Background Homeobox gene associated regulatory networks are among the key determinants of early hematopoietic development. Previously, the hematopoietic PBX interacting protein (HPIP) has been identified as a novel interacting partner of the TALE homeodomain protein PBX1, forming a microtubule signalling complex. Expression of HPIP has been associated with increased tumorigenicity of the MCF7 breast cancer cell line. We now demonstrate that HPIP is a novel regulatory protein in human hematopoiesis: constitutive expression of HPIP in human umbilical cord blood derived CD34+ cells increased the absolute number of clonogenic progenitors in liquid expansion culture as well as in methylcellulose assays with a significantly enhanced formation of erythroid colonies compared to the control (p0.01, n=6). Limiting dilution LTC-IC assays confirmed the hematopoietic activity of the protein on primitive human progenitor cells with an over 5fold increase in the absolute number of LTC-ICs compared to non-transduced cells (n=8; p<0.05). In vivo HPIP expression induced a significant shift towards myeloid engraftment (n=8;p<0.05) and doubled the proportion of hCD34+CD38+ human cells in transplanted mice (p0.05, n=8). Structure function analyses identified the C - terminal nuclear receptor/PBX interacting domain (NRPID; LXXLL domain) as a critical domain for the hematopoietic activity of HPIP. Gene expression data by microarray and Q-RT-PCR analysis demonstrated that HPIP induced particularly differential expression of genes involved in the MAPK pathway and cytokine-cytokine interaction. Taken together, these data demonstrate that proteins involved in the organization of microtubular signalling complexes such as HPIP can act as regulators of early human hematopoiesis.
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Specimen partView Samples
We are daily exposed to a multitude of health hazardous airborne particulate matter with notable deposition in the fragile alveolar region of our lungs. Hence, there is a great need for identification and prediction of material-associated diseases, currently hindered due to the lack of in-depth understanding of causal relationships, in particular between acute exposures and chronic symptoms. By applying advanced microscopies and omics to in vitro and in vivo systems, together with in silico molecular modelling, we have here determined that the long-lasting response to a single exposure can originate from the interplay between the newly discovered nanomaterial quarantining and nanomaterial cycling between different lung cell types. This new insight finally allows us to predict the spectrum of lung inflammation associated with materials of interest using only in vitro measurements and in silico modelling potentially relating outcomes to material properties for large number of materials thus boosting safe-by-design-based material development. Because of its profound implications for animal-free predictive toxicology, our work paves the way to a more efficient and hazard-free introduction of numerous new advanced materials into our lives.
Prediction of Chronic Inflammation for Inhaled Particles: the Impact of Material Cycling and Quarantining in the Lung Epithelium.
Cell lineView Samples
Objective: Physical exercise and vitamin E are considered effective treatments of nonalcoholic fatty liver and other metabolic diseases. However, vitamin E has also been shown to interfere with the adaptation to exercise training, in particular for the skeletal muscle. Here, we studied the hypothesis that vitamin E also interferes with the metabolic adaptation of the liver to acute exercise.
A Vitamin E-Enriched Antioxidant Diet Interferes with the Acute Adaptation of the Liver to Physical Exercise in Mice.
Sex, Specimen partView Samples
We performed gene expression microarray analysis of skeletal muscle biopsies from normal glucose tolerant subjects and type 2 diabetes subjects obtained during a 60 min bicycle ergometer exercise and the 180 min of recovery phase
Type 2 diabetes alters metabolic and transcriptional signatures of glucose and amino acid metabolism during exercise and recovery.
Background/aims: Serum concentrations of the hepatokine fibroblast growth factor (FGF) 21 are elevated in obesity, type2 diabetes, and the metabolic syndrome. We asked whether FGF21 levels differ between subjects with metabolically healthy vs. unhealthy obesity (MHO vs. MUHO) opening the possibility that FGF21 is a crosstalker between liver and adipose tissue in MUHO. Furthermore, we studied the effects of chronic FGF21 treatment on adipocyte differentiation, lipid storage, and adipokine secretion.
Fibroblast growth factor 21 is elevated in metabolically unhealthy obesity and affects lipid deposition, adipogenesis, and adipokine secretion of human abdominal subcutaneous adipocytes.
Specimen part, Treatment, SubjectView Samples
substantial number of people at risk to develop type 2 diabetes could not improve insulin sensitivity by physical training intervention. We studied the mechanisms of this impaired exercise response in 20 middle-aged individuals who performed a controlled eight weeks cycling and walking training at 80 % individual VO2max. Participants identified as non-responders in insulin sensitivity (based on Matsuda index) did not differ in pre-intervention parameters compared to high responders. The failure to increase insulin sensitivity after training correlates with impaired up-regulation of mitochondrial fuel oxidation genes in skeletal muscle, and with the suppression of the upstream regulators PGC1 and AMPK2. The muscle transcriptome of the non-responders is further characterized by an activation of TGF and TGF target genes, which is associated with increases in inflammatory and macrophage markers. TGF1 as inhibitor of mitochondrial regulators and insulin signaling is validated in human skeletal muscle cells. Activated TGF1 signaling down-regulates the abundance of PGC1, AMPK2, mitochondrial transcription factor TFAM, and of mitochondrial enzymes. Thus, increased TGF activity in skeletal muscle can attenuate the improvement of mitochondrial fuel oxidation after training and contribute to the failure to increase insulin sensitivity.
TGF-β Contributes to Impaired Exercise Response by Suppression of Mitochondrial Key Regulators in Skeletal Muscle.
Specimen partView Samples
Reprogramming offers the possibility to study cell fate acquisitions otherwise difficult to address in vivo. By monitoring the dynamics of gene expression during direct reprogramming of astrocytes into different neuronal subtypes via the activation of Neurog2 and Ascl1, we demonstrate that these proneural factors control largely different neurogenic programs. Among the cascades induced, however, we identified a common subset of transcription factors required for both Neurog2- and Ascl1-induced reprogramming, and combinations of these factors comprising NeuroD4 were sufficient to generate functional neurons. Notably, during astrocyte maturation REST prevents Neurog2 from binding to the NeuroD4 locus that becomes then enriched with histone H4 lysine 20 tri-methylation.
Transcriptional Mechanisms of Proneural Factors and REST in Regulating Neuronal Reprogramming of Astrocytes.
Sex, Specimen part, Treatment, TimeView Samples
BACKGROUND. Dietary intake of saturated fat is a likely contributor to nonalcoholic fatty liver disease (NAFLD) and insulin resistance, but the mechanisms that initiate these abnormalities in humans remain unclear. We examined the effects of a single oral saturated fat load on insulin sensitivity, hepatic glucose metabolism, and lipid metabolism in humans. Similarly, initiating mechanisms were examined after an equivalent challenge in mice.
Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance.
Sex, Age, Specimen part, TreatmentView Samples
Dieting is a popular yet often ineffective way to lower body weight, as the majority of people regain most of their pre-dieting weights in a relatively short time. The underlying molecular mechanisms driving weight regain and the increased risk for metabolic disease are still incompletely understood. Here we investigate the molecular alterations inherited from a history of obesity. In our model, male HFD fed obese C57BL/6J mice, were switched to a low caloric chow diet, resulting in a decline of body weight to that of lean mice. Within seven weeks after diet switch, most obesity associated phenotypes, such as body mass, glucose intolerance and blood metabolite levels were reversed. However, hepatic inflammation, hepatic steatosis as well as hypertrophy and inflammation of perigonadal, but not subcutaneous, adipocytes persisted in formerly obese mice. Transcriptional profiling of liver and perigonadal fat revealed an upregulation of pathways associated with immune function and cellularity. Thus, we show that weight reduction leaves signs of inflammation in liver and perigonadal fat, indicating that persisting proinflammatory signals in liver and adipose tissue could contribute to an increased risk of formerly obese subjects to develop the metabolic syndrome upon recurring weight gain.
A history of obesity leaves an inflammatory fingerprint in liver and adipose tissue.
Sex, Age, Specimen partView Samples