Showing 1 - 12 of 167 results for "03434"
- ReferenceR. Liang et al. ( 2020) Cell stem cell 26 3 359--376.e7
Restraining Lysosomal Activity Preserves Hematopoietic Stem Cell Quiescence and Potency.
Quiescence is a fundamental property that maintains hematopoietic stem cell (HSC) potency throughout life. Quiescent HSCs are thought to rely on glycolysis for their energy, but the overall metabolic properties of HSCs remain elusive. Using combined approaches, including single-cell RNA sequencing (RNA-seq), we show that mitochondrial membrane potential (MMP) distinguishes quiescent from cycling-primed HSCs. We found that primed, but not quiescent, HSCs relied readily on glycolysis. Notably, in vivo inhibition of glycolysis enhanced the competitive repopulation ability of primed HSCs. We further show that HSC quiescence is maintained by an abundance of large lysosomes. Repression of lysosomal activation in HSCs led to further enlargement of lysosomes while suppressing glucose uptake. This also induced increased lysosomal sequestration of mitochondria and enhanced the competitive repopulation ability of primed HSCs by over 90-fold in vivo. These findings show that restraining lysosomal activity preserves HSC quiescence and potency and may be therapeutically relevant. View PublicationCatalog #: Product Name: 03434 MethoCult™ GF M3434 09600 StemSpan™ SFEM 19856 EasySep™ Mouse Hematopoietic Progenitor Cell Isolation Kit 74142 Hydrocortisone Catalog #: 03434 Product Name: MethoCult™ GF M3434 Catalog #: 09600 Product Name: StemSpan™ SFEM Catalog #: 19856 Product Name: EasySep™ Mouse Hematopoietic Progenitor Cell Isolation Kit Catalog #: 74142 Product Name: Hydrocortisone - ReferenceK. Aden et al. ( 2018) The Journal of experimental medicine 215 11 2868--2886
ATG16L1 orchestrates interleukin-22 signaling in the intestinal epithelium via cGAS-STING.
A coding variant of the inflammatory bowel disease (IBD) risk gene ATG16L1 has been associated with defective autophagy and deregulation of endoplasmic reticulum (ER) function. IL-22 is a barrier protective cytokine by inducing regeneration and antimicrobial responses in the intestinal mucosa. We show that ATG16L1 critically orchestrates IL-22 signaling in the intestinal epithelium. IL-22 stimulation physiologically leads to transient ER stress and subsequent activation of STING-dependent type I interferon (IFN-I) signaling, which is augmented in Atg16l1$\Delta$IEC intestinal organoids. IFN-I signals amplify epithelial TNF production downstream of IL-22 and contribute to necroptotic cell death. In vivo, IL-22 treatment in Atg16l1$\Delta$IEC and Atg16l1$\Delta$IEC/Xbp1$\Delta$IEC mice potentiates endogenous ileal inflammation and causes widespread necroptotic epithelial cell death. Therapeutic blockade of IFN-I signaling ameliorates IL-22-induced ileal inflammation in Atg16l1$\Delta$IEC mice. Our data demonstrate an unexpected role of ATG16L1 in coordinating the outcome of IL-22 signaling in the intestinal epithelium. View PublicationCatalog #: Product Name: 03434 MethoCult™ GF M3434 Catalog #: 03434 Product Name: MethoCult™ GF M3434 - ReferenceK. Aden et al. ( 2019) Gastroenterology 156 1 145--159.e19
Epithelial RNase H2 Maintains Genome Integrity and Prevents Intestinal Tumorigenesis in Mice.
BACKGROUND {\&} AIMS RNase H2 is a holoenzyme, composed of 3 subunits (ribonuclease H2 subunits A, B, and C), that cleaves RNA:DNA hybrids and removes mis-incorporated ribonucleotides from genomic DNA through ribonucleotide excision repair. Ribonucleotide incorporation by eukaryotic DNA polymerases occurs during every round of genome duplication and produces the most frequent type of naturally occurring DNA lesion. We investigated whether intestinal epithelial proliferation requires RNase H2 function and whether RNase H2 activity is disrupted during intestinal carcinogenesis. METHODS We generated mice with epithelial-specific deletion of ribonuclease H2 subunit B (H2b$\Delta$IEC) and mice that also had deletion of tumor-suppressor protein p53 (H2b/p53$\Delta$IEC); we compared phenotypes with those of littermate H2bfl/fl or H2b/p53fl/fl (control) mice at young and old ages. Intestinal tissues were collected and analyzed by histology. We isolated epithelial cells, generated intestinal organoids, and performed RNA sequence analyses. Mutation signatures of spontaneous tumors from H2b/p53$\Delta$IEC mice were characterized by exome sequencing. We collected colorectal tumor specimens from 467 patients, measured levels of ribonuclease H2 subunit B, and associated these with patient survival times and transcriptome data. RESULTS The H2b$\Delta$IEC mice had DNA damage to intestinal epithelial cells and proliferative exhaustion of the intestinal stem cell compartment compared with controls and H2b/p53$\Delta$IEC mice. However, H2b/p53$\Delta$IEC mice spontaneously developed small intestine and colon carcinomas. DNA from these tumors contained T{\textgreater}G base substitutions at GTG trinucleotides. Analyses of transcriptomes of human colorectal tumors associated lower levels of RNase H2 with shorter survival times. CONCLUSIONS In analyses of mice with disruption of the ribonuclease H2 subunit B gene and colorectal tumors from patients, we provide evidence that RNase H2 functions as a colorectal tumor suppressor. H2b/p53$\Delta$IEC mice can be used to study the roles of RNase H2 in tissue-specific carcinogenesis. View PublicationCatalog #: Product Name: 03434 MethoCult™ GF M3434 Catalog #: 03434 Product Name: MethoCult™ GF M3434 - ReferenceY. Zhang et al. (aug 2019) Nature communications 10 1 3667
PTPsigma inhibitors promote hematopoietic stem cell regeneration.
Receptor type protein tyrosine phosphatase-sigma (PTPsigma) is primarily expressed by adult neurons and regulates neural regeneration. We recently discovered that PTPsigma is also expressed by hematopoietic stem cells (HSCs). Here, we describe small molecule inhibitors of PTPsigma that promote HSC regeneration in vivo. Systemic administration of the PTPsigma inhibitor, DJ001, or its analog, to irradiated mice promotes HSC regeneration, accelerates hematologic recovery, and improves survival. Similarly, DJ001 administration accelerates hematologic recovery in mice treated with 5-fluorouracil chemotherapy. DJ001 displays high specificity for PTPsigma and antagonizes PTPsigma via unique non-competitive, allosteric binding. Mechanistically, DJ001 suppresses radiation-induced HSC apoptosis via activation of the RhoGTPase, RAC1, and induction of BCL-XL. Furthermore, treatment of irradiated human HSCs with DJ001 promotes the regeneration of human HSCs capable of multilineage in vivo repopulation. These studies demonstrate the therapeutic potential of selective, small-molecule PTPsigma inhibitors for human hematopoietic regeneration. View PublicationCatalog #: Product Name: 03434 MethoCult™ GF M3434 Catalog #: 03434 Product Name: MethoCult™ GF M3434 - ReferenceN. Vannini et al. (mar 2019) Cell stem cell 24 3 405--418.e7
The NAD-Booster Nicotinamide Riboside Potently Stimulates Hematopoiesis through Increased Mitochondrial Clearance.
It has been recently shown that increased oxidative phosphorylation, as reflected by increased mitochondrial activity, together with impairment of the mitochondrial stress response, can severely compromise hematopoietic stem cell (HSC) regeneration. Here we show that the NAD+-boosting agent nicotinamide riboside (NR) reduces mitochondrial activity within HSCs through increased mitochondrial clearance, leading to increased asymmetric HSC divisions. NR dietary supplementation results in a significantly enlarged pool of progenitors, without concurrent HSC exhaustion, improves survival by 80{\%}, and accelerates blood recovery after murine lethal irradiation and limiting-HSC transplantation. In immune-deficient mice, NR increased the production of human leucocytes from hCD34+ progenitors. Our work demonstrates for the first time a positive effect of NAD+-boosting strategies on the most primitive blood stem cells, establishing a link between HSC mitochondrial stress, mitophagy, and stem-cell fate decision, and unveiling the potential of NR to improve recovery of patients suffering from hematological failure including post chemo- and radiotherapy. View PublicationCatalog #: Product Name: 03434 MethoCult™ GF M3434 09600 StemSpan™ SFEM 09605 StemSpan™ SFEM II 04034 MethoCult™ H4034 Optimum 22000 STEMvision™ 02698 Human LDL Catalog #: 03434 Product Name: MethoCult™ GF M3434 Catalog #: 09600 Product Name: StemSpan™ SFEM Catalog #: 09605 Product Name: StemSpan™ SFEM II Catalog #: 04034 Product Name: MethoCult™ H4034 Optimum Catalog #: 22000 Product Name: STEMvision™ Catalog #: 02698 Product Name: Human LDL - ReferenceJ. Paris et al. (jul 2019) Cell stem cell 25 1 137--148.e6
Targeting the RNA m6A Reader YTHDF2 Selectively Compromises Cancer Stem Cells in Acute Myeloid Leukemia.
Acute myeloid leukemia (AML) is an aggressive clonal disorder of hematopoietic stem cells (HSCs) and primitive progenitors that blocks their myeloid differentiation, generating self-renewing leukemic stem cells (LSCs). Here, we show that the mRNA m6A reader YTHDF2 is overexpressed in a broad spectrum of human AML and is required for disease initiation as well as propagation in mouse and human AML. YTHDF2 decreases the half-life of diverse m6A transcripts that contribute to the overall integrity of LSC function, including the tumor necrosis factor receptor Tnfrsf2, whose upregulation in Ythdf2-deficient LSCs primes cells for apoptosis. Intriguingly, YTHDF2 is not essential for normal HSC function, with YTHDF2 deficiency actually enhancing HSC activity. Thus, we identify YTHDF2 as a unique therapeutic target whose inhibition selectively targets LSCs while promoting HSC expansion. View PublicationCatalog #: Product Name: 03231 MethoCult™ M3231 03434 MethoCult™ GF M3434 Catalog #: 03231 Product Name: MethoCult™ M3231 Catalog #: 03434 Product Name: MethoCult™ GF M3434 - ReferenceM. D. McKenzie et al. (aug 2019) Cell stem cell 25 2 258--272.e9
Interconversion between Tumorigenic and Differentiated States in Acute Myeloid Leukemia.
Tumors are composed of phenotypically heterogeneous cancer cells that often resemble various differentiation states of their lineage of origin. Within this hierarchy, it is thought that an immature subpopulation of tumor-propagating cancer stem cells (CSCs) differentiates into non-tumorigenic progeny, providing a rationale for therapeutic strategies that specifically eradicate CSCs or induce their differentiation. The clinical success of these approaches depends on CSC differentiation being unidirectional rather than reversible, yet this question remains unresolved even in prototypically hierarchical malignancies, such as acute myeloid leukemia (AML). Here, we show in murine and human models of AML that, upon perturbation of endogenous expression of the lineage-determining transcription factor PU.1 or withdrawal of established differentiation therapies, some mature leukemia cells can de-differentiate and reacquire clonogenic and leukemogenic properties. Our results reveal plasticity of CSC maturation in AML, highlighting the need to therapeutically eradicate cancer cells across a range of differentiation states. View PublicationCatalog #: Product Name: 03434 MethoCult™ GF M3434 04236 MethoCult™ SF H4236 04434 MethoCult™ H4434 Classic 09600 StemSpan™ SFEM 09605 StemSpan™ SFEM II Catalog #: 03434 Product Name: MethoCult™ GF M3434 Catalog #: 04236 Product Name: MethoCult™ SF H4236 Catalog #: 04434 Product Name: MethoCult™ H4434 Classic Catalog #: 09600 Product Name: StemSpan™ SFEM Catalog #: 09605 Product Name: StemSpan™ SFEM II - ReferenceM. A. Loberg et al. (jul 2019) Leukemia 33 7 1635--1649
Sequentially inducible mouse models reveal that Npm1 mutation causes malignant transformation of Dnmt3a-mutant clonal hematopoiesis.
Clonal hematopoiesis (CH) is a common aging-associated condition with increased risk of hematologic malignancy. Knowledge of the mechanisms driving evolution from CH to overt malignancy has been hampered by a lack of in vivo models that orthogonally activate mutant alleles. Here, we develop independently regulatable mutations in DNA methyltransferase 3A (Dnmt3a) and nucleophosmin 1 (Npm1), observed in human CH and AML, respectively. We find Dnmt3a mutation expands hematopoietic stem and multipotent progenitor cells (HSC/MPPs), modeling CH. Induction of mutant Npm1 after development of Dnmt3a-mutant CH causes progression to myeloproliferative disorder (MPD), and more aggressive MPD is observed with longer latency between mutations. MPDs uniformly progress to acute myeloid leukemia (AML) following transplant, accompanied by a decrease in HSC/MPPs and an increase in myeloid-restricted progenitors, the latter of which propagate AML in tertiary recipient mice. At a molecular level, progression of CH to MPD is accompanied by selection for mutations activating Ras/Raf/MAPK signaling. Progression to AML is characterized by additional oncogenic signaling mutations (Ptpn11, Pik3r1, Flt3) and/or mutations in epigenetic regulators (Hdac1, Idh1, Arid1a). Together, our study demonstrates that Npm1 mutation drives evolution of Dnmt3a-mutant CH to AML and rate of disease progression is accelerated with longer latency of CH. View PublicationCatalog #: Product Name: 03434 MethoCult™ GF M3434 Catalog #: 03434 Product Name: MethoCult™ GF M3434 - ReferenceJ. Lam et al. (JUN 2018) Nature communications 9 1 2418
miR-143/145 differentially regulate hematopoietic stem and progenitor activity through suppression of canonical TGFbeta$ signaling.
Expression of miR-143 and miR-145 is reduced in hematopoietic stem/progenitor cells (HSPCs) of myelodysplastic syndrome patients with a deletion in the long arm of chromosome 5. Here we show that mice lacking miR-143/145 have impaired HSPC activity with depletion of functional hematopoietic stem cells (HSCs), but activation of progenitor cells (HPCs). We identify components of the transforming growth factor beta$ (TGFbeta$) pathway as key targets of miR-143/145. Enforced expression of the TGFbeta$ adaptor protein and miR-145 target, Disabled-2 (DAB2), recapitulates the HSC defect seen in miR-143/145-/- mice. Despite reduced HSC activity, older miR-143/145-/- and DAB2-expressing mice show elevated leukocyte counts associated with increased HPC activity. A subset of mice develop a serially transplantable myeloid malignancy, associated with expansion of HPC. Thus, miR-143/145 play a cell context-dependent role in HSPC function through regulation of TGFbeta$/DAB2 activation, and loss of these miRNAs creates a preleukemic state. View PublicationCatalog #: Product Name: 03434 MethoCult™ GF M3434 Catalog #: 03434 Product Name: MethoCult™ GF M3434 - ReferenceHough MR et al. (JAN 1996) Journal of immunology (Baltimore, Md. : 1950) 156 2 479--88
Reduction of early B lymphocyte precursors in transgenic mice overexpressing the murine heat-stable antigen.
To study the role of the murine heat-stable Ag (HSA) in lymphocyte maturation, we generated transgenic mice in which the HSA cDNA was under the transcriptional control of the TCR V beta promoter and Ig mu enhancer. The HSA transgene was expressed during all stages of B lymphocyte maturation. Expression was first detected in the earliest lymphoid-committed progenitors, which normally do not express HSA, and subsequently reached the highest levels in pro- and pre-B cells. In bone marrow, the number of IL-7-responsive clonogenic progenitors was textless 4% of normal, whereas the frequency of earlier B lymphocyte-restricted precursors, detectable as Whitlock-Witte culture-initiating cells, was normal. Pro- and pre-B cells detected by flow cytometry were reduced by approximately 50% relative to controls. Mature splenic B cells were also reduced but to a lesser extent than in marrow, and their response to LPS stimulation was impaired. Reconstitution of SCID and BALB/c-nu/nu mice with HSA transgenic marrow indicated that the perturbations in B lymphopoiesis were not caused by a defective marrow microenvironment or by abnormal T cells. Our previous studies showed elevated HSA expression throughout thymocyte development, which resulted in a profound depletion of CD4+CD8+ double-positive and single-positive thymocytes. Together, these results indicate that HSA levels can determine the capacity of early T and B lymphoid progenitors to proliferate and survive. Therefore, HSA could serve as an important regulator during the early stages of B and T lymphopoiesis. View PublicationCatalog #: Product Name: 03630 MethoCult™ M3630 03134 MethoCult™ M3134 03231 MethoCult™ M3231 03234 MethoCult™ M3234 03334 MethoCult™ M3334 03434 MethoCult™ GF M3434 03236 MethoCult™ SF M3236 Catalog #: 03630 Product Name: MethoCult™ M3630 Catalog #: 03134 Product Name: MethoCult™ M3134 Catalog #: 03231 Product Name: MethoCult™ M3231 Catalog #: 03234 Product Name: MethoCult™ M3234 Catalog #: 03334 Product Name: MethoCult™ M3334 Catalog #: 03434 Product Name: MethoCult™ GF M3434 Catalog #: 03236 Product Name: MethoCult™ SF M3236 - ReferenceLemieux ME et al. (AUG 1995) Blood 86 4 1339--47
Characterization and purification of a primitive hematopoietic cell type in adult mouse marrow capable of lymphomyeloid differentiation in long-term marrow switch" cultures."
In this report, we describe a modification of the assay for long-term culture-initiating cells (LTC-IC) that allows a subset of murine LTC-IC (designated as LTC-ICML) to express both their myeloid (M) and lymphoid (L) differentiative potentials in vitro. The modified assay involves culturing test cells at limiting dilutions on irradiated mouse marrow feeder layers for an initial 4 weeks under conditions that support myelopoiesis and then for an additional week under conditions permissive for B-lymphopoiesis. All of the clonogenic pre-B progenitors (colony-forming unit [CFU] pre-B) detected in such postswitch LTC appear to be the progeny of uncommitted cells present in the original cell suspension because exposure of lymphoid-restricted progenitors to myeloid LTC conditions for textgreater or = 7 days was found to irreversibly terminate CFU-pre-B production and, in cultures initiated with limiting numbers of input cells (no progenitors of any type detected in textgreater 70% of cultures 1 week after the switch), the presence of CFU-pre-B was tightly associated with the presence of myeloid clonogenic cells, regardless of the purity of the input population. Limiting dilution analysis of the proportion of negative cultures measured for different numbers of input cells showed the frequency of LTC-ICML in normal adult mouse marrow to be 1 per 5 x 10(5) cells with an enrichment of approximately 500-fold in the Sca-1+ Lin-WGA+ fraction, as was also found for competitive in vivo repopulating units (CRU) and conventionally defined LTC-IC. LTC-ICML also exhibited the same resistance to treatment in vivo with 5-fluorouracil (5-FU) as CRU and LTC-IC, thereby distinguishing these three populations from the great majority of both in vitro clonogenic cells and day 12 CFU-S. The ability to quantitate cells with dual lymphoid and myeloid differentiation potentials in vitro, without the need for their prior purification, should facilitate studies of totipotent hematopoietic stem cell regulation. View PublicationCatalog #: Product Name: 03630 MethoCult™ M3630 03134 MethoCult™ M3134 03231 MethoCult™ M3231 03234 MethoCult™ M3234 03334 MethoCult™ M3334 03434 MethoCult™ GF M3434 03236 MethoCult™ SF M3236 03534 MethoCult™ GF M3534 Catalog #: 03630 Product Name: MethoCult™ M3630 Catalog #: 03134 Product Name: MethoCult™ M3134 Catalog #: 03231 Product Name: MethoCult™ M3231 Catalog #: 03234 Product Name: MethoCult™ M3234 Catalog #: 03334 Product Name: MethoCult™ M3334 Catalog #: 03434 Product Name: MethoCult™ GF M3434 Catalog #: 03236 Product Name: MethoCult™ SF M3236 Catalog #: 03534 Product Name: MethoCult™ GF M3534 - ReferenceDiaz MF et al. (MAY 2015) The Journal of experimental medicine 212 5 665--80
Biomechanical forces promote blood development through prostaglandin E2 and the cAMP-PKA signaling axis.
Blood flow promotes emergence of definitive hematopoietic stem cells (HSCs) in the developing embryo, yet the signals generated by hemodynamic forces that influence hematopoietic potential remain poorly defined. Here we show that fluid shear stress endows long-term multilineage engraftment potential upon early hematopoietic tissues at embryonic day 9.5, an embryonic stage not previously described to harbor HSCs. Effects on hematopoiesis are mediated in part by a cascade downstream of wall shear stress that involves calcium efflux and stimulation of the prostaglandin E2 (PGE2)-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling axis. Blockade of the PGE2-cAMP-PKA pathway in the aorta-gonad-mesonephros (AGM) abolished enhancement in hematopoietic activity. Furthermore, Ncx1 heartbeat mutants, as well as static cultures of AGM, exhibit lower levels of expression of prostaglandin synthases and reduced phosphorylation of the cAMP response element-binding protein (CREB). Similar to flow-exposed cultures, transient treatment of AGM with the synthetic analogue 16,16-dimethyl-PGE2 stimulates more robust engraftment of adult recipients and greater lymphoid reconstitution. These data provide one mechanism by which biomechanical forces induced by blood flow modulate hematopoietic potential. View PublicationCatalog #: Product Name: 03434 MethoCult™ GF M3434 07920 ACCUTASE™ Catalog #: 03434 Product Name: MethoCult™ GF M3434 Catalog #: 07920 Product Name: ACCUTASE™
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