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ABSTRACT: Hematopoietic differentiation is controlled by intrinsic regulators and the extrinsic hematopoietic niche. Activating transcription factor 4 (ATF4) plays a crucial role in the function of fetal and adult hematopoietic stem cell maintenance. However, the precise function of ATF4 in the bone marrow (BM) niche and the mechanism by which ATF4 regulates adult hematopoiesis remain largely unknown. Here, we used 4 cell-type-specific mouse Cre lines to achieve conditional knockout of Atf4 in Cdh5+ endothelial cells, Prx1+ BM stromal cells, Osx+ osteoprogenitor cells, and Mx1+ hematopoietic cells and uncovered the role of Atf4 in niche cells and hematopoiesis. Intriguingly, depletion of Atf4 in niche cells did not affect hematopoiesis; however, Atf4-deficient hematopoietic cells exhibited erythroid differentiation defects, leading to hypoplastic anemia. Mechanistically, ATF4 mediated direct regulation of Rps19bp1 transcription, which is, in turn, involved in 40 S ribosomal subunit assembly to coordinate ribosome biogenesis and promote erythropoiesis. Finally, we demonstrate that under conditions of 5-fluorouracil-induced stress, Atf4 depletion impedes the recovery of hematopoietic lineages, which requires efficient ribosome biogenesis. Taken together, our findings highlight the indispensable role of the ATF4-RPS19BP1 axis in the regulation of erythropoiesis.
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Factor de Transcripción Activador 4 , Eritropoyesis , Ribosomas , Animales , Factor de Transcripción Activador 4/metabolismo , Factor de Transcripción Activador 4/genética , Ratones , Ribosomas/metabolismo , Proteínas Ribosómicas/metabolismo , Proteínas Ribosómicas/genética , Ratones Noqueados , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/citologíaRESUMEN
BACKGROUND AND AIMS: Chronic hepatitis B (CHB) is caused by HBV infection and affects the lives of millions of people worldwide by causing liver inflammation, cirrhosis, and liver cancer. Interferon-alpha (IFN-α) therapy is a conventional immunotherapy that has been widely used in CHB treatment and achieved promising therapeutic outcomes by activating viral sensors and interferon-stimulated genes (ISGs) suppressed by HBV. However, the longitudinal landscape of immune cells of CHB patients and the effect of IFN-α on the immune system are not fully understood. APPROACH AND RESULTS: Here, we applied single-cell RNA sequencing (scRNA-seq) to delineate the transcriptomic landscape of peripheral immune cells in CHB patients before and after PegIFN-α therapy. Notably, we identified three CHB-specific cell subsets, pro-inflammatory (Pro-infla) CD14+ monocytes, Pro-infla CD16+ monocytes and IFNG+ CX3CR1- NK cells, which highly expressed proinflammatory genes and positively correlated with HBsAg. Furthermore, PegIFN-α treatment attenuated percentages of hyperactivated monocytes, increased ratios of long-lived naive/memory T cells and enhanced effector T cell cytotoxicity. Finally, PegIFN-α treatment switched the transcriptional profiles of entire immune cells from TNF-driven to IFN-α-driven pattern and enhanced innate antiviral response, including virus sensing and antigen presentation. CONCLUSIONS: Collectively, our study expands the understanding of the pathological characteristics of CHB and the immunoregulatory roles of PegIFN-α, which provides a new powerful reference for the clinical diagnosis and treatment of CHB.
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Hepatitis B Crónica , Humanos , Antivirales , Interferón-alfa , Transcriptoma , Análisis de Secuencia de ARN , Virus de la Hepatitis B , Antígenos de Superficie de la Hepatitis B , Antígenos e de la Hepatitis B , ADN ViralRESUMEN
Hematopoietic stem cell (HSC) aging is accompanied by hematopoietic reconstitution dysfunction, including loss of regenerative and engraftment ability, myeloid differentiation bias, and elevated risks of hematopoietic malignancies. Gut microbiota, a key regulator of host health and immunity, has recently been reported to affect hematopoiesis. However, there is currently limited empirical evidence explaining the direct impact of gut microbiome on aging hematopoiesis. In this study, we performed fecal microbiota transplantation (FMT) from young mice to aged mice and observed a significant increment in lymphoid differentiation and decrease in myeloid differentiation in aged recipient mice. Furthermore, FMT from young mice rejuvenated aged HSCs with enhanced short-term and long-term hematopoietic repopulation capacity. Mechanistically, single-cell RNA sequencing deciphered that FMT from young mice mitigated inflammatory signals, upregulated the FoxO signaling pathway, and promoted lymphoid differentiation of HSCs during aging. Finally, integrated microbiome and metabolome analyses uncovered that FMT reshaped gut microbiota composition and metabolite landscape, and Lachnospiraceae and tryptophan-associated metabolites promoted the recovery of hematopoiesis and rejuvenated aged HSCs. Together, our study highlights the paramount importance of the gut microbiota in HSC aging and provides insights into therapeutic strategies for aging-related hematologic disorders.
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Trasplante de Microbiota Fecal , Células Madre Hematopoyéticas , Animales , Ratones , Células Madre Hematopoyéticas/metabolismo , Inflamación/terapia , Inflamación/metabolismo , Diferenciación Celular , HematopoyesisRESUMEN
Hematopoietic stem cells (HSCs) have reduced capacities to properly maintain and replenish the hematopoietic system during myelosuppressive injury or aging. Expanding and rejuvenating HSCs for therapeutic purposes has been a long-sought goal with limited progress. Here, we show that the enzyme Sphk2 (sphingosine kinase 2), which generates the lipid metabolite sphingosine-1-phosphate, is highly expressed in HSCs. The deletion of Sphk2 markedly promotes self-renewal and increases the regenerative potential of HSCs. More importantly, Sphk2 deletion globally preserves the young HSC gene expression pattern, improves the function, and sustains the multilineage potential of HSCs during aging. Mechanistically, Sphk2 interacts with prolyl hydroxylase 2 and the Von Hippel-Lindau protein to facilitate HIF1α ubiquitination in the nucleus independent of the Sphk2 catalytic activity. Deletion of Sphk2 increases hypoxic responses by stabilizing the HIF1α protein to upregulate PDK3, a glycolysis checkpoint protein for HSC quiescence, which subsequently enhances the function of HSCs by improving their metabolic fitness; specifically, it enhances anaerobic glycolysis but suppresses mitochondrial oxidative phosphorylation and generation of reactive oxygen species. Overall, targeting Sphk2 to enhance the metabolic fitness of HSCs is a promising strategy to expand and rejuvenate functional HSCs.
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Células Madre Hematopoyéticas , Esfingosina , Glucólisis/genética , Células Madre Hematopoyéticas/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol) , Prolil Hidroxilasas/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Haematopoietic Stem cells (HSCs) have the potential for self-renewal and multilineage differentiation, and their behaviours are finely tuned by the microenvironment. HSC transplantation (HSCT) is widely used in the treatment of haematologic malignancies while limited by the quantity of available HSCs. With the development of tissue engineering, hydrogels have been deployed to mimic the HSC microenvironment in vitro. Engineered hydrogels influence HSC behaviour by regulating mechanical strength, extracellular matrix microstructure, cellular ligands and cytokines, cell-cell interaction, and oxygen concentration, which ultimately facilitate the acquisition of sufficient HSCs. Here, we review recent advances in the application of hydrogel-based microenvironment engineering of HSCs, and provide future perspectives on challenges in basic research and clinical practice.
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Neoplasias Hematológicas , Hidrogeles , Humanos , Células Madre Hematopoyéticas , Diferenciación Celular , Citocinas , Nicho de Células Madre , Microambiente TumoralRESUMEN
The success of allogeneic hematopoietic stem cell transplant for hematological malignancies is heavily dependent on the availability of suitable donors. Haploidentical donor (HID) and matched sibling donor (MSD) are two important donor options providing faster and easier sources of stem cells, however, due to confounding factors present in most retrospective studies, the validity of comparing outcomes between these two donor types remains uncertain. We conducted a post-hoc analysis of a prospective clinical trial (trial registration: Chinese Clinical Trial Registry; #ChiCTR-OCH-12002490; registered 22 February 2012; https://www.chictr.org.cn/showproj.aspx?proj=7061 ) to compare outcomes of HID versus MSD peripheral blood stem cell-derived transplants in patients with hematologic malignancies between 2015 and 2022. All HID-receiving patients had antithymocyte globulin-based conditioning. Propensity score matching was employed to minimize potential confounding factors between the two cohorts. A total of 1060 patients were initially reviewed and then 663 patients were ultimately included in the analysis after propensity score matching. The overall survival, relapse-free survival, non-relapse mortality rate and cumulative incidence of relapse were similar between HID and MSD cohorts. Subgroup analysis revealed that patients with positive measurable residual disease in first complete remission may have better overall survival with an HID transplant. The present demonstrated that haploidentical transplants can provide outcomes comparable to conventional MSD transplants, and HID should be recommended as one of the optimal donor choices for patients with positive measurable residual disease in first complete remission.
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Enfermedad Injerto contra Huésped , Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Humanos , Hermanos , Estudios Retrospectivos , Estudios Prospectivos , Puntaje de Propensión , Enfermedad Injerto contra Huésped/etiología , Recurrencia Local de Neoplasia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/complicaciones , Acondicionamiento Pretrasplante/efectos adversosRESUMEN
Hematopoietic stem cells (HSCs) are adult stem cells with the ability of self-renewal and multilineage differentiation into functional blood cells, thus playing important roles in the homeostasis of hematopoiesis and the immune response. Continuous self-renewal of HSCs offers fresh supplies for the HSC pool, which differentiate into all kinds of mature blood cells, supporting the normal functioning of the entire blood system. Nevertheless, dysregulation of the homeostasis of hematopoiesis is often the cause of many blood diseases. Excessive self-renewal of HSCs leads to hematopoietic malignancies (e.g., leukemia), while deficiency in HSC regeneration results in pancytopenia (e.g., anemia). The regulation of hematopoietic homeostasis is finely tuned, and the rapid development of high-throughput sequencing technologies has greatly boosted research in this field. In this chapter, we will summarize the recent understanding of epigenetic regulators including DNA methylation, histone modification, chromosome remodeling, noncoding RNAs, and RNA modification that are involved in hematopoietic homeostasis, which provides fundamental basis for the development of therapeutic strategies against hematopoietic diseases.
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Hematopoyesis , Células Madre Hematopoyéticas , Diferenciación Celular/genética , Hematopoyesis/genética , Homeostasis , Epigénesis GenéticaRESUMEN
Hematopoietic stem cells (HSCs) perceive both soluble signals and biomechanical inputs from their microenvironment and cells themselves. Emerging as critical regulators of the blood program, biomechanical cues such as extracellular matrix stiffness, fluid mechanical stress, confined adhesiveness, and cell-intrinsic forces modulate multiple capacities of HSCs through mechanotransduction. In recent years, research has furthered the scientific community's perception of mechano-based signaling networks in the regulation of several cellular processes. However, the underlying molecular details of the biomechanical regulatory paradigm in HSCs remain poorly elucidated and researchers are still lacking in the ability to produce bona fide HSCs ex vivo for clinical use. This review presents an overview of the mechanical control of both embryonic and adult HSCs, discusses some recent insights into the mechanisms of mechanosensing and mechanotransduction, and highlights the application of mechanical cues aiming at HSC expansion or differentiation.
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Fenómenos Biomecánicos/fisiología , Células Madre Hematopoyéticas/fisiología , Animales , Diferenciación Celular/fisiología , Señales (Psicología) , Matriz Extracelular/fisiología , Humanos , Mecanotransducción Celular/fisiología , Transducción de Señal/fisiología , Estrés MecánicoRESUMEN
The dysregulation of micro RNAs (miRNAs) is a crucial characteristic of human cancers. Herein, we observed frequent amplification of the MIR191/425 locus in breast cancer, which is correlated with poor survival outcome. We demonstrated that the miR-191/425 cluster binds the 3' untranslated region of the DICER1 transcript and posttranscriptionally represses DICER1 expression, thereby impairing global miRNAs biogenesis. Functionally, the forced expression of miR-191 or miR-425 stimulated the proliferation, survival, migration and invasion of breast cancer cells, whereas the inhibition of miR-191 or miR-425 suppressed these oncogenic behaviors of breast cancer cells, in a manner dependent on miR-191/425-mediated downregulation of DICER1. Furthermore, the miR-191/425 cluster promoted breast tumor growth, invasion and metastasis in vivo. The let-7 family of miRNAs was downregulated upon forced expression of miR-191 or miR-425, with a corresponding increase in the levels of let-7 target, high-mobility group AT-hook 2 (HMGA2). The forced expression of let-7 partially abrogated the miR-191/425-mediated oncogenic effects in breast cancer cells, suggestive of let-7 as a downstream effector of the miR-191/425-DICER1 axis. Collectively, we proposed that the inhibition of global miRNA processing, through miR-191/425-mediated downregulation of DICER1, promotes breast cancer progression.
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Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proliferación Celular/genética , ARN Helicasas DEAD-box/genética , MicroARNs/genética , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Ribonucleasa III/genética , Regiones no Traducidas 3'/genética , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Regulación hacia Abajo/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Oncogenes/genéticaRESUMEN
Human growth hormone (hGH) plays critical roles in pubertal mammary gland growth, development, and sexual maturation. Accumulated studies have reported that autocrine/paracrine hGH is an orthotopically expressed oncoprotein that promotes normal mammary epithelial cell oncogenic transformation. Autocrine/paracrine hGH has also been reported to promote mammary epithelial cell epithelial-mesenchymal transition (EMT) and invasion. However, the underlying mechanism remains largely obscure. MicroRNAs (miRNAs) are reported to be involved in regulation of multiple cellular functions of cancer. To determine whether autocrine/paracrine hGH promotes EMT and invasion through modulation of miRNA expression, we performed microarray profiling using MCF-7 cells stably expressing wild type or a translation-deficient hGH gene and identified miR-96-182-183 as an autocrine/paracrine hGH-regulated miRNA cluster. Forced expression of miR-96-182-183 conferred on epithelioid MCF-7 cells a mesenchymal phenotype and promoted invasive behavior in vitro and dissemination in vivo. Moreover, we observed that miR-96-182-183 promoted EMT and invasion by directly and simultaneously suppressing BRMS1L (breast cancer metastasis suppressor 1-like) gene expression. miR-96 and miR-182 also targeted GHR, providing a potential negative feedback loop in the hGH-GHR signaling pathway. We further demonstrated that autocrine/paracrine hGH stimulated miR-96-182-183 expression and facilitated EMT and invasion via STAT3 and STAT5 signaling. Consistent with elevated expression of autocrine/paracrine hGH in metastatic breast cancer tissue, miR-96-182-183 expression was also remarkably enhanced. Hence, we delineate the roles of the miRNA-96-182-183 cluster and elucidate a novel hGH-GHR-STAT3/STAT5-miR-96-182-183-BRMS1L-ZEB1/E47-EMT/invasion axis, which provides further understanding of the mechanism of autocrine/paracrine hGH-stimulated EMT and invasion in breast cancer.
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Neoplasias de la Mama/patología , Hormona de Crecimiento Humana/metabolismo , MicroARNs/metabolismo , Animales , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Células Epiteliales/citología , Transición Epitelial-Mesenquimal , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Hibridación in Situ , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Microscopía Confocal , Microscopía Fluorescente , Familia de Multigenes , Invasividad Neoplásica , Trasplante de Neoplasias , Análisis de Secuencia por Matrices de Oligonucleótidos , Plásmidos/metabolismo , ARN Interferente Pequeño/metabolismo , Proteínas Represoras/metabolismoRESUMEN
Lgr5 is a marker for proliferating stem cells in adult intestine, stomach, and hair follicle. However, Lgr5 is not expressed in adult hematopoietic stem and progenitor cells (HSPCs). Whether Lgr5 is expressed in the embryonic and fetal HSPCs that undergo rapid proliferation is unknown. Here we report the detection of Lgr5 expression in HSPCs in the aorta-gonad-mesonephros (AGM) and fetal liver. We also found that a portion of Lgr5(+) cells expressed the Runx1 gene that is critical for the ontogeny of HSPCs. A small portion of Lgr5(+) cells also expressed HSPC surface markers c-Kit and CD34 in AGM or CD41 in fetal liver. Furthermore, the majority of Lgr5(+) cells expressed Ki67, indicating their proliferating state. Transplantation of fetal liver-derived Lgr5-GFP(+) cells (E12.5) demonstrated that Lgr5-GFP(+) cells were able to reconstitute myeloid and lymphoid lineages in adult recipients, but the engraftment was short-term (4-8 weeks) and 20-fold lower compared with the Lgr5-GFP(-) control. Our data show that Lgr5-expressing cells mark short-term hematopoietic stem and progenitor cells, consistent with the role of Lgr5 in supporting HSPCs rapid proliferation during embryonic and fetal development.
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Desarrollo Embrionario , Células Madre Hematopoyéticas/citología , Leucina/química , Receptores Acoplados a Proteínas G/metabolismo , Animales , Secuencia de Bases , Cartilla de ADN , Hígado/embriología , Hígado/metabolismo , Ratones , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores Acoplados a Proteínas G/químicaRESUMEN
Previous studies have demonstrated that Artemin (ARTN) functions as a cancer stem cell (CSC) and metastatic factor in mammary carcinoma. Herein, we report that ARTN mediates acquired resistance to trastuzumab in HER2-positive mammary carcinoma cells. Ligands that increase HER2 activity increased ARTN expression in HER2-positive mammary carcinoma cells, whereas trastuzumab inhibited ARTN expression. Forced expression of ARTN decreased the sensitivity of HER2-positive mammary carcinoma cells to trastuzumab both in vitro and in vivo. Conversely, siRNA-mediated depletion of ARTN enhanced trastuzumab efficacy. Cells with acquired resistance to trastuzumab exhibited increased ARTN expression, the depletion of which restored trastuzumab sensitivity. Trastuzumab resistance produced an increased CSC population concomitant with enhanced mammospheric growth. ARTN mediated the enhancement of the CSC population by increased BCL-2 expression, and the CSC population in trastuzumab-resistant cells was abrogated upon inhibition of BCL-2. Hence, we conclude that ARTN is one mediator of acquired resistance to trastuzumab in HER2-positive mammary carcinoma cells.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Factor Neurotrófico Derivado de la Línea Celular Glial/fisiología , Células Madre Neoplásicas/efectos de los fármacos , Proteínas del Tejido Nervioso/fisiología , Receptor ErbB-2/fisiología , Anticuerpos Monoclonales Humanizados/farmacología , Secuencia de Bases , Neoplasias de la Mama/patología , Línea Celular Tumoral , Cartilla de ADN , Resistencia a Antineoplásicos , Femenino , Humanos , Células Madre Neoplásicas/patología , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Reacción en Cadena de la Polimerasa , TrastuzumabRESUMEN
INTRODUCTION: Estrogen signaling is pivotal in the progression of estrogen receptor positive breast cancer primarily by the regulation of cell survival and proliferation. Micro (mi)RNAs have been demonstrated to be regulated by estrogen to mediate estrogenic effects. Herein, we determined the role of estrogen regulated miR-26 and its underlying molecular mechanisms associated with estrogen receptor (ER)+ breast cancer proliferation. METHODS: The expression of miR-26a and miR-26b was evaluated by real-time quantitative (RT)-PCR. The expression of miR-26a or miR-26b was modulated in ER+ breast cancer cells (MCF-7 and T47D) and tumor cell growth in vitro and an in vivo xenograft model was determined. Bioinformatics analyses were utilized to screen for estrogen responsive genes, which were also predicted to be targeted by miR-26. Luciferase reporter assays were performed to confirm miR-26 regulation of the 3' UTR of target genes. The levels of miR-26 target genes (CHD1, GREB1 and KPNA2) were evaluated by western blotting and immunohistochemistry. RESULTS: Estrogen reduced the expression of miR-26a and miR-26b in ER+ breast cancer cells. Forced expression of miR-26a or miR-26b significantly inhibited the estrogen stimulated growth of ER+ breast cancer cells and tumor growth in xenograft models, whereas miR-26a/b depletion increased the growth of ER+ breast cancer cells in the absence of estrogen treatment. Screening of estrogen responsive genes, which were also predicted to be targeted by miR-26, identified GREB1 and nine other genes (AGPAT5, AMMECR1, CHD1, ERLIN1, HSPA8, KPNA2, MREG, NARG1, and PLOD2). Further verification has identified nine genes (AGPAT5, CHD1, ERLIN1, GREB1, HSPA8, KPNA2, MREG, NARG1 and PLOD2) which were directly targeted by miR-26 via their 3' UTR. Functional screening suggested only three estrogen regulated miR-26 target genes (CHD1, GREB1 and KPNA2) were involved in the regulation of estrogen promoted cell proliferation. Depletion of either CHD1, GREB1 or KPNA2 significantly abrogated the enhanced growth of ER+ breast cancer cells due to miR-26 depletion. We further demonstrated that estrogen stimulated c-MYC expression was both sufficient and necessary for the diminished expression of miR-26a and miR-26b. CONCLUSIONS: We have identified a novel estrogen/MYC/miR-26 axis that mediates estrogen stimulated cell growth via CHD1, GREB1 and KPNA2.
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Proliferación Celular/efectos de los fármacos , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Estrógenos/farmacología , MicroARNs/genética , Proteínas de Neoplasias/genética , alfa Carioferinas/genética , Animales , Western Blotting , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , ADN Helicasas/metabolismo , Proteínas de Unión al ADN/metabolismo , Estradiol/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células MCF-7 , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Interferencia de ARN , Receptores de Estrógenos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ensayos Antitumor por Modelo de Xenoinjerto , alfa Carioferinas/metabolismoRESUMEN
Accumulated evidence emerges that dynamic changes in human gut microbiota and microbial metabolites can alter the ecological balance of symbiotic hosts. The gut microbiota plays a role in various diseases through different mechanisms. More and more attention has been paid to the effects that human microbiota extends beyond the gut. This review summarized the current understanding of the roles that gut microbiota plays in hematopoietic regulation and the occurrence and development of benign and malignant hematologic diseases. The progress of the application of microbiota in treatment was discussed in order to provide new insights into clinical diagnosis and treatment in the future.
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Leukemias are refractory hematological malignancies, characterized by marked intrinsic heterogeneity which poses significant obstacles to effective treatment. However, traditional bulk sequencing techniques have not been able to effectively unravel the heterogeneity among individual tumor cells. With the emergence of single-cell sequencing technology, it has bestowed upon us an unprecedented resolution to comprehend the mechanisms underlying leukemogenesis and drug resistance across various levels, including the genome, epigenome, transcriptome and proteome. Here, we provide an overview of the currently prevalent single-cell sequencing technologies and a detailed summary of single-cell studies conducted on leukemia, with a specific focus on four key aspects: (1) leukemia's clonal architecture, (2) frameworks to determine leukemia subtypes, (3) tumor microenvironment (TME) and (4) the drug-resistant mechanisms of leukemia. This review provides a comprehensive summary of current single-cell studies on leukemia and highlights the markers and mechanisms that show promising clinical implications for the diagnosis and treatment of leukemia.
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Acute myeloid leukemia (AML) is an aggressive and heterogeneous hematologic malignancy. In elderly patients, AML incidence is high and has a poor prognosis due to a lack of effective therapies. G protein-coupled receptors (GPCR) play integral roles in physiologic processes and human diseases. Particularly, one third of adhesion GPCRs, the second largest group of GPCRs, are highly expressed in hematopoietic stem and progenitor cells or lineage cells. Here, we investigate the role of adhesion GPCRs in AML and whether they could be harnessed as antileukemia targets. Systematic screening of the impact of adhesion GPCRs on AML functionality by bioinformatic and functional analyses revealed high expression of ADGRE2 in AML, particularly in leukemic stem cells, which is associated with poor patient outcomes. Silencing ADGRE2 not only exerts antileukemic effects in AML cell lines and cells derived from patients with AML in vitro, but also delays AML progression in xenograft models in vivo. Mechanistically, ADGRE2 activates phospholipase Cß/protein kinase C/MEK/ERK signaling to enhance the expression of AP1 and transcriptionally drive the expression of DUSP1, a protein phosphatase. DUSP1 dephosphorylates Ser16 in the J-domain of the co-chaperone DNAJB1, which facilitates the DNAJB1-HSP70 interaction and maintenance of proteostasis in AML. Finally, combined inhibition of MEK, AP1, and DUSP1 exhibits robust therapeutic efficacy in AML xenograft mouse models. Collectively, this study deciphers the roles and mechanisms of ADGRE2 in AML and provides a promising therapeutic strategy for treating AML. Significance: Increased expression of the adhesion GPCR member ADGRE2 in AML supports leukemia stem cell self-renewal and leukemogenesis by modulating proteostasis via an MEK/AP1/DUSP1 axis, which can be targeted to suppress AML progression.
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Leucemia Mieloide Aguda , Receptores Acoplados a Proteínas G , Animales , Humanos , Ratones , Línea Celular Tumoral , Proliferación Celular , Progresión de la Enfermedad , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/genética , Ratones Endogámicos NOD , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Proteostasis , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Aging of hematopoietic stem cells (HSCs) is accompanied by impaired self-renewal ability, myeloid skewing, immunodeficiencies and increased susceptibility to malignancies. Although previous studies highlighted the pivotal roles of individual metabolites in hematopoiesis, comprehensive and high-resolution metabolomic profiles of different hematopoietic cells across ages are still lacking. In this study, we created a metabolome atlas of different blood cells across ages in mice. We reveal here that purine, pyrimidine and retinol metabolism are enriched in young hematopoietic stem and progenitor cells (HSPCs), whereas glutamate and sphingolipid metabolism are concentrated in aged HSPCs. Through metabolic screening, we identified uridine as a potential regulator to rejuvenate aged HSPCs. Mechanistically, uridine treatment upregulates the FoxO signaling pathway and enhances self-renewal while suppressing inflammation in aged HSCs. Finally, we constructed an open-source platform for public easy access and metabolomic analysis in blood cells. Collectively, we provide a resource for metabolic studies in hematopoiesis that can contribute to future anti-aging metabolite screening.
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Leukemia is a kind of hematological malignancy originating from bone marrow, which provides essential signals for initiation, progression, and recurrence of leukemia. However, how to specifically deliver drugs to the bone marrow remains elusive. Here, we develop biomimetic vesicles by infusing hematopoietic stem and progenitor cell (HSPC) membrane with liposomes (HSPC liposomes), which migrate to the bone marrow of leukemic mice via hyaluronic acid-CD44 axis. Moreover, the biomimetic vesicles exhibit superior binding affinity to leukemia cells through intercellular cell adhesion molecule-1 (ICAM-1)/integrin ß2 (ITGB2) interaction. Further experiments validate that the vesicles carrying chemotherapy drug cytarabine (Ara-C@HSPC-Lipo) markedly inhibit proliferation, induce apoptosis and differentiation of leukemia cells, and decrease number of leukemia stem cells. Mechanically, RNA-seq reveals that Ara-C@HSPC-Lipo treatment induces apoptosis and differentiation and inhibits the oncogenic pathways. Finally, we verify that HSPC liposomes are safe in mice. This study provides a method for targeting bone marrow and treating leukemia.
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Apoptosis , Médula Ósea , Citarabina , Sistemas de Liberación de Medicamentos , Células Madre Hematopoyéticas , Leucemia , Liposomas , Animales , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Ratones , Citarabina/farmacología , Médula Ósea/efectos de los fármacos , Médula Ósea/patología , Médula Ósea/metabolismo , Apoptosis/efectos de los fármacos , Leucemia/tratamiento farmacológico , Leucemia/patología , Humanos , Diferenciación Celular/efectos de los fármacos , Membrana Celular/metabolismo , Membrana Celular/efectos de los fármacos , Línea Celular Tumoral , Antígenos CD18/metabolismo , Proliferación Celular/efectos de los fármacos , Receptores de Hialuranos/metabolismo , Ácido Hialurónico/química , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Células Madre Neoplásicas/metabolismoRESUMEN
Microplastics (MPs) are contaminants ubiquitously found in the global biosphere that enter the body through inhalation or ingestion, posing significant risks to human health. Recent studies emerge that MPs are present in the bone marrow and damage the hematopoietic system. However, it remains largely elusive about the specific mechanisms by which MPs affect hematopoietic stem cells (HSCs) and their clinical relevance in HSC transplantation (HSCT). Here, we established a long-term MPs intake mouse model and found that MPs caused severe damage to the hematopoietic system. Oral gavage administration of MPs or fecal transplantation of microbiota from MPs-treated mice markedly undermined the self-renewal and reconstitution capacities of HSCs. Mechanistically, MPs did not directly kill HSCs but disrupted gut structure and permeability, which eventually ameliorated the abundance of Rikenellaceae and hypoxanthine in the intestine and inactivated the HPRT-Wnt signaling in bone marrow HSCs. Furthermore, administration of Rikenellaceae or hypoxanthine in mice as well as treatment of WNT10A in the culture system substantially rescued the MPs-induced HSC defects. Finally, we validated in a cohort of human patients receiving allogenic HSCT from healthy donors, and revealed that the survival time of patients was negatively correlated with levels of MPs, while positively with the abundance of Rikenellaceae, and hypoxanthine in the HSC donors' feces and blood. Overall, our study unleashes the detrimental roles and mechanisms of MPs in HSCs, which provides potential strategies to prevent hematopoietic damage from MPs and serves as a fundamental critique for selecting suitable donors for HSCT in clinical practice.
RESUMEN
RNA-binding proteins (RBPs) are pivotal in acute myeloid leukaemia (AML), a lethal disease. Although specific phase separation-competent RBPs are recognized in AML, the effect of their condensate formation on AML leukaemogenesis, and the therapeutic potential of inhibition of phase separation are underexplored. In our in vivo CRISPR RBP screen, fibrillarin (FBL) emerges as a crucial nucleolar protein that regulates AML cell survival, primarily through its phase separation domains rather than methyltransferase or acetylation domains. These phase separation domains, with specific features, coordinately drive nucleoli formation and early processing of pre-rRNA (including efflux, cleavage and methylation), eventually enhancing the translation of oncogenes such as MYC. Targeting the phase separation capability of FBL with CGX-635 leads to elimination of AML cells, suggesting an additional mechanism of action for CGX-635 that complements its established therapeutic effects. We highlight the potential of PS modulation of critical proteins as a possible therapeutic strategy for AML.