The traditional view of hematopoiesis has been that all the cells of the peripheral blood are the progeny of a unitary homogeneous pool of hematopoietic stem cells (HSCs). Recent evidence suggests that the hematopoietic system is actually maintained by a consortium of HSC subtypes with distinct functional characteristics. We show here that myeloid-biased HSCs (My-HSCs) and lymphoid-biased (Ly-HSCs) can be purified according to their capacity for Hoechst dye efflux in combination with canonical HSC markers.
Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-beta1.
Sex, Specimen part
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Elevated interferon gamma signaling contributes to impaired regeneration in the aged liver.
Sex, Treatment
View SamplesThe process of liver regeneration can be divided into a series of stages that include initial inductive or priming events through cellular mitosis. Following two-thirds liver resection, the liver undergoes the priming phase, in which cytokines TNF-a and IL-6 activate their respective receptors in hepatocytes. This leads to the activation of several key transcription factors: NF-kB, AP-1, Stat 3, Stat 1, and C/EBP-b and -d . These transcription factors induce the expression of immediate early genes. HGF is also expressed at this time and involved in the transition of quiescent hepatocytes into the G1 phase of the cell cycle. During the G1 phase, delayed early genes are expressed followed by induction of cell cyclerelated genes, both of which require new protein synthesis for their production. Increased expression of FoxM1B and TGF-a occurs at the G1/S transition and is correlated with increased expression of cyclinD1 and decreased expression of cdk inhibitors. During the G2/M phase of the cell cycle, FoxM1B directly elevates cyclinB1, cyclinB2, and cdc25B expression. Additionally, FoxM1B is associated with increased cyclinF and p55cdc, which are involved in completion of the cell cycle following partial hepatectomy. In mice, two-thirds partial hepatectomy promotes proliferation of liver cells and rapid growth of the remaining liver tissue, resulting in complete restoration of organ mass in approximately 7 days (Mackey S. et al. Hepatology 2003 Dec;38(6):1349-52).
Elevated interferon gamma signaling contributes to impaired regeneration in the aged liver.
Sex, Treatment
View SamplesThe process of liver regeneration can be divided into a series of stages that include initial inductive or priming events through cellular mitosis. Following two-thirds liver resection, the liver undergoes the priming phase, in which cytokines TNF-a and IL-6 activate their respective receptors in hepatocytes. This leads to the activation of several key transcription factors: NF-kB, AP-1, Stat 3, Stat 1, and C/EBP-b and -d . These transcription factors induce the expression of immediate early genes. HGF is also expressed at this time and involved in the transition of quiescent hepatocytes into the G1 phase of the cell cycle. During the G1 phase, delayed early genes are expressed followed by induction of cell cyclerelated genes, both of which require new protein synthesis for their production. Increased expression of FoxM1B and TGF-a occurs at the G1/S transition and is correlated with increased expression of cyclinD1 and decreased expression of cdk inhibitors. During the G2/M phase of the cell cycle, FoxM1B directly elevates cyclinB1, cyclinB2, and cdc25B expression. Additionally, FoxM1B is associated with increased cyclinF and p55cdc, which are involved in completion of the cell cycle following partial hepatectomy. In mice, two-thirds partial hepatectomy promotes proliferation of liver cells and rapid growth of the remaining liver tissue, resulting in complete restoration of organ mass in approximately 7 days (Mackey S. et al. Hepatology 2003 Dec;38(6):1349-52).
Elevated interferon gamma signaling contributes to impaired regeneration in the aged liver.
Sex, Treatment
View SamplesAge-related defects in stem cells can limit proper tissue maintenance and hence contribute to a shortened life-span. Using highly purified hematopoietic stem cells from mice aged 2 to 21 months, we demonstrate a deficit in function yet an increase in stem cell number with advancing age. Expression analysis of more than 14,000 genes identified 1500 that were age-induced and 1600 that were age-repressed. Genes associated with the stress response, inflammation, and protein aggregation dominated the upregulated expression profile, while the downregulated profile was marked by genes involved in the preservation of genomic integrity and chromatin remodeling. Many chromosomal regions showed coordinate loss of transcriptional regulation, and an overall increase in transcriptional activity with aged, and inappropriate expression genes normally regulated by epigenetic mechanisms was observed. Hematopoietic stem cells from early-aging mice expressing a mutant p53 allele reveal that aging of stem cells can be uncoupled from aging at an organismal level. These studies show that HSC are not protected from aging. Instead, loss of epigenetic regulation at the chromatin level may drive both functional attenuation of cells, as well as other manifestations of aging, including the increased propensity for neoplastic transformation.
Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation.
No sample metadata fields
View SamplesdMyc is a conserved transcription factor that controls growth and proliferation by regulating its target genes.
MicroRNA miR-308 regulates dMyc through a negative feedback loop in Drosophila.
Specimen part
View SamplesMyelin-reactive T cells have been identified in patients with multiple sclerosis (MS) and healthy subjects with comparable frequencies, but the contribution of these autoreactive T cells to disease pathology remains unknown. A total of 13,324 T cell libraries generated from blood of 23 patients and 22 healthy controls were interrogated for reactivity to myelin antigens. Libraries derived from CCR6+ myelin-reactive T cells from patients with MS exhibited significantly enhanced production of IFN-?, IL-17, and GM-CSF compared to healthy controls. Single-cell clones isolated by MHC/peptide tetramers from CCR6+ T cell libraries also secreted more pro-inflammatory cytokines while clones isolated from controls secreted more IL-10. The transcriptomes of myelin-specific CCR6+ T cells from patients with MS were distinct from those derived from healthy controls, and of note, were enriched in Th17-induced experimental autoimmune encephalitis (EAE) gene signatures and gene signatures derived from Th17 cells isolated other human autoimmune diseases. These data, although not casual, imply that functional differences between antigen specific T cells from MS and healthy controls is fundamental to disease development and support the notion that IL-10 production from myelin-reactive T cells may act to limit disease progression, or even pathogenesis. Overall design: Four conditions of purified T cells with between 3 and 5 replicates per condition
Functional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis.
No sample metadata fields
View SamplesHSC (Sca+ SP) were isolated from 8-12 week C57B6 mice at various time points after treatment with 5-Fluorouracil. RNA was isolated from 50,000-100,000 FACS sorted cells and subjected to two rounds of T7 based linear amplification using Ambion's Message Amp kit. Two replicates from each time point were analyzed.
Molecular signatures of proliferation and quiescence in hematopoietic stem cells.
No sample metadata fields
View SamplesTET-family dioxygenases oxidize 5-methylcytosine (5mC) in DNA, and exert tumor suppressor activity in many types of cancers. Even in the absence of TET coding region mutations, TET loss-of-function is strongly associated with cancer. We show that acute elimination of TET function induces the rapid development of an aggressive, fully-penetrant and cell-autonomous myeloid leukemia in mice, pointing to a causative role for TET-loss-of-function in this myeloid malignancy. Phenotypic and transcriptional profiling showed aberrant differentiation of hematopoietic stem/ progenitor cells, impaired erythroid and lymphoid differentiation and strong skewing to the myeloid lineage, with only a mild relation to changes in DNA modification. We also observed progressive accumulation of DNA damage and strong impairment of DNA break repair, suggesting a key role for TET proteins in maintaining genomic integrity. Overall design: Jungeun, An
Acute loss of TET function results in aggressive myeloid cancer in mice.
Specimen part, Subject
View SamplesWe compared gene expression differences in Atxn1L knockout vs wildtype HSCs
Ataxin1L is a regulator of HSC function highlighting the utility of cross-tissue comparisons for gene discovery.
Specimen part
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