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1.
Immunity ; 56(7): 1578-1595.e8, 2023 07 11.
Artículo en Inglés | MEDLINE | ID: mdl-37329888

RESUMEN

It is currently not well known how necroptosis and necroptosis responses manifest in vivo. Here, we uncovered a molecular switch facilitating reprogramming between two alternative modes of necroptosis signaling in hepatocytes, fundamentally affecting immune responses and hepatocarcinogenesis. Concomitant necrosome and NF-κB activation in hepatocytes, which physiologically express low concentrations of receptor-interacting kinase 3 (RIPK3), did not lead to immediate cell death but forced them into a prolonged "sublethal" state with leaky membranes, functioning as secretory cells that released specific chemokines including CCL20 and MCP-1. This triggered hepatic cell proliferation as well as activation of procarcinogenic monocyte-derived macrophage cell clusters, contributing to hepatocarcinogenesis. In contrast, necrosome activation in hepatocytes with inactive NF-κB-signaling caused an accelerated execution of necroptosis, limiting alarmin release, and thereby preventing inflammation and hepatocarcinogenesis. Consistently, intratumoral NF-κB-necroptosis signatures were associated with poor prognosis in human hepatocarcinogenesis. Therefore, pharmacological reprogramming between these distinct forms of necroptosis may represent a promising strategy against hepatocellular carcinoma.


Asunto(s)
Neoplasias Hepáticas , FN-kappa B , Humanos , FN-kappa B/metabolismo , Proteínas Quinasas/metabolismo , Necroptosis , Inflamación/patología , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Apoptosis
2.
Cell ; 165(2): 303-16, 2016 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-27058663

RESUMEN

Leukemia stem cells (LSCs) have the capacity to self-renew and propagate disease upon serial transplantation in animal models, and elimination of this cell population is required for curative therapies. Here, we describe a series of pooled, in vivo RNAi screens to identify essential transcription factors (TFs) in a murine model of acute myeloid leukemia (AML) with genetically and phenotypically defined LSCs. These screens reveal the heterodimeric, circadian rhythm TFs Clock and Bmal1 as genes required for the growth of AML cells in vitro and in vivo. Disruption of canonical circadian pathway components produces anti-leukemic effects, including impaired proliferation, enhanced myeloid differentiation, and depletion of LSCs. We find that both normal and malignant hematopoietic cells harbor an intact clock with robust circadian oscillations, and genetic knockout models reveal a leukemia-specific dependence on the pathway. Our findings establish a role for the core circadian clock genes in AML.


Asunto(s)
Factores de Transcripción ARNTL/genética , Proteínas CLOCK/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Células Madre Neoplásicas/patología , Animales , Ritmo Circadiano , Modelos Animales de Enfermedad , Técnicas de Inactivación de Genes , Hematopoyesis , Humanos , Leucemia Mieloide Aguda/metabolismo , Ratones , Ratones Endogámicos C57BL , Células Madre Neoplásicas/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo
3.
Nature ; 608(7924): 766-777, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35948637

RESUMEN

Myocardial infarction is a leading cause of death worldwide1. Although advances have been made in acute treatment, an incomplete understanding of remodelling processes has limited the effectiveness of therapies to reduce late-stage mortality2. Here we generate an integrative high-resolution map of human cardiac remodelling after myocardial infarction using single-cell gene expression, chromatin accessibility and spatial transcriptomic profiling of multiple physiological zones at distinct time points in myocardium from patients with myocardial infarction and controls. Multi-modal data integration enabled us to evaluate cardiac cell-type compositions at increased resolution, yielding insights into changes of the cardiac transcriptome and epigenome through the identification of distinct tissue structures of injury, repair and remodelling. We identified and validated disease-specific cardiac cell states of major cell types and analysed them in their spatial context, evaluating their dependency on other cell types. Our data elucidate the molecular principles of human myocardial tissue organization, recapitulating a gradual cardiomyocyte and myeloid continuum following ischaemic injury. In sum, our study provides an integrative molecular map of human myocardial infarction, represents an essential reference for the field and paves the way for advanced mechanistic and therapeutic studies of cardiac disease.


Asunto(s)
Remodelación Atrial , Ensamble y Desensamble de Cromatina , Perfilación de la Expresión Génica , Infarto del Miocardio , Análisis de la Célula Individual , Remodelación Ventricular , Remodelación Atrial/genética , Estudios de Casos y Controles , Cromatina/genética , Epigenoma , Humanos , Infarto del Miocardio/genética , Infarto del Miocardio/patología , Miocardio/metabolismo , Miocardio/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Factores de Tiempo , Remodelación Ventricular/genética
4.
Nature ; 589(7841): 281-286, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33176333

RESUMEN

Kidney fibrosis is the hallmark of chronic kidney disease progression; however, at present no antifibrotic therapies exist1-3. The origin, functional heterogeneity and regulation of scar-forming cells that occur during human kidney fibrosis remain poorly understood1,2,4. Here, using single-cell RNA sequencing, we profiled the transcriptomes of cells from the proximal and non-proximal tubules of healthy and fibrotic human kidneys to map the entire human kidney. This analysis enabled us to map all matrix-producing cells at high resolution, and to identify distinct subpopulations of pericytes and fibroblasts as the main cellular sources of scar-forming myofibroblasts during human kidney fibrosis. We used genetic fate-tracing, time-course single-cell RNA sequencing and ATAC-seq (assay for transposase-accessible chromatin using sequencing) experiments in mice, and spatial transcriptomics in human kidney fibrosis, to shed light on the cellular origins and differentiation of human kidney myofibroblasts and their precursors at high resolution. Finally, we used this strategy to detect potential therapeutic targets, and identified NKD2 as a myofibroblast-specific target in human kidney fibrosis.


Asunto(s)
Linaje de la Célula , Fibrosis/patología , Túbulos Renales/patología , Miofibroblastos/patología , Insuficiencia Renal Crónica/patología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Proteínas de Unión al Calcio/metabolismo , Estudios de Casos y Controles , Diferenciación Celular , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Femenino , Fibroblastos/citología , Fibroblastos/metabolismo , Humanos , Masculino , Mesodermo/citología , Mesodermo/patología , Ratones , Miofibroblastos/metabolismo , Pericitos/citología , Pericitos/patología , RNA-Seq , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Análisis de la Célula Individual , Transcriptoma
5.
Development ; 149(9)2022 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-35417019

RESUMEN

Nephrotic syndrome (NS) is characterized by severe proteinuria as a consequence of kidney glomerular injury due to podocyte damage. In vitro models mimicking in vivo podocyte characteristics are a prerequisite to resolve NS pathogenesis. The detailed characterization of organoid podocytes resulting from a hybrid culture protocol showed a podocyte population that resembles adult podocytes and was superior compared with 2D counterparts, based on single-cell RNA sequencing, super-resolution imaging and electron microscopy. In this study, these next-generation podocytes in kidney organoids enabled personalized idiopathic nephrotic syndrome modeling, as shown by activated slit diaphragm signaling and podocyte injury following protamine sulfate, puromycin aminonucleoside treatment and exposure to NS plasma containing pathogenic permeability factors. Organoids cultured from cells of a patient with heterozygous NPHS2 mutations showed poor NPHS2 expression and aberrant NPHS1 localization, which was reversible after genetic correction. Repaired organoids displayed increased VEGFA pathway activity and transcription factor activity known to be essential for podocyte physiology, as shown by RNA sequencing. This study shows that organoids are the preferred model of choice to study idiopathic and congenital podocytopathies.


Asunto(s)
Síndrome Nefrótico , Células Madre Pluripotentes , Podocitos , Femenino , Humanos , Riñón/metabolismo , Masculino , Síndrome Nefrótico/genética , Síndrome Nefrótico/metabolismo , Síndrome Nefrótico/patología , Organoides , Células Madre Pluripotentes/metabolismo , Podocitos/metabolismo , Podocitos/patología
6.
Br J Haematol ; 200(5): 643-651, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36382360

RESUMEN

Nestin is an intermediate filament protein, which was originally detected in neuroepithelial stem cells. Besides its use as a phenotypic marker of mesenchymal stem cells in the hematopoeitic stem cell niche, the functional interpretation of nestin+ cells remains elusive. We investigated the cellular expression of nestin in bone marrow trephine biopsies of MPN patients, following myeloablation at a stage of hypocellularity during early regeneration. Here, nestin is highly expressed in mature osteocytes, arteriolar endothelial and perivascular cells and small capillaries within the bone marrow space, but not in sinusoid lining cells. This is in stark contrast to nestin expression pattern in myeloproliferative neoplasms that show hypercellularity due to oncogenic driver mutations. Here, nestin is expressed exclusively in endothelial cells of arterioles, but not in osteocytes or small capillaries. Thus, the pattern of nestin expression following myeloablation inversely correlates with cellularity in the bone marrow. This nestin expression pattern is mimicking early postnatal transcriptional programming during bone marrow development. We show that nestin expression in osteocytes occurs across different species following transplant and also in bone marrow metastasis.


Asunto(s)
Neoplasias de la Médula Ósea , Médula Ósea , Humanos , Nestina/genética , Nestina/metabolismo , Médula Ósea/metabolismo , Células Endoteliales/metabolismo , Osteocitos/metabolismo , Neoplasias de la Médula Ósea/metabolismo
7.
BMC Bioinformatics ; 23(1): 276, 2022 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-35831796

RESUMEN

BACKGROUND: Single-cell RNA sequencing (scRNA-seq) allows the detection of rare cell types in complex tissues. The detection of markers for rare cell types is useful for further biological analysis of, for example, flow cytometry and imaging data sets for either physical isolation or spatial characterization of these cells. However, only a few computational approaches consider the problem of selecting specific marker genes from scRNA-seq data. RESULTS: Here, we propose sc2marker, which is based on the maximum margin index and a database of proteins with antibodies, to select markers for flow cytometry or imaging. We evaluated the performances of sc2marker and competing methods in ranking known markers in scRNA-seq data of immune and stromal cells. The results showed that sc2marker performed better than the competing methods in accuracy, while having a competitive running time.


Asunto(s)
Análisis de la Célula Individual , Programas Informáticos , Perfilación de la Expresión Génica/métodos , RNA-Seq , Análisis de Secuencia de ARN/métodos , Análisis de la Célula Individual/métodos , Secuenciación del Exoma
8.
Br J Haematol ; 198(1): 114-130, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35362549

RESUMEN

Evolution of erythrocyte transfusion-dependent (RBC-TD) anaemia associated with haploinsufficiency of the ribosomal protein subunit S14 gene (RPS14) is a characteristic complication of myelodysplastic syndromes (MDS) with del(5q) [MDS.del(5q)]. Evaluating 39 patients with MDS.del(5q), <5% of anaemia progression was attributable to RPS14-dependent alterations of normoblasts, pro-erythroblasts, or CD34+ CD71+ precursors. Ninety-three percent of anaemia progression and 70% of the absolute decline in peripheral blood Hb value were attributable to disappearance of erythroblastic islands (Ery-Is). Ery-Is loss occurred independently of blast excess, TP53 mutation, additional chromosome aberrations and RPS14-dependent alterations of normoblasts and pro-erythroblasts. It was associated with RPS14-dependent intrinsic (S100A8+ ) and extrinsic [tumour necrosis factor α (TNF-α)-overproduction] alterations of (CD169+ ) marrow macrophages (p < 0.00005). In a mouse model of RPS14 haploinsufficiency, Ery-Is disappeared to a similar degree: approximately 70% of Ery-Is loss was related to RPS14-dependent S100A8 overexpression of marrow macrophages, less than 20% to that of CD71high Ter119- immature precursors, and less than 5% to S100A8/p53 overexpression of normoblasts or pro-erythroblasts. Marked Ery-Is loss predicted reduced efficacy (erythrocyte transfusion independence) of lenalidomide therapy (p = 0.0006). Thus, erythroid hypoplasia, a characteristic complication of MDS.del(5q), seems to result primarily from a macrophage-associated failure of the erythropoietic niche markedly reducing the productive capacity of erythropoiesis as the leading factor in anaemia progression and evolution of RBC-TD in MDS.del(5q).


Asunto(s)
Anemia , Síndromes Mielodisplásicos , Anemia/complicaciones , Animales , Aberraciones Cromosómicas , Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Humanos , Lenalidomida , Macrófagos/metabolismo , Ratones , Síndromes Mielodisplásicos/patología , Talidomida
9.
Bioinformatics ; 37(22): 4263-4265, 2021 11 18.
Artículo en Inglés | MEDLINE | ID: mdl-35032393

RESUMEN

MOTIVATION: Ligand-receptor (LR) network analysis allows the characterization of cellular crosstalk based on single cell RNA-seq data. However, current methods typically provide a list of inferred LR interactions and do not allow the researcher to focus on specific cell types, ligands or receptors. In addition, most of these methods cannot quantify changes in crosstalk between two biological phenotypes. RESULTS: CrossTalkeR is a framework for network analysis and visualization of LR interactions. CrossTalkeR identifies relevant ligands, receptors and cell types contributing to changes in cell communication when contrasting two biological phenotypes, i.e. disease versus homeostasis. A case study on scRNA-seq of human myeloproliferative neoplasms reinforces the strengths of CrossTalkeR for characterization of changes in cellular crosstalk in disease. AVAILABILITY AND IMPLEMENTATION: CrosstalkeR is an R package available at: Github: https://github.com/CostaLab/CrossTalkeR. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Asunto(s)
Análisis de la Célula Individual , Programas Informáticos , Perfilación de la Expresión Génica , Humanos , Ligandos , Análisis de Secuencia de ARN
10.
Blood ; 136(18): 2051-2064, 2020 10 29.
Artículo en Inglés | MEDLINE | ID: mdl-32726410

RESUMEN

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) that leads to progressive bone marrow (BM) fibrosis. Although the cellular mutations involved in the pathogenesis of PMF have been extensively investigated, the sequential events that drive stromal activation and fibrosis by hematopoietic-stromal cross-talk remain elusive. Using an unbiased approach and validation in patients with MPN, we determined that the differential spatial expression of the chemokine CXCL4/platelet factor-4 marks the progression of fibrosis. We show that the absence of hematopoietic CXCL4 ameliorates the MPN phenotype, reduces stromal cell activation and BM fibrosis, and decreases the activation of profibrotic pathways in megakaryocytes, inflammation in fibrosis-driving cells, and JAK/STAT activation in both megakaryocytes and stromal cells in 3 murine PMF models. Our data indicate that higher CXCL4 expression in MPN has profibrotic effects and is a mediator of the characteristic inflammation. Therefore, targeting CXCL4 might be a promising strategy to reduce inflammation in PMF.


Asunto(s)
Médula Ósea/patología , Fibrosis/patología , Inflamación/patología , Trastornos Mieloproliferativos/complicaciones , Factor Plaquetario 4/metabolismo , Mielofibrosis Primaria/patología , Animales , Médula Ósea/inmunología , Médula Ósea/metabolismo , Proliferación Celular , Progresión de la Enfermedad , Fibrosis/etiología , Fibrosis/inmunología , Fibrosis/metabolismo , Humanos , Inflamación/etiología , Inflamación/inmunología , Inflamación/metabolismo , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Masculino , Megacariocitos , Ratones , Ratones Noqueados , Mutación , Factor Plaquetario 4/genética , Mielofibrosis Primaria/etiología , Mielofibrosis Primaria/inmunología , Mielofibrosis Primaria/metabolismo
11.
Curr Opin Hematol ; 28(5): 364-371, 2021 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-34232140

RESUMEN

PURPOSE OF REVIEW: Bone marrow fibrosis is the progressive replacement of blood-forming cells by reticulin fibres, caused by the acquisition of somatic mutations in hematopoietic stem cells. The molecular and cellular mechanisms that drive the progression of bone marrow fibrosis remain unknown, yet chronic inflammation appears to be a conserved feature in most patients suffering from myeloproliferative neoplasms. RECENT FINDINGS: Here, we review recent literature pertaining to the role of inflammation in driving bone marrow fibrosis, and its effect on the various hematopoietic and nonhematopoietic cell populations. SUMMARY: Recent evidence suggests that the pathogenesis of MPN is primarily driven by the hematopoietic stem and progenitor cells, together with their mutated progeny, which in turn results in chronic inflammation that disrupts the bone marrow niche and perpetuates a disease-permissive environment. Emerging data suggests that specifically targeting stromal inflammation in combination with JAK inhibition may be the way forward to better treat MPNs, and bone marrow fibrosis specifically.


Asunto(s)
Médula Ósea , Neoplasias Hematológicas , Células Madre Hematopoyéticas , Mielofibrosis Primaria , Médula Ósea/metabolismo , Médula Ósea/patología , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patología , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Trastornos Mieloproliferativos/tratamiento farmacológico , Trastornos Mieloproliferativos/metabolismo , Trastornos Mieloproliferativos/patología , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/metabolismo , Mielofibrosis Primaria/patología
12.
Ann Hematol ; 100(1): 97-104, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33104881

RESUMEN

Bone marrow (BM) fibrosis in myeloproliferative neoplasms (MPNs) is associated with a poor prognosis. The development of myelofibrosis and differentiation of mesenchymal stromal cells to profibrotic myofibroblasts depends on macrophages. Here, we compared macrophage frequencies in BM biopsies of MPN patients and controls (patients with non-neoplastic processes), including primary myelofibrosis (PMF, n = 18), essential thrombocythemia (ET, n = 14), polycythemia vera (PV, n = 12), and Philadelphia chromosome-positive chronic myeloid leukemia (CML, n = 9). In PMF, CD68-positive macrophages were greatly increased compared to CML (p = 0.017) and control BM (p < 0.001). Similar findings were observed by CD163 staining (PMF vs. CML: p = 0.017; PMF vs. control: p < 0.001). Moreover, CD68-positive macrophages were increased in PV compared with ET (p = 0.009) and reactive cases (p < 0.001). PMF had higher frequencies of macrophages than PV (CD68: p < 0.001; CD163: p < 0.001) and ET (CD68: p < 0.001; CD163: p < 0.001). CD163 and CD68 were often co-expressed in macrophages with stellate morphology in Philadelphia chromosome-negative MPN, resulting in a sponge-like reticular network that may be a key regulator of unbalanced hematopoiesis in the BM space and may explain differences in cellularity and clinical course.


Asunto(s)
Médula Ósea/patología , Macrófagos/patología , Trastornos Mieloproliferativos/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Humanos , Persona de Mediana Edad , Clasificación del Tumor/métodos , Policitemia Vera/patología , Mielofibrosis Primaria/patología , Trombocitemia Esencial/patología , Adulto Joven
13.
Nature ; 523(7559): 183-188, 2015 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-26131937

RESUMEN

Lenalidomide is a highly effective treatment for myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)). Here, we demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1α) by the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)), resulting in CK1α degradation. CK1α is encoded by a gene within the common deleted region for del(5q) MDS and haploinsufficient expression sensitizes cells to lenalidomide therapy, providing a mechanistic basis for the therapeutic window of lenalidomide in del(5q) MDS. We found that mouse cells are resistant to lenalidomide but that changing a single amino acid in mouse Crbn to the corresponding human residue enables lenalidomide-dependent degradation of CK1α. We further demonstrate that minor side chain modifications in thalidomide and a novel analogue, CC-122, can modulate the spectrum of substrates targeted by CRL4(CRBN). These findings have implications for the clinical activity of lenalidomide and related compounds, and demonstrate the therapeutic potential of novel modulators of E3 ubiquitin ligases.


Asunto(s)
Quinasa de la Caseína I/metabolismo , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/fisiopatología , Talidomida/análogos & derivados , Ubiquitinación/efectos de los fármacos , Secuencia de Aminoácidos , Animales , Quinasa de la Caseína I/genética , Línea Celular , Regulación de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Factores Inmunológicos/farmacología , Células Jurkat , Células K562 , Lenalidomida , Ratones , Datos de Secuencia Molecular , Péptido Hidrolasas/química , Proteolisis/efectos de los fármacos , Alineación de Secuencia , Eliminación de Secuencia , Especificidad de la Especie , Talidomida/farmacología , Ubiquitina-Proteína Ligasas/metabolismo
14.
Blood ; 131(19): 2111-2119, 2018 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-29572380

RESUMEN

Myofibroblasts are fibrosis-driving cells and are well characterized in solid organ fibrosis, but their role and cellular origin in bone marrow fibrosis remains obscure. Recent work has demonstrated that Gli1+ and LepR+ mesenchymal stromal cells (MSCs) are progenitors of fibrosis-causing myofibroblasts in the bone marrow. Genetic ablation of Gli1+ MSCs or pharmacologic targeting of hedgehog (Hh)-Gli signaling ameliorated fibrosis in mouse models of myelofibrosis (MF). Moreover, pharmacologic or genetic intervention in platelet-derived growth factor receptor α (Pdgfrα) signaling in Lepr+ stromal cells suppressed their expansion and ameliorated MF. Improved understanding of cellular and molecular mechanisms in the hematopoietic stem cell niche that govern the transition of MSCs to myofibroblasts and myofibroblast expansion in MF has led to new paradigms in the pathogenesis and treatment of MF. Here, we highlight the central role of malignant hematopoietic clone-derived megakaryocytes in reprogramming the hematopoietic stem cell niche in MF with potential detrimental consequences for hematopoietic reconstitution after allogenic stem cell transplantation, so far the only therapeutic approach in MF considered to be curative. We and others have reported that targeting Hh-Gli signaling is a therapeutic strategy in solid organ fibrosis. Data indicate that targeting Gli proteins directly inhibits Gli1+ cell proliferation and myofibroblast differentiation, which results in reduced fibrosis severity and improved organ function. Although canonical Hh inhibition (eg, smoothened [Smo] inhibition) failed to improve pulmonary fibrosis, kidney fibrosis, or MF, the direct inhibition of Gli proteins ameliorated fibrosis. Therefore, targeting Gli proteins directly might be an interesting and novel therapeutic approach in MF.


Asunto(s)
Miofibroblastos/metabolismo , Mielofibrosis Primaria/etiología , Mielofibrosis Primaria/metabolismo , Biomarcadores , Células Cultivadas , Reprogramación Celular , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Humanos , Mielofibrosis Primaria/patología , Mielofibrosis Primaria/terapia , Transducción de Señal/efectos de los fármacos , Nicho de Células Madre , Células del Estroma/metabolismo , Transcriptoma , Proteína con Dedos de Zinc GLI1/metabolismo
15.
J Pathol ; 245(2): 138-146, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29570794

RESUMEN

Bone marrow fibrosis is the continuous replacement of blood-forming cells in the bone marrow with excessive scar tissue, leading to failure of the body to produce blood cells and ultimately to death. Myofibroblasts are fibrosis-driving cells and are well characterized in solid organ fibrosis, but their role and cellular origin in bone marrow fibrosis have remained obscure. Recent work has demonstrated that Gli1+ and leptin receptor+ mesenchymal stromal cells are progenitors of fibrosis-causing myofibroblasts in the bone marrow. Genetic ablation or pharmacological inhibition of Gli1+ mesenchymal stromal cells ameliorated fibrosis in mouse models of myelofibrosis. Conditional deletion of the platelet-derived growth factor (PDGF) receptor-α (PDGFRA) gene (Pdgfra) and inhibition of PDGFRA by imatinib in leptin receptor+ stromal cells suppressed their expansion and ameliorated bone marrow fibrosis. Understanding the cellular and molecular mechanisms in the haematopoietic stem cell niche that govern the mesenchymal stromal cell-to-myofibroblast transition and myofibroblast expansion will be critical to understand the pathogenesis of bone marrow fibrosis in both malignant and non-malignant conditions, and will guide the development of novel therapeutics. In this review, we summarize recent discoveries of mesenchymal stromal cells as part of the haematopoietic niche and as myofibroblast precursors, and discuss potential therapeutic strategies in the specific targeting of fibrotic transformation in bone marrow fibrosis. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Asunto(s)
Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de los fármacos , Terapia Molecular Dirigida/métodos , Mielofibrosis Primaria/tratamiento farmacológico , Nicho de Células Madre , Animales , Linaje de la Célula , Regulación de la Expresión Génica , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Humanos , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/patología , Fenotipo , Mielofibrosis Primaria/genética , Mielofibrosis Primaria/metabolismo , Mielofibrosis Primaria/patología , Transducción de Señal/efectos de los fármacos
16.
Genome Res ; 25(12): 1860-72, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26430063

RESUMEN

Both intrinsic cell state changes and variations in the composition of stem cell populations have been implicated as contributors to aging. We used single-cell RNA-seq to dissect variability in hematopoietic stem cell (HSC) and hematopoietic progenitor cell populations from young and old mice from two strains. We found that cell cycle dominates the variability within each population and that there is a lower frequency of cells in the G1 phase among old compared with young long-term HSCs, suggesting that they traverse through G1 faster. Moreover, transcriptional changes in HSCs during aging are inversely related to those upon HSC differentiation, such that old short-term (ST) HSCs resemble young long-term (LT-HSCs), suggesting that they exist in a less differentiated state. Our results indicate both compositional changes and intrinsic, population-wide changes with age and are consistent with a model where a relationship between cell cycle progression and self-renewal versus differentiation of HSCs is affected by aging and may contribute to the functional decline of old HSCs.


Asunto(s)
Ciclo Celular/genética , Diferenciación Celular/genética , Senescencia Celular/genética , Regulación de la Expresión Génica , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Factores de Edad , Animales , Biomarcadores , Análisis por Conglomerados , Biología Computacional/métodos , Femenino , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Ratones , Modelos Biológicos , Células Madre Multipotentes/citología , Células Madre Multipotentes/metabolismo , Especificidad de Órganos/genética , Fenotipo , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Transcripción Genética , Transcriptoma
18.
Blood ; 125(2): 327-35, 2015 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-25281607

RESUMEN

Signaling mutations (eg, JAK2V617F) and mutations in genes involved in epigenetic regulation (eg, TET2) are the most common cooccurring classes of mutations in myeloproliferative neoplasms (MPNs). Clinical correlative studies have demonstrated that TET2 mutations are enriched in more advanced phases of MPNs such as myelofibrosis and leukemic transformation, suggesting that they may cooperate with JAK2V617F to promote disease progression. To dissect the effects of concomitant Jak2V617F expression and Tet2 loss within distinct hematopoietic compartments in vivo, we generated Jak2V617F/Tet2 compound mutant genetic mice. We found that the combination of Jak2V617F expression and Tet2 loss resulted in a more florid MPN phenotype than that seen with either allele alone. Concordant with this, we found that Tet2 deletion conferred a strong functional competitive advantage to Jak2V617F-mutant hematopoietic stem cells (HSCs). Transcriptional profiling revealed that both Jak2V617F expression and Tet2 loss were associated with distinct and nonoverlapping gene expression signatures within the HSC compartment. In aggregate, our findings indicate that Tet2 loss drives clonal dominance in HSCs, and Jak2V617F expression causes expansion of downstream precursor cell populations, resulting in disease progression through combinatorial effects. This work provides insight into the functional consequences of JAK2V617F-TET2 comutation in MPNs, particularly as it pertains to HSCs.


Asunto(s)
Proteínas de Unión al ADN/genética , Células Madre Hematopoyéticas/patología , Janus Quinasa 2/genética , Trastornos Mieloproliferativos/genética , Proteínas Proto-Oncogénicas/genética , Animales , Dioxigenasas , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Citometría de Flujo , Perfilación de la Expresión Génica , Ratones , Ratones Transgénicos , Mutación
19.
Nature ; 465(7301): E1; discussion E3, 2010 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-20577160

RESUMEN

Conrad et al. have generated human adult germline stem cells (haGSCs) from human testicular tissue, which they claim have similar pluripotent properties to human embryonic stem cells (hESCs). Here we investigate the pluripotency of haGSCs by using global gene-expression analysis based on their gene array data and comparing the expression of pluripotency marker genes in haGSCs and hESCs, and in haGSCs and human fibroblast samples derived from different laboratories, including our own. We find that haGSCs and fibroblasts have a similar gene-expression profile, but that haGSCs and hESCs do not. The pluripotency of Conrad and colleagues' haGSCs is therefore called into question.


Asunto(s)
Células Germinativas/citología , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Adulto , Animales , Biomarcadores/análisis , Biopsia , Células Cultivadas , Células Madre Embrionarias/citología , Células Madre Embrionarias/metabolismo , Fibroblastos/citología , Fibroblastos/metabolismo , Perfilación de la Expresión Génica , Humanos , Masculino , Ratones , ARN Mensajero/análisis , ARN Mensajero/genética , Reproducibilidad de los Resultados , Testículo/citología
20.
Blood ; 131(26): 2871-2872, 2018 06 28.
Artículo en Inglés | MEDLINE | ID: mdl-29954818
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