Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
1.
Cell ; 187(12): 3090-3107.e21, 2024 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-38749423

RESUMEN

Platelet dysregulation is drastically increased with advanced age and contributes to making cardiovascular disorders the leading cause of death of elderly humans. Here, we reveal a direct differentiation pathway from hematopoietic stem cells into platelets that is progressively propagated upon aging. Remarkably, the aging-enriched platelet path is decoupled from all other hematopoietic lineages, including erythropoiesis, and operates as an additional layer in parallel with canonical platelet production. This results in two molecularly and functionally distinct populations of megakaryocyte progenitors. The age-induced megakaryocyte progenitors have a profoundly enhanced capacity to engraft, expand, restore, and reconstitute platelets in situ and upon transplantation and produce an additional platelet population in old mice. The two pools of co-existing platelets cause age-related thrombocytosis and dramatically increased thrombosis in vivo. Strikingly, aging-enriched platelets are functionally hyper-reactive compared with the canonical platelet populations. These findings reveal stem cell-based aging as a mechanism for platelet dysregulation and age-induced thrombosis.


Asunto(s)
Envejecimiento , Plaquetas , Diferenciación Celular , Células Madre Hematopoyéticas , Trombosis , Animales , Células Madre Hematopoyéticas/metabolismo , Plaquetas/metabolismo , Trombosis/patología , Trombosis/metabolismo , Ratones , Humanos , Megacariocitos/metabolismo , Ratones Endogámicos C57BL , Células Progenitoras de Megacariocitos/metabolismo , Masculino
2.
Development ; 149(8)2022 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-35072209

RESUMEN

Tissue-resident lymphoid cells (TLCs) span the spectrum of innate-to-adaptive immune function. Unlike traditional, circulating lymphocytes that are continuously generated from hematopoietic stem cells (HSCs), many TLCs are of fetal origin and poorly generated from adult HSCs. Here, we sought to further understand murine TLC development and the roles of Flk2 and IL7Rα, two cytokine receptors with known function in traditional lymphopoiesis. Using Flk2- and Il7r-Cre lineage tracing, we found that peritoneal B1a cells, splenic marginal zone B (MZB) cells, lung ILC2s and regulatory T cells (Tregs) were highly labeled. Despite high labeling, loss of Flk2 minimally affected the generation of these cells. In contrast, loss of IL7Rα, or combined deletion of Flk2 and IL7Rα, dramatically reduced the number of B1a cells, MZBs, ILC2s and Tregs, both in situ and upon transplantation, indicating an intrinsic and essential role for IL7Rα. Surprisingly, reciprocal transplants of wild-type HSCs showed that an IL7Rα-/- environment selectively impaired reconstitution of TLCs when compared with TLC numbers in situ. Taken together, our data defined Flk2- and IL7Rα-positive TLC differentiation paths, and revealed functional roles of Flk2 and IL7Rα in TLC establishment.


Asunto(s)
Células Madre Hematopoyéticas/inmunología , Linfopoyesis/genética , Receptores de Interleucina-7/genética , Tirosina Quinasa 3 Similar a fms/genética , Inmunidad Adaptativa/genética , Animales , Linfocitos B/inmunología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Linaje de la Célula/genética , Linaje de la Célula/inmunología , Regulación del Desarrollo de la Expresión Génica/genética , Células Madre Hematopoyéticas/citología , Inmunidad Innata/genética , Linfocitos/citología , Linfocitos/inmunología , Tejido Linfoide/citología , Tejido Linfoide/inmunología , Linfopoyesis/inmunología , Ratones , Especificidad de Órganos/genética , Linfocitos T Reguladores/inmunología
3.
Stem Cells ; 41(5): 520-539, 2023 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-36945732

RESUMEN

Epigenetic mechanisms regulate the multilineage differentiation capacity of hematopoietic stem cells (HSCs) into a variety of blood and immune cells. Mapping the chromatin dynamics of functionally defined cell populations will shed mechanistic insight into 2 major, unanswered questions in stem cell biology: how does epigenetic identity contribute to a cell type's lineage potential, and how do cascades of chromatin remodeling dictate ensuing fate decisions? Our recent work revealed evidence of multilineage gene priming in HSCs, where open cis-regulatory elements (CREs) exclusively shared between HSCs and unipotent lineage cells were enriched for DNA binding motifs of known lineage-specific transcription factors. Oligopotent progenitor populations operating between the HSCs and unipotent cells play essential roles in effecting hematopoietic homeostasis. To test the hypothesis that selective HSC-primed lineage-specific CREs remain accessible throughout differentiation, we used ATAC-seq to map the temporal dynamics of chromatin remodeling during progenitor differentiation. We observed epigenetic-driven clustering of oligopotent and unipotent progenitors into distinct erythromyeloid and lymphoid branches, with multipotent HSCs and MPPs associating with the erythromyeloid lineage. We mapped the dynamics of lineage-primed CREs throughout hematopoiesis and identified both unique and shared CREs as potential lineage reinforcement mechanisms at fate branch points. Additionally, quantification of genome-wide peak count and size revealed overall greater chromatin accessibility in HSCs, allowing us to identify HSC-unique peaks as putative regulators of self-renewal and multilineage potential. Finally, CRISPRi-mediated targeting of ATACseq-identified putative CREs in HSCs allowed us to demonstrate the functional role of selective CREs in lineage-specific gene expression. These findings provide insight into the regulation of stem cell multipotency and lineage commitment throughout hematopoiesis and serve as a resource to test functional drivers of hematopoietic lineage fate.


Asunto(s)
Cromatina , Hematopoyesis , Cromatina/genética , Cromatina/metabolismo , Hematopoyesis/genética , Células Madre Hematopoyéticas/metabolismo , Diferenciación Celular/genética , Linaje de la Célula/genética
4.
J Immunol ; 208(8): 1886-1900, 2022 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-35365562

RESUMEN

Our respiratory system is vital to protect us from the surrounding nonsterile environment; therefore, it is critical for a state of homeostasis to be maintained through a balance of inflammatory cues. Recent studies have shown that actively transcribed noncoding regions of the genome are emerging as key regulators of biological processes, including inflammation. lincRNA-Cox2 is one such example of an inflammatory inducible long intergenic noncoding RNA functioning to fine-tune immune gene expression. Using bulk and single-cell RNA sequencing, in addition to FACS, we find that lincRNA-Cox2 is most highly expressed in the lung and is most upregulated after LPS-induced lung injury (acute lung injury [ALI]) within alveolar macrophages, where it functions to regulate inflammation. We previously reported that lincRNA-Cox2 functions to regulate its neighboring protein Ptgs2 in cis, and in this study, we use genetic mouse models to confirm its role in regulating gene expression more broadly in trans during ALI. Il6, Ccl3, and Ccl5 are dysregulated in the lincRNA-Cox2-deficient mice and can be rescued to wild type levels by crossing the deficient mice with our newly generated lincRNA-Cox2 transgenic mice, confirming that this gene functions in trans. Many genes are specifically regulated by lincRNA-Cox2 within alveolar macrophages originating from the bone marrow because the phenotype can be reversed by transplantation of wild type bone marrow into the lincRNA-Cox2-deficient mice. In conclusion, we show that lincRNA-Cox2 is a trans-acting long noncoding RNA that functions to regulate immune responses and maintain homeostasis within the lung at baseline and on LPS-induced ALI.


Asunto(s)
Lesión Pulmonar Aguda , Ciclooxigenasa 2 , Inflamación , Macrófagos Alveolares , ARN Largo no Codificante , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/genética , Lesión Pulmonar Aguda/metabolismo , Animales , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Modelos Animales de Enfermedad , Inflamación/genética , Inflamación/metabolismo , Lipopolisacáridos/farmacología , Macrófagos Alveolares/metabolismo , Ratones , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo
5.
Environ Microbiol ; 18(11): 4055-4067, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27348808

RESUMEN

Thermal stress increases the incidence of coral disease, which is predicted to become more common with climate change, even on pristine reefs such as those surrounding Palmyra Atoll in the Northern Line Islands that experience minimal anthropogenic stress. Here we describe a strain of Vibrio coralliilyticus, OCN014, which was isolated from Acropora cytherea during an outbreak of Acropora white syndrome (AWS), a tissue loss disease that infected 25% of the A. cytherea population at Palmyra Atoll in 2009. OCN014 recreated signs of disease in experimentally infected corals in a temperature-dependent manner. Genes in OCN014 with expression levels positively correlated with temperature were identified using a transposon-mediated genetic screen. Mutant strains harbouring transposon insertions in two such genes, toxR (a toxin regulator) and mshA (the 11th gene of the 16-gene mannose-sensitive hemagglutinin (MSHA) type IV pilus operon), had reduced infectivity of A. cytherea. Deletion of toxR and the MSHA operon in a second strain of V. coralliilyticus, OCN008, that induces acute Montipora white syndrome in a temperature-independent manner had similarly reduced virulence. This work provides a link between temperature-dependent expression of virulence factors in a pathogen and infection of its coral host.


Asunto(s)
Antozoos/microbiología , Proteínas Bacterianas/genética , Mutación , Vibrio cholerae/metabolismo , Vibrio/fisiología , Animales , Proteínas Bacterianas/metabolismo , Cambio Climático , Fimbrias Bacterianas , Operón , Temperatura , Vibrio/genética , Vibrio cholerae/genética , Vibrio cholerae/patogenicidad , Virulencia , Factores de Virulencia/genética , Factores de Virulencia/metabolismo
6.
Artículo en Inglés | MEDLINE | ID: mdl-35037001

RESUMEN

Platelets provide life-saving functions by halting external and internal bleeding. There is also a dark side to platelet biology, however. Recent reports provide evidence for increased platelet reactivity during aging of mice and humans, making platelets main suspects in the most prevalent aging-related human pathologies, including cardiovascular diseases, stroke, and cancer. What drives this platelet hyperreactivity during aging? Here, we discuss how hematopoietic stem cell differentiation pathways into the platelet lineage offer avenues to understand the fundamental differences between young and old platelets. Recent advances begin to unravel how the cellular and molecular regulation of the parent hematopoietic stem and progenitor cells likely imbue aging characteristics on the resulting Plt progeny. The resulting mechanistic insights into intrinsic platelet reactivity will provide strategies for selectively targeting age-related pathways. This brief viewpoint focuses on current concepts on aging hematopoiesis and the implications for platelet hyperactivity during aging.

7.
Stem Cell Reports ; 16(6): 1598-1613, 2021 06 08.
Artículo en Inglés | MEDLINE | ID: mdl-34019813

RESUMEN

Age-related morbidity is associated with a decline in hematopoietic stem cell (HSC) function, but the mechanisms of HSC aging remain unclear. We performed heterochronic HSC transplants followed by quantitative analysis of cell reconstitution. Although young HSCs outperformed old HSCs in young recipients, young HSCs unexpectedly failed to outcompete the old HSCs of aged recipients. Interestingly, despite substantial enrichment of megakaryocyte progenitors (MkPs) in old mice in situ and reported platelet (Plt) priming with age, transplanted old HSCs were deficient in reconstitution of all lineages, including MkPs and Plts. We therefore performed functional analysis of young and old MkPs. Surprisingly, old MkPs displayed unmistakably greater regenerative capacity compared with young MkPs. Transcriptome analysis revealed putative molecular regulators of old MkP expansion. Collectively, these data demonstrated that aging affects HSCs and megakaryopoiesis in fundamentally different ways: whereas old HSCs functionally decline, MkPs gain expansion capacity upon aging.


Asunto(s)
Envejecimiento/fisiología , Células Madre Hematopoyéticas/fisiología , Células Progenitoras de Megacariocitos/fisiología , Trombopoyesis , Transcriptoma , Animales , Linaje de la Célula , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Masculino , Ratones , Ratones Endogámicos C57BL
8.
Exp Hematol ; 90: 39-45.e3, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32916215

RESUMEN

Respiratory diseases are a leading cause of death worldwide, with vulnerability to disease varying greatly between individuals. The reasons underlying disease susceptibility are unknown, but there is often a variable immune response in lungs often. Recently, we identified a surprising novel role for the interleukin 7 receptor (IL7R), a primarily lymphoid-associated regulator, in fetal-specified, lung-resident macrophage development. Here, we report that traditional, hematopoietic stem cell-derived myeloid cells in the adult lung, peripheral blood, and bone marrow also depend on IL7R expression. Using single- and double-germline knockout models, we found that eosinophil numbers were reduced on deletion of IL7Rα. We then employed two Cre recombinase models in lineage tracing experiments to test whether these cells developed through an IL7Rα+ pathway. Despite the impact of IL7Rα deletion, IL7R-Cre labeled only a minimal fraction of eosinophils. We therefore examined the intrinsic versus extrinsic requirement for IL7R in the production of eosinophils using reciprocal hematopoietic stem cell transplantation assays. These assays revealed that extrinsic, but not eosinophil-intrinsic, IL7R is required for eosinophil reconstitution by HSCs in the adult lung. To determine which external factors may be influencing eosinophil development and survival, we performed a cytokine array analysis between wild-type and IL7Rα-deficient mice and found several differentially regulated proteins. These findings expand on our previous report that IL7R is required not only for proper lymphoid cell development and homeostasis, but also for myeloid cell homeostasis in tissues.


Asunto(s)
Células Madre Hematopoyéticas/inmunología , Homeostasis/inmunología , Pulmón/inmunología , Células Mieloides/inmunología , Receptores de Interleucina-7/inmunología , Transducción de Señal/inmunología , Animales , Femenino , Homeostasis/genética , Pulmón/citología , Linfocitos/citología , Linfocitos/inmunología , Masculino , Ratones , Ratones Noqueados , Células Mieloides/citología , Receptores de Interleucina-7/genética , Transducción de Señal/genética
9.
Genome Announc ; 2(6)2014 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-25523774

RESUMEN

Vibrio coralliilyticus is a marine gammaproteobacterium that has been implicated as an etiological agent of disease for multiple coral genera on reefs worldwide. We report the complete genome of V. coralliilyticus strain OCN014, isolated from a diseased Acropora cytherea colony off the western reef terrace of Palmyra Atoll.

SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA