PDGFR-alpha signaling in P5-P15 small and large cCFU-fibroblasts
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ABSTRACT:
PROVIDER: PRJNA417975 | ENA |
REPOSITORIES: ENA
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Project description:The interstitial and perivascular spaces of the heart contain stem-like cells including cardiac colony forming units - fibroblast (cCFU-F), a sub-fraction of SCA1+PDGFR-alpha +CD31- (S+P+) immature stromal cells with the qualities of mesenchymal stem cells, that we have characterized previously. Here we explore the role of platelet-derived growth factor receptor (PDGFR-alpha in cCFU-F and S+P+ cell niche regulation in homeostasis and repair. PDGFR-alpha signaling modulated quiescence, metabolic state, mitogenic propensity and colony formation, as well as the rate and stability of self-renewal. Exogenously administered PDGF-AB ligand had anti-aging effects on cCFU-F, akin to those seen in heterochronic parabiotic mice. Post-myocardial infarction (MI), PDGF-AB stimulated S+P+ cell proliferation and conversion to myofibroblasts through a metabolic priming effect, yet significantly enhanced anatomical and functional repair via multiple cellular processes. Our study provides a rationale for a novel therapeutic approach to cardiac injury involving stimulating endogenous repair mechanisms via activation of cardiac stem and stromal cells.
2019-11-01 | GSE106779 | GEO
Project description:PDGFR-alpha signaling in P0 cCFU-fibroblasts
| PRJNA417976 | ENA
Project description:The interstitial and perivascular spaces of the heart contain stem-like cells including cardiac colony forming units - fibroblast (cCFU-F), a sub-fraction of SCA1+PDGFR-alpha +CD31- (S+P+) immature stromal cells with the qualities of mesenchymal stem cells, that we have characterized previously. Here we explore the role of platelet-derived growth factor receptor (PDGFR-alpha in cCFU-F and S+P+ cell niche regulation in homeostasis and repair. PDGFR-alpha signaling modulated quiescence, metabolic state, mitogenic propensity and colony formation, as well as the rate and stability of self-renewal. Exogenously administered PDGF-AB ligand had anti-aging effects on cCFU-F, akin to those seen in heterochronic parabiotic mice. Post-myocardial infarction (MI), PDGF-AB stimulated S+P+ cell proliferation and conversion to myofibroblasts through a metabolic priming effect, yet significantly enhanced anatomical and functional repair via multiple cellular processes. Our study provides a rationale for a novel therapeutic approach to cardiac injury involving stimulating endogenous repair mechanisms via activation of cardiac stem and stromal cells.
2019-11-01 | GSE106778 | GEO
Project description:PDGFR-alpha signaling in cardiac stems
| PRJNA418455 | ENA
Project description:Cutaneous melanoma is the most aggressive skin cancer showing high mortality at advanced clinical stages. Platelet-Derived Growth Factor Receptor alpha (PDGFR-alpha) is known to strongly inhibit melanoma and endothelial cell proliferation, in vitro as well in vivo. PDGFR-alpha expression has been found to be reduced in metastatic human melanoma-biopsies, as compared to benign nevi-biopsies, thus implying a negative selection of PDGFR-alpha expressing cells, in melanoma. In the present study PDGFR-alpha was transiently overexpressed in endothelial (HUVEC) and melanoma (SK-Mel-28) human cells; a strong anti-proliferation effect was observed, along with profound effects on mRNA and miR- expression. More in detail, gene-expression profiling showed that PDGFR-alpha over-expression affects the expression of 82 genes in HUVEC (41 up-, 41 down-regulated), and 52 genes in SK-Mel-28 (43 up-, 9 down-regulated). miRNA profiling showed that 14 miRs are up-regulated and 40 are down-regulated in PDGFR-alpha overexpressing cells. Accurate validation with alternative techniques demonstrated that CXCL10 gene expression is one of the most significantly up-regulated at both gene- and protein level, in combination with a strong down-regulation of miR-503 in both HUVEC and SK-Mel-28 overexpressing PDGFR-alpha. We then demonstrate that CXCL10 is a validated miR-503 target, and that the anti-proliferation effect of PDGFR-alpha is reverted by specific CXCL-10 neutralization. Several molecular pathways were identified in cells overexpressing PDGFR-alpha, according to KEGG and Gene Ontology analysis (p < 0.01). In conclusion, PDGFR-alpha overexpression strongly inhibits endothelial- and melanoma- proliferation in a CXCL-10 dependent way, by significantly down-regulating miR-503 expression. This dataset contains the results of the microRNA analysis.
2016-11-14 | E-MTAB-4266 | biostudies-arrayexpress
Project description:Cutaneous melanoma is the most aggressive skin cancer showing high mortality at advanced clinical stages. Platelet-Derived Growth Factor Receptor alpha (PDGFR-alpha) is known to strongly inhibit melanoma and endothelial cells proliferation, in vitro as well in vivo. PDGFR-alpha expression has been found to be reduced in metastatic human melanoma-biopsies, as compared to benign nevi-biopsies, thus implying a negative selection of PDGFR-alpha expressing cells, in melanoma. In the present study PDGFR-alpha was transiently overexpressed in endothelial (HUVEC) and melanoma (SK-Mel-28) human cells; a strong anti-proliferation effect was observed, along with profound effects on mRNA and miRNA expression. In detail, gene-expression profiling showed that PDGFR-alpha over-expression affects the expression of 82 transcripts in HUVEC (41 up-, 41 down-regulated), and 52 Transcripts in SK-Mel-28 (43 up-, 9 down-regulated). Finally, a miRNA profiling showed that 14 miRs are up-regulated and 39 are down-regulated in PDGFR-alpha overexpressing cells. Accurate validation with alternative techniques demonstrated that CXCL10 is one of the most significantly up-regulated at both gene- and protein level, in combination with a strong down-regulation of miR-503 in both HUVEC and SK-Mel-28 overexpressing PDGFR-alpha. We then demonstrate that CXCL10 is a validated miR-503 target, and that the anti-proliferation effect of PDGFR-alpha is reverted by specific CXCL-10 neutralization. In conclusion, PDGFR-alpha overexpression strongly inhibits endothelial- and melanoma- proliferation in a CXCL-10 dependent way, by significantly down-regulating miR-503 expression. This data set contains the results of the mRNA analysis.
2016-11-14 | E-MTAB-4261 | biostudies-arrayexpress
Project description:The scaffold protein synectin plays a critical role in the trafficking and regulation of membrane receptor pathways. As the platelet derived growth factor receptor (PDGFR) pathway is essential for hepatic stellate cell (HSC) activation and liver fibrosis, we sought to determine the role of synectin on the PDGFR pathway in HSC. To study the role of synectin in the development of liver fibrosis, mice with selective deletion of synectin from HSC were generated and found to be protected from fibrosis. RNAseq revealed that knockdown of synectin in HSC demonstrated reductions in the fibrosis pathway of genes including PDGFR-β, but not PDGFR-α. Chromatin Immunoprecipitation assay of the PDGFR-β promoter upon synectin knockdown revealed a pattern of histone marks associated with decreased transcription, dependent on p300. In contradistinction, synectin was found to regulate PDGFR-α through an alternative mechanism: protection from autophagic degradation. Site directed mutagenesis revealed that ubiquitination of specific PDGFR-α lysine residues is responsible for its autophagic degradation. Furthermore, functional studies showed decreased PDGF dependent proliferation and migration after synectin knockdown. Finally, human cirrhotic livers demonstrated increased synectin expression. This work provides insight into differential transcriptional and post-translational mechanisms of synectin regulation of PDGFRs, which are critical to fibrogenesis.
2017-12-31 | GSE93629 | GEO
Project description:Background: Human bone marrow mesenchymal stem cells (MSCs) expanded in vitro exhibit not only a tendency to lose their proliferative potential, homing ability and telomere length but also genetic or epigenetic modifications such as DNA methylation and the noncoding RNA-mediated mechanism. This results in the senescence of MSCs. We compared differential methylation patterns of genes and miRNAs between early-passage and late-passage cells and estimated the relationship between senescence and DNA methylation patterns. Genomic DNA of MSCs cultured at passage 5 (P5) and passage 15 (P15) was enriched using methylated DNA immunoprecipitation assays, and DNA methylation changes due to long-term culture of MSCs were analyzed using Human 2.1M Deluxe Promoter Arrays (NimbleGen). Results: When we analyzed the methylation differences between P5 and P15 more than twice, 3,338 genes showed more than two-fold higher methylation at P5 than P15, whereas 4,670 genes showed more than two-fold higher methylation at P15 than P5. When we examined hypermethylated genes (methylation peak ≥ 2) at P5 or P15, 2,739 genes, including those related to fructose and mannose metabolism and calcium signaling pathways, and 2,587 genes, including those related to DNA replication, cell cycle and the PPAR signaling pathway, were hypermethylated at P5 and P15, respectively. There was common hypermethylation of 1,205 genes at both P5 and P15. In addition, genes that were hypermethylated at P5 (CPEB1, GMPPA, CDKN1A, TBX2, SMAD9 and MCM2) showed lower mRNA expression than did those hypermethylated at P15, whereas genes that were hypermethylated at P15 (MAML2, FEN1 and CDK4) showed lower mRNA expression than did those that were hypermethylated at P5, demonstrating that hypermethylation at DNA promoter regions inhibited gene expression and that hypomethylation increased gene expression. In the case of hypermethylation on miRNA, 27 miRNAs were hypermethylated at P5, whereas 44 miRNAs were hypermethylated at P15. Conclusion: These results show that hypermethylation increases at genes related to DNA replication, cell cycle and adipogenic differentiation due to long-term culture, which may in part affect MSC senescence.
2011-06-17 | GSE30018 | GEO
Project description:Rhodovulum sp. P5 strain:P5 Genome sequencing and assembly
| PRJNA316381 | ENA
Project description:Clostridioides difficile P5 strain:P5 Genome sequencing and assembly
| PRJNA85967 | ENA