PH regulates hematopoietic stem cell potential via polyamines
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ABSTRACT:
PROVIDER: PRJNA934856 | ENA |
REPOSITORIES: ENA
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Project description:Identification of a culture condition for maintaining the potential of HSCs ex vivo.
2023-02-24 | GSE225267 | GEO
Project description:Upon ex vivo culture, hematopoietic stem cells (HSCs) quickly lose potential and differentiate into progenitors. The identification of culture conditions that maintain the potential of HSCs ex vivo is therefore of high clinical interest. Here, we demonstrate that the potential of murine and human HSCs is maintained when cultivated for 2 days ex vivo at a pH of 6.9, in contrast to cultivation at the commonly used pH of 7.4. When cultivated at a pH of 6.9, HSCs remain smaller, less metabolically active, less proliferative and show enhanced reconstitution ability upon transplantation compared to HSC cultivated at pH 7.4. HSCs kept at pH 6.9 show an attenuated polyamine pathway. Pharmacological inhibition of the polyamine pathway in HSCs cultivated at pH 7.4 with DFMO mimics phenotypes and potential of HSCs cultivated at pH 6.9. Ex vivo exposure to a pH of 6.9 is therefore a positive regulator of HSC function by reducing polyamines. These findings might improve HSC short-term cultivation protocols for transplantation and gene therapy interventions.
| S-EPMC10157373 | biostudies-literature
Project description:Upon ex vivo culture, hematopoietic stem cells (HSCs) quickly lose potential and differentiate into progenitors. The identification of culture conditions that maintain the potential of HSCs ex vivo is therefore of high clinical interest. Here, we demonstrate that the potential of murine and human HSCs is maintained when cultivated for 2 days ex vivo at a pH of 6.9, in contrast to cultivation at the commonly used pH of 7.4. When cultivated at a pH of 6.9, HSCs remain smaller, less metabolically active, less proliferative and show enhanced reconstitution ability upon transplantation compared to HSC cultivated at pH 7.4. HSCs kept at pH 6.9 show an attenuated polyamine pathway. Pharmacological inhibition of the polyamine pathway in HSCs cultivated at pH 7.4 with DFMO mimics phenotypes und potential of HSCs cultivated at pH 6.9. Ex-vivo exposure to a pH of 6.9 is therefore a positive regulator of HSC function by reducing polyamines. These findings might improve HSC short-term cultivation protocols for transplantation and gene therapy interventions.
| S-SCDT-10_15252-EMBR_202255373 | biostudies-other
Project description:Snapshot of translation in mammalian cells that are depleted of polyamines or replete with polyamines. Hek293T cells treated with DFMO or Spermidine.
2018-10-11 | GSE111517 | GEO
Project description:To study the physiological roles of polyamines, we have carried out a global microarray analysis on the effect of adding polyamines to an Escherichia coli mutant that lacks polyamines because of deletions in the genes in the polyamine biosynthetic pathway. Previously, we have reported that the earliest response to the polyamine addition is the increased expression of the genes for the glutamate dependent acid resistance system (GDAR). We also presented preliminary evidence for the involvement of rpoS and gadE regulators. In the current study further confirmation of the regulatory roles of rpoS and gadE is shown by a comparison of genome-wide expression profiling data from a series of microarrays comparing the genes induced by polyamine addition to polyamine-free rpoS+/gadE+ cells with genes induced by polyamine addition to polyamine-free ∆rpoS and ∆gadE cells. The results indicate that most of the genes in the E. coli GDAR system that are induced by polyamines require rpoS and gadE. Our data also show that, gadE is the main regulator of GDAR and other acid-fitness-island genes. Both polyamines and rpoS are necessary for the expression of gadE genes from the three promoters of gadE (P1, P2 and P3). The most important effect of polyamine addition is the very rapid post-transcriptional increase in the level of RpoS sigma factor. Our current hypothesis is that polyamines increase the level of RpoS protein, and that this increased RpoS level is responsible for the stimulation of gadE expression, which in turn induces the GDAR system in E. coli. Three replications for E. coli strains HT874, HT873, HT875, HT873 treated with or no polyamines(PA)
2015-08-06 | E-GEOD-67119 | biostudies-arrayexpress
Project description:Snapshot of translation in mammalian cells that are depleted of polyamines or replete with polyamines
| PRJNA437287 | ENA
Project description:To study the physiological roles of polyamines, we have carried out a global microarray analysis on the effect of adding polyamines to an Escherichia coli mutant that lacks polyamines because of deletions in the genes in the polyamine biosynthetic pathway. Previously, we have reported that the earliest response to the polyamine addition is the increased expression of the genes for the glutamate dependent acid resistance system (GDAR). We also presented preliminary evidence for the involvement of rpoS and gadE regulators. In the current study further confirmation of the regulatory roles of rpoS and gadE is shown by a comparison of genome-wide expression profiling data from a series of microarrays comparing the genes induced by polyamine addition to polyamine-free rpoS+/gadE+ cells with genes induced by polyamine addition to polyamine-free ∆rpoS and ∆gadE cells. The results indicate that most of the genes in the E. coli GDAR system that are induced by polyamines require rpoS and gadE. Our data also show that, gadE is the main regulator of GDAR and other acid-fitness-island genes. Both polyamines and rpoS are necessary for the expression of gadE genes from the three promoters of gadE (P1, P2 and P3). The most important effect of polyamine addition is the very rapid post-transcriptional increase in the level of RpoS sigma factor. Our current hypothesis is that polyamines increase the level of RpoS protein, and that this increased RpoS level is responsible for the stimulation of gadE expression, which in turn induces the GDAR system in E. coli.
2015-08-06 | GSE67119 | GEO
Project description:We aim to compare the genomic discrepancies across de novo Ph+ ALL, Ph+ MPAL and Ph+ AML, three diseases characterized by the occurrence of BCR-ABL1 transcripts but showing varied immunophenotypes. The data we are now submitting is the genomic copy number variants of these three groups. The following is the abstract with associated manuscript. The chromosome abnormality of Philadelphia (Ph) is typically seen in de novo acute lymphoblastic leukemia (ALL). It has also been identified in mixed phenotype acute leukemia (MPAL) and acute myeloid leukemia (AML) in the revisions to World Health Organization classification of myeloid neoplasms and actue leukemia. The discrepancies between these patients and potential mechanisms underlying differentiation fate of the leukemia cells remain poorly defined. We evaluated the clinical, genomic and transcriptomic features of Ph+ ALL, Ph+ MPAL and Ph+ AML by taking advantage of high-density genomic analysis, including next-generation sequencing array comparative genomic hybridization and gene expression profiling for transcriptomic analysis. Our results showed that the three cohorts demonstrated diversified clinical features. Ph+ ALL had the best response to induction therapy, with a complete remission (CR) rate of 93.5 and molecular response of 43.5%. Ph+ MPAL had a 90.0% CR rate but only 5.9% of molecular response. The CR rate of Ph+ AML was only 68.8%. Ph+ ALL was characterized by loss and mutations of B-cell development gene IKZF1 and PAX5, and frequent histone H3K36 trimethyltransferase SETD2 mutations. SETD2 mutations were detected in 11.3% of Ph+ ALL patients and predicted higher relapse rate. Ph+ MPAL and Ph+ AML featured high frequency of RUNX1 mutations. Further studies showed RUNX1-R177X mutation inhibited 32D cell differentiation induced by G-Csf, and cooperated with BCR-ABL1 to lead to myeloid differentiation arrest of human cord blood CD34+ cells. It is therefore presumed that these additional mutations work in synergy with BCR-ABL1 fusion gene to facilitate the development of Ph-positive acute leukemia in different immunophenotypic classifications.
2022-04-29 | GSE130484 | GEO
Project description:To investigate the effect of pharmacological targeting of polyamines catabolic enzymes in the establishment and reversion of the senescent phenotype
2022-10-18 | GSE212085 | GEO
Project description:Inflammatory bowel disease (IBD) is characterized by chronic mucosal inflammation of the gastrointestinal tract and is associated with extracellular acidification of mucosal tissue. Several extracellular pH-sensing receptors, including G protein-coupled receptor 4 (GPR4), play an important role in the regulation of inflammatory and immune responses and GPR4 deficiency has been shown to be protective in IBD animal models. To confirm the therapeutic potential of GPR4 antagonism in IBD, we tested Compound 13, a selective GPR4 antagonist, in the IL10-/- mouse model of colitis. Despite reasonable bioavailability, Compound 13 treatment did not improve colitis in this model and there were no signs of target engagement. Interestingly, Compound 13 behaved as an “orthosteric” antagonist, i.e., its potency was pH-dependent and mostly inactive at pH levels lower than 6.8 with preferential binding to the inactive conformation of GPR4. Mutagenesis studies confirmed Compound 13 likely binds to the conserved orthosteric binding site in G protein-coupled receptors, where a histidine sits in GPR4 likely preventing Compound 13 binding when protonated in acidic conditions. While the exact mucosal pH in the human disease and relevant IBD mice models is unknown, it is well established that the degree of acidosis is positively correlated with the degree of inflammation, suggesting Compound 13 is not an ideal tool to study the role of GPR4 in moderate-to-severe inflammatory conditions.
2024-01-03 | GSE225694 | GEO