemic evolution. Importantly, adoptive MSC infusion from healthy donors can be exploited to heal the "sick" niche, with even better outcomes if cotransplanted with allogeneic hematopoietic stem cells. Finally, future studies on MSCs and the whole microenvironment will further elucidate AA and MDS pathogenesis and possibly improve treatment.


Assuntos
Anemia Aplástica/imunologia , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Mesenquimais/imunologia , Síndromes Mielodisplásicas/imunologia , Anemia Aplástica/patologia , Anemia Aplástica/terapia , Hematopoese/imunologia , Células-Tronco Hematopoéticas/patologia , Humanos , Imunomodulação/imunologia , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/terapia , Nicho de Células-Tronco/genética
15.
Exp Hematol ; 89: 26-36, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32735908

RESUMO

The coordinated differentiation of hematopoietic stem and progenitor cells (HSPCs) into the various mature blood cell types is responsible for sustaining blood and immune system homeostasis. The cell fate decisions underlying this important biological process are made at the level of single cells. Methods to trace the fate of single cells are therefore essential for understanding hematopoietic system activity in health and disease and have had a major impact on how we understand and represent hematopoiesis. Here, we discuss the basic methodologies and technical considerations for three important clonal assays: single-cell transplantation, lentiviral barcoding, and Sleeping Beauty barcoding. This perspective is a synthesis of presentations and discussions from the 2019 International Society for Experimental Hematology (ISEH) Annual Meeting New Investigator Technology Session and the 2019 ISEH Winter Webinar.


Assuntos
Rastreamento de Células/métodos , Transplante de Células/métodos , Hematologia/métodos , Hematopoese/genética , Células-Tronco Hematopoéticas/citologia , Animais , Diferenciação Celular , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Congressos como Assunto , Código de Barras de DNA Taxonômico/métodos , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Hematopoese/imunologia , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/virologia , Homeostase/genética , Homeostase/imunologia , Humanos , Lentivirus/genética , Lentivirus/metabolismo , Camundongos , Análise de Célula Única/métodos , Transgenes , Transposases/genética , Transposases/imunologia
16.
Blood ; 136(14): 1606-1614, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32736379

RESUMO

Clonal expansions of mutated hematopoietic cells, termed clonal hematopoiesis, are common in aging humans. One expected consequence of mutation-associated clonal hematopoiesis is an increased risk of hematologic cancers, which has now been shown in several studies. However, the hematopoietic stem cells that acquire these somatic mutations also give rise to mutated immune effector cells, such as monocytes, granulocytes, and lymphocytes. These effector cells can potentially influence many disease states, especially those with a chronic inflammatory component. Indeed, several studies have now shown that clonal hematopoiesis associates with increased risk of atherosclerotic cardiovascular disease. Emerging data also associate clonal hematopoiesis with other nonhematologic diseases. Here, we will review recent studies linking clonal hematopoiesis to altered immune function, inflammation, and nonmalignant diseases of aging.


Assuntos
Hematopoiese Clonal , Suscetibilidade a Doenças , Hematopoese , Animais , Biomarcadores , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Evolução Clonal/genética , Hematopoiese Clonal/genética , Hematopoiese Clonal/imunologia , Suscetibilidade a Doenças/imunologia , Estudos de Associação Genética , Predisposição Genética para Doença , Hematopoese/genética , Hematopoese/imunologia , Humanos , Mutação , Especificidade de Órgãos , Fenótipo , Terminologia como Assunto
17.
Biomed Res ; 41(4): 169-178, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801266

RESUMO

Theileria orientalis (T. orientalis) is a bovine protozoal disease similar to malaria in humans. Although the common outcome of malaria in humans and T. orientalis infection in cattle is hepatic disorder, the mechanisms of its development remain unknown. In this study, we investigated hepatocyte injury characterized by accumulation of macrophages with ingested erythrocytes in sinusoid and extramedullary hematopoiesis in cattle and mice experimentally infected with T. orientalis (T. orientalis-infected cattle and T. orientalis-infected mice). Vacuolization of hepatic cells was frequently observed in the vicinity of the aggregated macrophages in the liver sinusoids of T. orientalis-infected mice. A significant percentage of the macrophages accumulated in the liver sinusoids of the severely infected cattle and mice (14.6% and 24.2 to 53.2%, respectively) reacted positively with interleukin-1, interleukin-6 and TNF-α antibodies. Increase in the production of these cytokines was confirmed in T. orientalis-infected cattle and mice by real-time RT-PCR. These findings strongly suggest that increased cytokine production by the macrophages that have phagocytosed T. orientalis-infected erythrocytes causes hepatic disorder in T. orientalis-infected animals.


Assuntos
Eritrócitos/parasitologia , Hepatócitos/patologia , Fígado/patologia , Macrófagos/parasitologia , Theileria/patogenicidade , Theileriose/patologia , Animais , Bovinos , Transfusão de Eritrócitos , Eritrócitos/patologia , Feminino , Expressão Gênica , Hematopoese/genética , Hematopoese/imunologia , Hepatócitos/parasitologia , Interleucina-1/genética , Interleucina-1/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Fígado/imunologia , Fígado/parasitologia , Testes de Função Hepática , Macrófagos/imunologia , Masculino , Camundongos , Camundongos SCID , Esplenectomia , Theileria/crescimento & desenvolvimento , Theileriose/genética , Theileriose/imunologia , Theileriose/parasitologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
18.
Trends Immunol ; 41(8): 706-720, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32631635

RESUMO

Rodent models for human diseases contribute significantly to understanding human physiology and pathophysiology. However, given the accelerating pace of drug development, there is a crucial need for in vivo preclinical models of human biology and pathology. The humanized mouse is one tool to bridge the gap between traditional animal models and the clinic. The development of immunodeficient mouse strains with high-level engraftment of normal and diseased human immune/hematopoietic cells has made in vivo functional characterization possible. As a patient-derived xenograft (PDX) model, humanized mice functionally correlate putative mechanisms with in vivo behavior and help to reveal pathogenic mechanisms. Combined with single-cell genomics, humanized mice can facilitate functional precision medicine such as risk stratification and individually optimized therapeutic approaches.


Assuntos
Hematopoese , Medicina de Precisão , Animais , Modelos Animais de Doenças , Hematopoese/imunologia , Humanos , Medicina de Precisão/tendências
19.
Int J Immunogenet ; 47(4): 329-331, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32515168

RESUMO

We provide evidence for a linear correlation between the frequency of clonal haematopoiesis and COVID-19 mortality rate. We discuss the mechanistic explanations for this association mediated by a pathological inflammatory response. Our hypothesis can be tested in COVID-19-infected patients and eventually lead to new approaches to risk stratification and therapy.


Assuntos
Envelhecimento/imunologia , Seleção Clonal Mediada por Antígeno/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Hematopoese/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Fatores Etários , Idoso de 80 Anos ou mais , Betacoronavirus/imunologia , COVID-19 , Infecções por Coronavirus/mortalidade , Humanos , Pandemias , Pneumonia Viral/mortalidade , SARS-CoV-2
20.
Immunity ; 52(6): 1007-1021.e8, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32497523

RESUMO

N6-methyladenosine (m6A) is the most abundant RNA modification, but little is known about its role in mammalian hematopoietic development. Here, we show that conditional deletion of the m6A writer METTL3 in murine fetal liver resulted in hematopoietic failure and perinatal lethality. Loss of METTL3 and m6A activated an aberrant innate immune response, mediated by the formation of endogenous double-stranded RNAs (dsRNAs). The aberrantly formed dsRNAs were long, highly m6A modified in their native state, characterized by low folding energies, and predominantly protein coding. We identified coinciding activation of pattern recognition receptor pathways normally tasked with the detection of foreign dsRNAs. Disruption of the aberrant immune response via abrogation of downstream Mavs or Rnasel signaling partially rescued the observed hematopoietic defects in METTL3-deficient cells in vitro and in vivo. Our results suggest that m6A modification protects against endogenous dsRNA formation and a deleterious innate immune response during mammalian hematopoietic development.


Assuntos
Adenosina/química , Hematopoese/genética , Hematopoese/imunologia , Imunidade Inata/genética , RNA de Cadeia Dupla/metabolismo , Animais , Biomarcadores , Transtornos da Insuficiência da Medula Óssea/etiologia , Transtornos da Insuficiência da Medula Óssea/metabolismo , Transtornos da Insuficiência da Medula Óssea/patologia , Diferenciação Celular/genética , Modelos Animais de Doenças , Epigênese Genética , Expressão Gênica , Células-Tronco Hematopoéticas , Imunofenotipagem , Metilação , Metiltransferases/genética , Metiltransferases/metabolismo , Camundongos , Camundongos Knockout , RNA de Cadeia Dupla/química
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