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1.
Blood ; 142(26): 2282-2295, 2023 12 28.
Artículo en Inglés | MEDLINE | ID: mdl-37774374

RESUMEN

ABSTRACT: The spatial anatomy of hematopoiesis in the bone marrow (BM) has been extensively studied in mice and other preclinical models, but technical challenges have precluded a commensurate exploration in humans. Institutional pathology archives contain thousands of paraffinized BM core biopsy tissue specimens, providing a rich resource for studying the intact human BM topography in a variety of physiologic states. Thus, we developed an end-to-end pipeline involving multiparameter whole tissue staining, in situ imaging at single-cell resolution, and artificial intelligence-based digital whole slide image analysis and then applied it to a cohort of disease-free samples to survey alterations in the hematopoietic topography associated with aging. Our data indicate heterogeneity in marrow adipose tissue (MAT) content within each age group and an inverse correlation between MAT content and proportions of early myeloid and erythroid precursors, irrespective of age. We identify consistent endosteal and perivascular positioning of hematopoietic stem and progenitor cells (HSPCs) with medullary localization of more differentiated elements and, importantly, uncover new evidence of aging-associated changes in cellular and vascular morphologies, microarchitectural alterations suggestive of foci with increased lymphocytes, and diminution of a potentially active megakaryocytic niche. Overall, our findings suggest that there is topographic remodeling of human hematopoiesis associated with aging. More generally, we demonstrate the potential to deeply unravel the spatial biology of normal and pathologic human BM states using intact archival tissue specimens.


Asunto(s)
Inteligencia Artificial , Células Madre Hematopoyéticas , Humanos , Ratones , Animales , Células Madre Hematopoyéticas/patología , Médula Ósea/patología , Hematopoyesis/fisiología , Envejecimiento
2.
J Mol Cell Biol ; 15(6)2023 Nov 27.
Artículo en Inglés | MEDLINE | ID: mdl-37327088

RESUMEN

Chemoresistance is a primary cause of treatment failure in pancreatic cancer. Identifying cell surface markers specifically expressed in chemoresistant cancer cells (CCCs) could facilitate targeted therapies to overcome chemoresistance. We performed an antibody-based screen and found that TRA-1-60 and TRA-1-81, two 'stemness' cell surface markers, are highly enriched in CCCs. Furthermore, TRA-1-60+/TRA-1-81+ cells are chemoresistant compared to TRA-1-60-/TRA-1-81- cells. Transcriptome profiling identified UGT1A10, shown to be both necessary and sufficient to maintain TRA-1-60/TRA-1-81 expression and chemoresistance. From a high-content chemical screen, we identified Cymarin, which downregulates UGT1A10, eliminates TRA-1-60/TRA-1-81 expression, and increases chemosensitivity both in vitro and in vivo. Finally, TRA-1-60/TRA-1-81 expression is highly specific in primary cancer tissue and positively correlated with chemoresistance and short survival, which highlights their potentiality for targeted therapy. Therefore, we discovered a novel CCC surface marker regulated by a pathway that promotes chemoresistance, as well as a leading drug candidate to target this pathway.


Asunto(s)
Resistencia a Antineoplásicos , Neoplasias Pancreáticas , Humanos , Línea Celular Tumoral , Perfilación de la Expresión Génica
3.
bioRxiv ; 2023 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-37034724

RESUMEN

Transition between activation and quiescence programs in hematopoietic stem and progenitor cells (HSC/HSPCs) is perceived to be governed intrinsically and by microenvironmental co-adaptation. However, HSC programs dictating both transition and adaptability, remain poorly defined. Single cell multiome analysis divulging differential transcriptional activity between distinct HSPC states, indicated for the exclusive absence of Fli-1 motif from quiescent HSCs. We reveal that Fli-1 activity is essential for HSCs during regenerative hematopoiesis. Fli-1 directs activation programs while manipulating cellular sensory and output machineries, enabling HSPCs co-adoptability with a stimulated vascular niche. During regenerative conditions, Fli-1 presets and enables propagation of niche-derived Notch1 signaling. Constitutively induced Notch1 signaling is sufficient to recuperate functional HSC impairments in the absence of Fli-1. Applying FLI-1 modified-mRNA transduction into lethargic adult human mobilized HSPCs, enables their vigorous niche-mediated expansion along with superior engraftment capacities. Thus, decryption of stem cell activation programs offers valuable insights for immune regenerative medicine.

4.
Cell Stem Cell ; 29(4): 593-609.e7, 2022 04 07.
Artículo en Inglés | MEDLINE | ID: mdl-35364013

RESUMEN

The liver vascular network is patterned by sinusoidal and hepatocyte co-zonation. How intra-liver vessels acquire their hierarchical specialized functions is unknown. We study heterogeneity of hepatic vascular cells during mouse development through functional and single-cell RNA-sequencing. The acquisition of sinusoidal endothelial cell identity is initiated during early development and completed postnatally, originating from a pool of undifferentiated vascular progenitors at E12. The peri-natal induction of the transcription factor c-Maf is a critical switch for the sinusoidal identity determination. Endothelium-restricted deletion of c-Maf disrupts liver sinusoidal development, aberrantly expands postnatal liver hematopoiesis, promotes excessive postnatal sinusoidal proliferation, and aggravates liver pro-fibrotic sensitivity to chemical insult. Enforced c-Maf overexpression in generic human endothelial cells switches on a liver sinusoidal transcriptional program that maintains hepatocyte function. c-Maf represents an inducible intra-organotypic and niche-responsive molecular determinant of hepatic sinusoidal cell identity and lays the foundation for the strategies for vasculature-driven liver repair.


Asunto(s)
Capilares , Células Endoteliales , Animales , Endotelio , Hígado/patología , Cirrosis Hepática/patología , Regeneración Hepática , Ratones , Proteínas Proto-Oncogénicas c-maf
6.
Nat Commun ; 13(1): 1584, 2022 03 24.
Artículo en Inglés | MEDLINE | ID: mdl-35332125

RESUMEN

Hematopoietic stem cells (HSCs) develop from hemogenic endothelium within embryonic arterial vessels such as the aorta of the aorta-gonad-mesonephros region (AGM). To identify the signals responsible for HSC formation, here we use single cell RNA-sequencing to simultaneously analyze the transcriptional profiles of AGM-derived cells transitioning from hemogenic endothelium to HSCs, and AGM-derived endothelial cells which provide signals sufficient to support HSC maturation and self-renewal. Pseudotemporal ordering reveals dynamics of gene expression during the hemogenic endothelium to HSC transition, identifying surface receptors specifically expressed on developing HSCs. Transcriptional profiling of niche endothelial cells identifies corresponding ligands, including those signaling to Notch receptors, VLA-4 integrin, and CXCR4, which, when integrated in an engineered platform, are sufficient to support the generation of engrafting HSCs. These studies provide a transcriptional map of the signaling interactions necessary for the development of HSCs and advance the goal of engineering HSCs for therapeutic applications.


Asunto(s)
Hemangioblastos , Transcriptoma , Gónadas , Hematopoyesis/genética , Células Madre Hematopoyéticas/metabolismo , Mesonefro
8.
Nat Cell Biol ; 24(1): 99-111, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34961794

RESUMEN

Histone variants and the associated post-translational modifications that govern the stemness of haematopoietic stem cells (HSCs) and differentiation thereof into progenitors (HSPCs) have not been well defined. H3.3 is a replication-independent H3 histone variant in mammalian systems that is enriched at both H3K4me3- and H3K27me3-marked bivalent genes as well as H3K9me3-marked endogenous retroviral repeats. Here we show that H3.3, but not its chaperone Hira, prevents premature HSC exhaustion and differentiation into granulocyte-macrophage progenitors. H3.3-null HSPCs display reduced expression of stemness and lineage-specific genes with a predominant gain of H3K27me3 marks at their promoter regions. Concomitantly, loss of H3.3 leads to a reduction of H3K9me3 marks at endogenous retroviral repeats, opening up binding sites for the interferon regulatory factor family of transcription factors, allowing the survival of rare, persisting H3.3-null HSCs. We propose a model whereby H3.3 maintains adult HSC stemness by safeguarding the delicate interplay between H3K27me3 and H3K9me3 marks, enforcing chromatin adaptability.


Asunto(s)
Cromatina/metabolismo , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Histonas/metabolismo , Mielopoyesis/fisiología , Animales , Linfocitos T CD8-positivos/citología , Proteínas de Ciclo Celular , Línea Celular , Granulocitos/citología , Hematopoyesis/fisiología , Chaperonas de Histonas , Células Endoteliales de la Vena Umbilical Humana , Humanos , Macrófagos/citología , Metilación , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Regiones Promotoras Genéticas/genética , Procesamiento Proteico-Postraduccional/fisiología , Factores de Transcripción
9.
Nat Cardiovasc Res ; 1: 882-899, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36713285

RESUMEN

Current dogma dictates that during adulthood, endothelial cells (ECs) are locked in an immutable stable homeostatic state. By contrast, herein we show that maintenance of EC fate and function are linked and active processes, which depend on the constitutive cooperativity of only two ETS-transcription factors (TFs) ERG and Fli1. While deletion of either Fli1 or ERG manifest subtle vascular dysfunction, their combined genetic deletion in adult EC results in acute vasculopathy and multiorgan failure, due to loss of EC fate and integrity, hyperinflammation, and spontaneous thrombosis, leading to death. ERG and Fli1 co-deficiency cause rapid transcriptional silencing of pan- and organotypic vascular core genes, with dysregulation of inflammation and coagulation pathways. Vascular hyperinflammation leads to impaired hematopoiesis with myeloid skewing. Accordingly, enforced ERG and FLI1 expression in adult human mesenchymal stromal cells activates vascular programs and functionality enabling engraftment of perfusable vascular network. GWAS-analysis identified vascular diseases are associated with FLI1/Erg mutations. Constitutive expression of ERG and Fli1 uphold EC fate, physiological function, and resilience in adult vasculature; while their functional loss can contribute to systemic human diseases.

11.
Dev Cell ; 56(22): 3042-3051, 2021 11 22.
Artículo en Inglés | MEDLINE | ID: mdl-34813766

RESUMEN

Adult organs are vascularized by specialized blood vessels. In addition to inter-organ vascular heterogeneity, each organ is arborized by structurally and functionally diversified populations of endothelial cells (ECs). The molecular pathways that are induced to orchestrate inter- and intra- organ vascular heterogeneity and zonation are shaped during development and fully specified postnatally. Notably, intra-organ specialization of ECs is associated with induction of angiocrine factors that guide cross-talk between ECs and parenchymal cells, establishing co-zonated vascular regions within each organ. In this review, we describe how microenvironmental tissue-specific biophysical, biochemical, immune, and inflammatory cues dictate the specialization of ECs with zonated functions. We delineate how physiological and biophysical stressors in the developing liver, lung, and kidney vasculature induce specialization of capillary beds. Deciphering mechanisms by which vascular microvasculature diversity is attained could set the stage for treating regenerative disorders and promote healing of organs without provoking fibrosis.


Asunto(s)
Células Endoteliales/citología , Riñón/irrigación sanguínea , Microvasos/citología , Neovascularización Fisiológica/fisiología , Regeneración/fisiología , Animales , Diferenciación Celular/fisiología , Humanos , Riñón/citología
12.
Front Cell Dev Biol ; 9: 645496, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33996805

RESUMEN

The bone marrow (BM) tissue is the main physiological site for adult hematopoiesis. In recent years, the cellular and matrix components composing the BM have been defined with unprecedent resolution, both at the molecular and structural levels. With the expansion of this knowledge, the possibility of reproducing a BM-like structure, to ectopically support and study hematopoiesis, becomes a reality. A number of experimental systems have been implemented and have displayed the feasibility of bioengineering BM tissues, supported by cells of mesenchymal origin. Despite being known as an abundant component of the BM, the vasculature has been largely disregarded for its role in regulating tissue formation, organization and determination. Recent reports have highlighted the crucial role for vascular endothelial cells in shaping tissue development and supporting steady state, emergency and malignant hematopoiesis, both pre- and postnatally. Herein, we review the field of BM-tissue bioengineering with a particular focus on vascular system implementation and integration, starting from describing a variety of applicable in vitro models, ending up with in vivo preclinical models. Additionally, we highlight the challenges of the field and discuss the clinical perspectives in terms of adoptive transfer of vascularized BM-niche grafts in patients to support recovering hematopoiesis.

13.
Nat Commun ; 11(1): 3547, 2020 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-32669546

RESUMEN

Neutrophils provide first line of host defense against bacterial infections utilizing glycolysis for their effector functions. How glycolysis and its major byproduct lactate are triggered in bone marrow (BM) neutrophils and their contribution to neutrophil mobilization in acute inflammation is not clear. Here we report that bacterial lipopolysaccharides (LPS) or Salmonella Typhimurium triggers lactate release by increasing glycolysis, NADPH-oxidase-mediated reactive oxygen species and HIF-1α levels in BM neutrophils. Increased release of BM lactate preferentially promotes neutrophil mobilization by reducing endothelial VE-Cadherin expression, increasing BM vascular permeability via endothelial lactate-receptor GPR81 signaling. GPR81-/- mice mobilize reduced levels of neutrophils in response to LPS, unless rescued by VE-Cadherin disrupting antibodies. Lactate administration also induces release of the BM neutrophil mobilizers G-CSF, CXCL1 and CXCL2, indicating that this metabolite drives neutrophil mobilization via multiple pathways. Our study reveals a metabolic crosstalk between lactate-producing neutrophils and BM endothelium, which controls neutrophil mobilization under bacterial infection.


Asunto(s)
Células de la Médula Ósea/inmunología , Ácido Láctico/metabolismo , Neutrófilos/inmunología , Receptores Acoplados a Proteínas G/metabolismo , Infecciones por Salmonella/inmunología , Animales , Médula Ósea/irrigación sanguínea , Células de la Médula Ósea/metabolismo , Modelos Animales de Enfermedad , Endotelio Vascular/metabolismo , Femenino , Humanos , Lipopolisacáridos/inmunología , Masculino , Ratones , Ratones Noqueados , Neutrófilos/metabolismo , Receptores Acoplados a Proteínas G/genética , Infecciones por Salmonella/microbiología , Salmonella typhimurium/inmunología , Transducción de Señal/inmunología
14.
Cell Stem Cell ; 23(4): 572-585.e7, 2018 10 04.
Artículo en Inglés | MEDLINE | ID: mdl-30174297

RESUMEN

Hematopoietic stem and progenitor cells (HSPCs) tightly couple maintenance of the bone marrow (BM) reservoir, including undifferentiated long-term repopulating hematopoietic stem cells (LT-HSCs), with intensive daily production of mature leukocytes and blood replenishment. We found two daily peaks of BM HSPC activity that are initiated by onset of light and darkness providing this coupling. Both peaks follow transient elevation of BM norepinephrine and TNF secretion, which temporarily increase HSPC reactive oxygen species (ROS) levels. Light-induced norepinephrine and TNF secretion augments HSPC differentiation and increases vascular permeability to replenish the blood. In contrast, darkness-induced TNF increases melatonin secretion to drive renewal of HSPCs and LT-HSC potential through modulating surface CD150 and c-Kit expression, increasing COX-2/αSMA+ macrophages, diminishing vascular permeability, and reducing HSPC ROS levels. These findings reveal that light- and darkness-induced daily bursts of norepinephrine, TNF, and melatonin within the BM are essential for synchronized mature blood cell production and HSPC pool repopulation.


Asunto(s)
Diferenciación Celular/efectos de la radiación , Oscuridad , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/efectos de la radiación , Luz , Animales , Células Cultivadas , Epigénesis Genética/genética , Células Madre Hematopoyéticas/metabolismo , Ratones , Ratones Endogámicos C57BL , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
15.
J Clin Invest ; 127(12): 4231-4234, 2017 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-29130939

RESUMEN

Mobilization of hematopoietic stem and progenitor cells (HSPCs) from the bone marrow (BM) into the peripheral blood is a complex process that is enhanced dramatically under stress-induced conditions. A better understanding of how the mobilization process is regulated will likely facilitate the development of improved clinical protocols for stem cell harvesting and transplantation. In this issue of the JCI, Singh et al. (1) showed that the truncated cleaved form of neurotransmitter neuropeptide Y (NPY) actively promotes a breach of BM vascular sinusoidal portals, thereby augmenting HSPC trafficking to the circulation. The authors report a previously unrecognized axis, in which expression of the enzyme dipeptidylpeptidase-4 (DPP4)/CD26 by endothelial cells activates NPY-mediated signaling by increasing the bioavailability of the truncated form of NPY. These findings underscore the importance of and urgency to develop pharmacological therapies that target the vasculature and regulate diverse aspects of hematopoiesis, such as HSPC trafficking, in steady-state and stress-induced conditions.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Neuropéptido Y , Médula Ósea , Células Madre Hematopoyéticas , Transducción de Señal
16.
Cancer Cell ; 32(3): 276-278, 2017 09 11.
Artículo en Inglés | MEDLINE | ID: mdl-28898691

RESUMEN

In this issue of Cancer Cell, Passaro et al. demonstrate how leukemia through aberrant induction of reactive oxygen species and nitric oxide production trigger marrow vessel leakiness, instigating pro-leukemic function. Disrupted tumor blood vessels promote exhaustion of non-malignant stem and progenitor cells and may facilitate leukemia relapse following chemotherapeutic treatment.


Asunto(s)
Médula Ósea , Leucemia , Células de la Médula Ósea , Células Madre Hematopoyéticas , Humanos , Óxido Nítrico , Células Madre
18.
Annu Rev Cell Dev Biol ; 32: 649-675, 2016 10 06.
Artículo en Inglés | MEDLINE | ID: mdl-27576121

RESUMEN

In addition to their conventional role as a versatile transport system, blood vessels provide signals controlling organ development, regeneration, and stem cell behavior. In the skeletal system, certain capillaries support perivascular osteoprogenitor cells and thereby control bone formation. Blood vessels are also a critical component of niche microenvironments for hematopoietic stem cells. Here we discuss key pathways and factors controlling endothelial cell behavior in bone, the role of vessels in osteogenesis, and the nature of vascular stem cell niches in bone marrow.


Asunto(s)
Vasos Sanguíneos/metabolismo , Hematopoyesis , Osteogénesis , Transducción de Señal , Animales , Médula Ósea/irrigación sanguínea , Células Endoteliales/metabolismo , Humanos
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