RESUMEN
Although multiple myeloma (MM) responds well to immunotherapeutic treatment, certain portions of MM are still unresponsive or relapse after immunotherapy. Other immune molecules are needed for the immunotherapy of MM. Here, we revealed that leukocyte immunoglobulin-like receptor B4 (LILRB4) was highly expressed in multiple myeloma cell lines and patient samples and that the expression of LILRB4 was adversely correlated with the overall survival of MM patients. Knockdown of LILRB4 efficiently delayed the growth of MM cells both in vitro and in vivo. Mechanistically, IKZF1 transactivated LILRB4 expression to trigger the downstream of STAT3-PFKFB1 pathways to support MM cell proliferation. Blockade of LILRB4 signaling by blocking antibodies can effectively inhibit MM progression. Our data show that targeting LILRB4 is potentially an additional therapeutic strategy for the immunotherapeutic treatment of MM.
Asunto(s)
Mieloma Múltiple , Receptores Inmunológicos , Factor de Transcripción STAT3 , Transducción de Señal , Mieloma Múltiple/patología , Mieloma Múltiple/metabolismo , Mieloma Múltiple/genética , Humanos , Factor de Transcripción STAT3/metabolismo , Animales , Línea Celular Tumoral , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Ratones , Proliferación Celular , Factor de Transcripción Ikaros/metabolismo , Factor de Transcripción Ikaros/genética , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Femenino , Regulación Neoplásica de la Expresión Génica , MasculinoRESUMEN
BACKGROUND: There is a dearth of research combining geographical big data on medical resource allocation and growth with various statistical data. Given the recent achievements of China in economic development and healthcare, this study takes China as an example to investigate the dynamic geographical distribution patterns of medical resources, utilizing data on healthcare resources from 290 cities in China, as well as economic and population-related data. The study aims to examine the correlation between economic growth and spatial distribution of medical resources, with the ultimate goal of providing evidence for promoting global health equity. METHODS: The data used in this study was sourced from the China City Statistical Yearbook from 2001 to 2020. Two indicators were employed to measure medical resources: the number of doctors per million population and the number of hospital and clinic beds per million population. We employed dynamic convergence model and fixed-effects model to examine the correlation between economic growth and the spatial distribution of medical resources. Ordinary least squares (OLS) were used to estimate the ß values of the samples. RESULTS: The average GDP for all city samples across all years was 36,019.31 ± 32,029.36, with an average of 2016.31 ± 1104.16 doctors per million people, and an average of 5986.2 ± 6801.67 hospital beds per million people. In the eastern cities, the average GDP for all city samples was 47,672.71 ± 37,850.77, with an average of 2264.58 ± 1288.89 doctors per million people, and an average of 3998.92 ± 1896.49 hospital beds per million people. Cities with initially low medical resources experienced faster growth (all ß < 0, P < 0.001). The long-term convergence rate of the geographic distribution of medical resources in China was higher than the short-term convergence rate (|ßi + 1| > |ßi|, i = 1, 2, 3, , 9, all ß < 0, P < 0.001), and the convergence speed of doctor density exceeded that of bed density (bed: |ßi| >doc: |ßi|, i = 3, 4, 5, , 10, P < 0.001). Economic growth significantly affected the convergence speed of medical resources, and this effect was nonlinear (doc: ßi < 0, i = 1, 2, 3, , 9, P < 0.05; bed: ßi < 0, i = 1, 2, 3, , 10, P < 0.01). The heterogeneity between provinces had a notable impact on the convergence of medical resources. CONCLUSIONS: The experiences of China have provided significant insights for nations worldwide. Governments and institutions in all countries worldwide, should actively undertake measures to actively reduce health inequalities. This includes enhancing healthcare standards in impoverished regions, addressing issues of unequal distribution, and emphasizing the examination of social determinants of health within the domain of public health research.
Asunto(s)
Desarrollo Económico , Instituciones de Salud , Humanos , Hospitales , China , CiudadesRESUMEN
BACKGROUND: Current research lacks examination of the relationship between different subtypes of hearing loss (HL) and cognitive decline (CD). Additionally, the co-effects of HL and depression on CD remain unexplored. This study aims to investigate the relationship between HL, various types of HL, and CD, as well as the combined impact of HL and depression on CD. METHODS: Data from a total of 5218 older adults who participated in the most recent three waves of Chinese Longitudinal Healthy Longevity Survey (CLHLS) (2011-2012, 2014, and 2018) were included. HL was assessed through self-report and objective measures. CD was defined as a decrease in MMSE score of≥3 between any two survey periods for older adults. Cox proportional hazards model was applied to analyzed. RESULTS: Among Chinese older adults, bilateral HL (HR = 1.202, 95%CI = 1.093-1.322, P < 0.001), onset of HL after the age of 40 (HR = 1.155, 95%CI = 1.056-1.264, P = 0.002), and chronic HL (HR = 1.143, 95%CI = 1.040-1.255, P = 0.005) posed a greater risk. HL (HR = 1.146, 95%CI = 1.048-1.254, P = 0.003) and depression (HR = 1.162, 95%CI = 1.038-1.301, P = 0.009) were independently or jointly associated with CD. Participants who were simultaneously exposed to both HL and depression experienced the highest risk of CD (HR = 1.314, 95%CI = 1.117-1.545, P = 0.001). LIMITATIONS: Given the observational design, unidentified confounding variables may still be present, such as whether to wear a hearing aid. CONCLUSION: This study emphasizes the high risk of specific types of HL for CD and the importance of implementing health interventions that address both physiological and psychological aspects to enhance cognitive function and prevent CD in older adults.
Asunto(s)
Disfunción Cognitiva , Pérdida Auditiva , Anciano , Humanos , China/epidemiología , Cognición , Disfunción Cognitiva/diagnóstico , Depresión/epidemiología , Pérdida Auditiva/epidemiología , Pérdida Auditiva/complicaciones , Pérdida Auditiva/diagnósticoRESUMEN
ABSTRACT: Acute myeloid leukemia (AML) is an aggressive hematological malignancy originating from transformed hematopoietic stem or progenitor cells. AML prognosis remains poor owing to resistance and relapse driven by leukemia stem cells (LSCs). Targeting molecules essential for LSC function is a promising therapeutic approach. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is often dysregulated in AML. We found that although PI3Kγ is highly enriched in LSCs and critical for self-renewal, it was dispensable for normal hematopoietic stem cells. Mechanistically, PI3Kγ-AKT signaling promotes nuclear factor erythroid 2-related factor 2 (NRF2) nuclear accumulation, which induces 6-phosphogluconate dehydrogenase (PGD) and the pentose phosphate pathway, thereby maintaining LSC stemness. Importantly, genetic or pharmacological inhibition of PI3Kγ impaired expansion and stemness of murine and human AML cells in vitro and in vivo. Together, our findings reveal a key role for PI3Kγ in selectively maintaining LSC function by regulating AKT-NRF2-PGD metabolic pathway. Targeting the PI3Kγ pathway may, therefore, eliminate LSCs without damaging normal hematopoiesis, providing a promising therapeutic strategy for AML.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase Ib , Leucemia Mieloide Aguda , Células Madre Neoplásicas , Vía de Pentosa Fosfato , Animales , Humanos , Ratones , Autorrenovación de las Células , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Fosfatidilinositol 3-Quinasa Clase Ib/genética , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/genética , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Vía de Pentosa Fosfato/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de SeñalRESUMEN
PURPOSE: The bone marrow niche plays an important role in leukemia development. However, the contributions of different niche components to leukemia development and their underlying mechanisms remain largely unclear. METHOD: Cre/LoxP-based conditional knockout technology was used to delete VPS33B or ANGPTL2 gene in niche cells. Murine B-ALL model was established by overexpressing the N-Myc oncogene in hematopoietic stem progenitor cells. The frequency of leukemia cells and immunophenotypic B220+ CD43+ LICs was detected by flow cytometry. SEVs was isolated by sequential centrifugation and mass spectrometry was performed to analyze the different components of SEVs. Immunoprecipitation and western blot were used to measure the interaction of VPS33B and ANGPTL2. RESULTS: Here, we showed that specific knockout of vascular protein sorting 33b (Vps33b) in endothelial cells (ECs), but not megakaryocytes or mesenchymal stem cells, resulted in a significant decrease in the secretion of small extracellular vesicles (SEVs) and a delay in the development of B-cell lymphoblastic leukemia (B-ALL). Vps33b knockdown endothelial cells contained much lower levels of SEVs that contained angiopoietin-like protein 2 (ANGPTL2) than the control cells. Importantly, conditional knockout of Angptl2 in ECs significantly delayed B-ALL progression. Moreover, C-terminal region of ANGPTL2 (aa247-471) could directly interact with Sec1-like domain 1 of VPS33B (aa1-aa146). We further demonstrated that the point mutations R399H and G402S in ANGPTL2 led to a dramatic decrease in the secretion of ANGPTL2-SEVs. We also showed that wild-type ANGPTL2-containing SEVs, but not mutant ANGPTL2-containing SEVs, significantly enhanced B-ALL development. CONCLUSION: In summary, our findings indicate that the secretion of ANGPTL2-containing SEVs in ECs sustains the leukemogenic activities of B-ALL cells, which is fine-tuned by the direct interaction of VPS33B and ANGPTL2. These findings reveal that niche-specific SEVs play an important role in B-ALL development.
Asunto(s)
Vesículas Extracelulares , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Ratones , Animales , Células Endoteliales/metabolismo , Proteína 2 Similar a la Angiopoyetina , Transporte de Proteínas , Proteínas de Transporte Vesicular/metabolismoRESUMEN
OBJECTIVES: Our research intended to explore the association and mediators (perceived social support and sleep quality) between the impact of oral health-related quality of life (OHRQoL) and depression among Chinese older adults. METHODS: A stratified, multi-stage random sampling approach was used in our study. A total of 3896 older individuals aged 60 years and older were included. Process macro 3.5 for SPSS was utilized for testing mediation hypotheses. RESULTS: The mean score of the OHRQoL of the elderly was 3.26 ± 7.15. The correlation coefficient between OHRQoL and depression was 0.25 (p < 0.001). Perceived social support (ß = 0.009, 95% CI = 0.006, 0.012) and sleep quality (ß = 0.073, 95% CI = 0.074, 0.093) mediated the relationship between OHRQoL and depression, respectively. The association between OHRQoL and depression was mediated sequentially by perceived social support and sleep quality (ß = 0.004, 95% CI = 0.002, 0.006). CONCLUSIONS: The participants reported relatively good OHRQoL. OHRQoL and depression showed a significant positive correlation. The relationship between OHRQoL and depression among Chinese seniors was mediated by perceived social support and sleep quality. Both directly and indirectly, OHRQoL can affect depression.
RESUMEN
Rewiring of redox metabolism has a profound impact on tumor development, but how the cellular heterogeneity of redox balance affects leukemogenesis remains unknown. To precisely characterize the dynamic change in redox metabolism in vivo, we developed a bright genetically encoded biosensor for H2O2 (named HyPerion) and tracked the redox state of leukemic cells in situ in a transgenic sensor mouse. A H2O2-low (HyPerion-low) subset of acute myeloid leukemia (AML) cells was enriched with leukemia-initiating cells, which were endowed with high colony-forming ability, potent drug resistance, endosteal rather than vascular localization, and short survival. Significantly high expression of malic enzymes, including ME1/3, accounted for nicotinamide adenine dinucleotide phosphate (NADPH) production and the subsequent low abundance of H2O2. Deletion of malic enzymes decreased the population size of leukemia-initiating cells and impaired their leukemogenic capacity and drug resistance. In summary, by establishing an in vivo redox monitoring tool at single-cell resolution, this work reveals a critical role of redox metabolism in leukemogenesis and a potential therapeutic target.
Asunto(s)
Peróxido de Hidrógeno , Leucemia Mieloide Aguda , Ratones , Animales , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Oxidación-Reducción , Ratones Transgénicos , Resistencia a Antineoplásicos/genéticaRESUMEN
BACKGROUND: Oligodendrocytes have robust regenerative ability and are key players in remyelination during physiological and pathophysiological states. However, the mechanisms of brain microenvironmental cue in regulation of the differentiation of oligodendrocytes still needs to be further investigated. RESULTS: We demonstrated that myelin-associated glycoprotein (MAG) was a novel receptor for angiopoietin-like protein 2 (ANGPTL2). The binding of ANGPTL2 to MAG efficiently promoted the differentiation of oligodendrocytes in vitro, as evaluated in an HCN cell line. Angptl2-null mice had a markedly impaired myelination capacity in the early stage of oligodendrocyte development. These mice had notably decreased remyelination capacities and enhanced motor disability in a cuprizone-induced demyelinating mouse model, which was similar to the Mag-null mice. The loss of remyelination ability in Angptl2-null/Mag-null mice was similar to the Angptl2-WT/Mag-null mice, which indicated that the ANGPTL2-mediated oligodendrocyte differentiation effect depended on the MAG receptor. ANGPTL2 bound MAG to enhance its phosphorylation level and recruit Fyn kinase, which increased Fyn phosphorylation levels, followed by the transactivation of myelin regulatory factor (MYRF). CONCLUSION: Our study demonstrated an unexpected cross-talk between the environmental protein (ANGPTL2) and its surface receptor (MAG) in the regulation of oligodendrocyte differentiation, which may benefit the treatment of many demyelination disorders, including multiple sclerosis.
RESUMEN
How bone marrow niches regulate leukemogenic activities of leukemia-initiating cells (LICs) is unclear. The present study revealed that the metabolic niche component, ATP, efficiently induced ion influx in LICs through its ligand-gated ion channel, P2X1. P2X1 deletion impaired LIC self-renewal capacities and resulted in an approximately 8-fold decrease in functional LIC numbers in a murine acute myeloid leukemia (AML) model without affecting normal hematopoiesis. P2X1 phosphorylation at specific sites of S387 and T389 was essential for sustaining its promoting effects on leukemia development. ATP-P2X1-mediated signaling upregulated the PBX3 level to transactivate BCAT1 to maintain LIC fates. P2X1 knockdown inhibited the proliferation of both human AML cell lines and primary cells. The P2X1 antagonist sufficiently suppressed AML cell proliferation. These results provided a unique perspective on how metabolic niche factor ATP fine-tunes LIC activities, which may benefit the development of strategies for targeting LICs or other cancer stem cells.
Asunto(s)
Leucemia Mieloide Aguda , Ratones , Humanos , Animales , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Médula Ósea/metabolismo , Transducción de Señal , Carcinogénesis , Adenosina Trifosfato , Transaminasas/metabolismoRESUMEN
During the early phase of primary humoral responses, activated B cells can differentiate into different types of effector cells, dependent on B cell receptor affinity for antigen. However, the pivotal transcription factors governing these processes remain to be elucidated. Here, we show that transcription factor Bach2 protein in activated B cells is transiently induced by affinity-related signals and mechanistic target of rapamycin complex 1 (mTORC1)-dependent translation to restrain their expansion and differentiation into plasma cells while promoting memory and germinal center (GC) B cell fates. Affinity-related signals also downregulate Bach2 mRNA expression in activated B cells and their descendant memory B cells. Sustained and higher concentrations of Bach2 antagonize the GC fate. Repression of Bach2 in memory B cells predisposes their cell-fate choices upon memory recall. Our study reveals that differential dynamics of Bach2 protein and transcripts in activated B cells control their cell-fate outcomes and imprint the fates of their descendant effector cells.
Asunto(s)
Linfocitos B , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Diferenciación Celular/genética , Centro Germinal , ARN/metabolismo , Factores de Transcripción/metabolismoRESUMEN
The mechanism by which redox metabolism regulates the fates of acute myeloid leukemia (AML) cells remains largely unknown. Using a highly sensitive, genetically encoded fluorescent sensor of nicotinamide adenine dinucleotide phosphate (NADPH), iNap1, we find three heterogeneous subpopulations of AML cells with different cytosolic NADPH levels in an MLL-AF9-induced murine AML model. The iNap1-high AML cells have enhanced proliferation capacities both in vitro and in vivo and are enriched for more functional leukemia-initiating cells than iNap1-low counterparts. The iNap1-high AML cells prefer localizing in the bone marrow endosteal niche and are resistant to methotrexate treatment. Furthermore, iNap1-high human primary AML cells have enhanced proliferation abilities both in vitro and in vivo. Mechanistically, the MTHFD1-mediated folate cycle regulates NADPH homeostasis to promote leukemogenesis and methotrexate resistance. These results provide important clues for understanding mechanisms by which redox metabolism regulates cancer cell fates and a potential metabolic target for AML treatments.
Asunto(s)
Resistencia a Antineoplásicos , Leucemia Mieloide Aguda , NADP , Animales , Médula Ósea/metabolismo , Resistencia a Antineoplásicos/fisiología , Humanos , Leucemia Mieloide Aguda/metabolismo , Metotrexato/farmacología , Ratones , NADP/metabolismoRESUMEN
Bone marrow niche cells have been reported to fine-tune hematopoietic stem cell (HSC) stemness via direct interaction or secreted components. Nevertheless, how niche cells control HSC activities remains largely unknown. We previously showed that angiopoietin-like protein 2 (ANGPTL2) can support the ex vivo expansion of HSCs by binding to human leukocyte immunoglobulin-like receptor B2. However, how ANGPTL2 from specific niche cell types regulates HSC activities under physiological conditions is still not clear. Herein, we generated an Angptl2-flox/flox transgenic mouse line and conditionally deleted Angptl2 expression in several niche cells, including Cdh5+ or Tie2+ endothelial cells, Prx1+ mesenchymal stem cells, and Pf4+ megakaryocytes, to evaluate its role in the regulation of HSC fate. Interestingly, we demonstrated that only endothelial cell-derived ANGPTL2 and not ANGPTL2 from other niche cell types plays important roles in supporting repopulation capacity, quiescent status, and niche localization. Mechanistically, ANGPTL2 enhances peroxisome-proliferator-activated receptor D (PPARD) expression to transactivate G0s2 to sustain the perinuclear localization of nucleolin to prevent HSCs from entering the cell cycle. These findings reveal that endothelial cell-derived ANGPTL2 serves as a critical niche component to maintain HSC stemness, which may benefit the understanding of stem cell biology in bone marrow niches and the development of a unique strategy for the ex vivo expansion of HSCs.
Asunto(s)
Proteína 2 Similar a la Angiopoyetina/metabolismo , Médula Ósea , Animales , Médula Ósea/metabolismo , Células de la Médula Ósea , Células Endoteliales , Células Madre Hematopoyéticas/metabolismo , Ratones , Nicho de Células MadreRESUMEN
How metabolic status controls the fates of different types of leukemia cells remains elusive. Using a SoNar-transgenic mouse line, we demonstrated that B cell acute lymphoblastic leukemia (B-ALL) cells had a preference in using oxidative phosphorylation. B-ALL cells with a low SoNar ratio (SoNar-low) had enhanced mitochondrial respiration capacity, mainly resided in the vascular niche, and were enriched with more functional leukemia-initiating cells than that of SoNar-high cells in a murine B-ALL model. The SoNar-low cells were more resistant to cytosine arabinoside (Ara-C) treatment. cyclic adenosine 3',5'-monophosphate response element-binding protein transactivated pyruvate dehydrogenase complex component X and cytidine deaminase to maintain the oxidative phosphorylation level and Ara-C-induced resistance. SoNar-low human primary B-ALL cells also had a preference for oxidative phosphorylation. Suppressing oxidative phosphorylation with several drugs sufficiently attenuated Ara-C-induced resistance. Our study provides a unique angle for understanding the potential connections between metabolism and B-ALL cell fates.
Asunto(s)
Fosforilación Oxidativa , Leucemia-Linfoma Linfoblástico de Células Precursoras , Animales , Citarabina/metabolismo , Citarabina/farmacología , Citidina Desaminasa/genética , Citidina Desaminasa/metabolismo , Ratones , Ratones TransgénicosRESUMEN
Small extracellular vesicles (SEVs) are functional messengers of certain cellular niches that permit noncontact cell communications. Whether niche-specific SEVs fulfill this role in cancer is unclear. Here, we used 7 cell type-specific mouse Cre lines to conditionally knock out Vps33b in Cdh5+ or Tie2+ endothelial cells (ECs), Lepr+ BM perivascular cells, Osx+ osteoprogenitor cells, Pf4+ megakaryocytes, and Tcf21+ spleen stromal cells. We then examined the effects of reduced SEV secretion on progression of MLL-AF9-induced acute myeloid leukemia (AML), as well as normal hematopoiesis. Blocking SEV secretion from ECs, but not perivascular cells, megakaryocytes, or spleen stromal cells, markedly delayed the leukemia progression. Notably, reducing SEV production from ECs had no effect on normal hematopoiesis. Protein analysis showed that EC-derived SEVs contained a high level of ANGPTL2, which accelerated leukemia progression via binding to the LILRB2 receptor. Moreover, ANGPTL2-SEVs released from ECs were governed by VPS33B. Importantly, ANGPTL2-SEVs were also required for primary human AML cell maintenance. These findings demonstrate a role of niche-specific SEVs in cancer development and suggest targeting of ANGPTL2-SEVs from ECs as a potential strategy to interfere with certain types of AML.
Asunto(s)
Proteínas Similares a la Angiopoyetina/metabolismo , Células Endoteliales/metabolismo , Vesículas Extracelulares/metabolismo , Leucemia Mieloide Aguda/metabolismo , Proteínas de Neoplasias/metabolismo , Proteína 2 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina/genética , Animales , Células Endoteliales/patología , Vesículas Extracelulares/genética , Vesículas Extracelulares/patología , Técnicas de Inactivación de Genes , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Ratones , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Proteínas de Neoplasias/genéticaRESUMEN
How particular bone marrow niche factors contribute to the leukemogenic activities of leukemia-initiating cells (LICs) remains largely unknown. Here, we showed that ATP levels were markedly increased in the bone marrow niches of mice with acute myeloid leukemia (AML), and LICs preferentially localized to the endosteal niche with relatively high ATP levels, as indicated by a sensitive ATP indicator. ATP could efficiently induce the influx of ions into LICs in an MLL-AF9-induced murine AML model via the ligand-gated ion channel P2X7. P2x7 deletion led to notably impaired homing and self-renewal capacities of LICs and contributed to an approximately 5-fold decrease in the number of functional LICs but had no effect on normal hematopoiesis. ATP/P2X7 signaling enhanced the calcium flux-mediated phosphorylation of CREB, which further transactivated phosphoglycerate dehydrogenase (Phgdh) expression to maintain serine metabolism and LIC fates. P2X7 knockdown resulted in a markedly extended survival of recipients transplanted with either human AML cell lines or primary leukemia cells. Blockade of ATP/P2X7 signaling could efficiently inhibit leukemogenesis. Here, we provide a perspective for understanding how ATP/P2X7 signaling sustains LIC activities, which may benefit the development of specific strategies for targeting LICs or other types of cancer stem cells.
Asunto(s)
Adenosina Trifosfato/metabolismo , Médula Ósea/metabolismo , Leucemia Mieloide Aguda/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Experimentales , Células Madre Neoplásicas/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Microambiente Tumoral , Adenosina Trifosfato/genética , Animales , Humanos , Leucemia Mieloide Aguda/genética , Ratones , Ratones Noqueados , Proteínas de Neoplasias/genética , Receptores Purinérgicos P2X7/genética , Transducción de Señal/genéticaRESUMEN
The connections between energy metabolism and stemness of hematopoietic stem cells (HSCs) at different developmental stages remain largely unknown. We generated a transgenic mouse line for the genetically encoded NADH/NAD+ sensor (SoNar) and demonstrate that there are 3 distinct fetal liver hematopoietic cell populations according to the ratios of SoNar fluorescence. SoNar-low cells had an enhanced level of mitochondrial respiration but a glycolytic level similar to that of SoNar-high cells. Interestingly, 10% of SoNar-low cells were enriched for 65% of total immunophenotypic fetal liver HSCs (FL-HSCs) and contained approximately fivefold more functional HSCs than their SoNar-high counterparts. SoNar was able to monitor sensitively the dynamic changes of energy metabolism in HSCs both in vitro and in vivo. Mechanistically, STAT3 transactivated MDH1 to sustain the malate-aspartate NADH shuttle activity and HSC self-renewal and differentiation. We reveal an unexpected metabolic program of FL-HSCs and provide a powerful genetic tool for metabolic studies of HSCs or other types of stem cells.
Asunto(s)
Células Madre Hematopoyéticas/metabolismo , Metabolómica/métodos , Imagen Óptica/métodos , Animales , Ácido Aspártico/metabolismo , Feto , Células Madre Hematopoyéticas/citología , Hígado/citología , Malatos/metabolismo , Ratones , Ratones Transgénicos , NAD/análisisRESUMEN
One of the bottlenecks of the treatments for malignant hematopoietic disorders is the unavailability of sufficient amount of hematopoietic stem cells (HSCs). HSCs are considered to be originated from the aorta-gonad-mesonephros and gradually migrates into fetal liver and resides in a unique microenvironment/niche of bone marrow. Although many intrinsic and extrinsic factors (niche components) are reported to be involved in the origination, maturation, migration, and localization of HSCs at different developmental stages, the detailed molecular mechanisms still remain largely unknown. Previous studies have shown that intrinsic metabolic networks may be critical for the cell fate determinations of HSCs. For example, HSCs mainly utilize glycolysis as the main energy sources; oxidative phosphorylation is required for the homeostasis of HSCs; lipid or amino acid metabolisms may also sustain HSC stemness. Mechanistically, lots of regulatory pathways, such as MEIS1/HIF1A and PI3K/AKT/mTOR signaling, are found to fine-tune the different nutrient metabolisms and cell fate commitments of HSCs. However, more efforts are required for the optimization and establishment of precise metabolic techniques specific for the HSCs with relatively rare cell frequency and understanding of the basic metabolic properties and their underlying regulatory mechanisms of different nutrients (such as glucose) during the different developmental stages of HSCs.
Asunto(s)
Diferenciación Celular , Células Madre Hematopoyéticas , Transducción de Señal , Médula Ósea/metabolismo , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , HumanosRESUMEN
The metabolic properties of leukemia-initiating cells (LICs) in distinct bone marrow niches and their relationships to cell-fate determinations remain largely unknown. Using a metabolic imaging system with a highly responsive genetically encoded metabolic sensor, SoNar, we reveal that SoNar-high cells are more glycolytic, enriched for higher LIC frequency, and develop leukemia much faster than SoNar-low counterparts in an MLL-AF9-induced murine acute myeloid leukemia model. SoNar-high cells mainly home to and locate in the hypoxic endosteal niche and maintain their activities through efficient symmetric division. SoNar can indicate the dynamics of metabolic changes of LICs in the endosteal niche. SoNar-high human leukemia cells or primary samples have enhanced clonogenic capacities in vitro or leukemogenesis in vivo. PDK2 fine-tunes glycolysis, homing, and symmetric division of LICs. These findings provide a unique angle for the study of metabolisms in stem cells, and may lead to development of novel strategies for cancer treatment.
Asunto(s)
Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Nicho de Células Madre , Animales , División Celular , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones SCID , Ratones TransgénicosRESUMEN
Hematopoietic stem cells (HSCs) are considered to originate from the aorta-gonad-mesonephros, migrate into fetal liver for a rapid expansion, and eventually reside into a unique hypoxic bone marrow niche, where they maintain their homeostasis throughout their life span. HSCs have been widely used for the treatment of many begin or malignant hematopoietic disorders. However, the unavailability of sufficient amount of HSCs still impedes their applications in the clinic. It is urgent to understand how HSC stemness or cell fates are determined at different developmental stages. Although many intrinsic and extrinsic factors (niche components) have been identified in the regulation of HSC origination, expansion, migration, and localization, the underlying mechanisms remain largely unknown. In this article, we summarize current views on the metabolic profiles of HSCs and related regulatory networks, which shows that intrinsic metabolic regulation may be critical for the cell fate determinations of HSCs: HSCs utilize glycolysis as their major energy sources; mitochondrial respiration is also required for the homeostasis of HSCs; amino acids, lipids, or other nutrient metabolisms also have unique roles in sustaining HSC activities. Mechanistically, many important regulatory pathways, such as MEIS1/HIF1A, MYC, PPM1K/CDC20, and ROS signals, are identified to fine-tune the nutrient metabolisms and cell fate commitments in HSCs. Nevertheless, more effort is required for the optimization or establishment of sensitive and specific metabolic techniques/systems for the metabolism studies in HSCs with limited cell numbers and exploring the metabolic profiles and fundamental regulatory mechanisms of different types of nutrients at each developmental stage of HSCs.