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Activating PIK3CA mutation promotes osteogenesis of bone marrow mesenchymal stem cells in macrodactyly

ABSTRACT: Activating PIK3CA mutation promotes osteogenesis of bone marrow mesenchymal stem cells in macrodactyly

PROVIDER: PRJNA621634 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11458989_1.fastq.gz	Fastqsanger.gz
	SRR11458989_2.fastq.gz	Fastqsanger.gz
	SRR11458990_1.fastq.gz	Fastqsanger.gz
	SRR11458990_2.fastq.gz	Fastqsanger.gz
	SRR11458991_1.fastq.gz	Fastqsanger.gz

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Activating PIK3CA mutation promotes osteogenesis of bone marrow mesenchymal stem cells in macrodactyly.

Project description:Macrodactyly is a disabling congenital disease characterized by overgrowth of soft tissues and bones, which leads to finger enlargement and joint deformity. The mechanism of bone overgrowth in macrodactyly was rarely understood. In our study bone manifestations of three macrodactyly patients were analyzed by micro-CT. PIK3CA mutation was detected by next-generation sequencing (NGS) of a tumor gene-panel. The PI3K/AKT/mTOR pathway activation and target genes were analyzed. The osteogenic potential of macrodactyly-derived bone marrow mesenchymal stem cells (MAC-BMSCs) was compared with polydactyly-derived bone marrow mesenchymal stem cells (PD-BMSCs). PIK3CA inhibitors were tested for proliferation and osteogenesis potential of MAC-BMSCs. Activating PIK3CA mutations and activation of PI3K/AKT/mTOR pathway were detected in all MAC-BMSCs. MAC-BMSCs had enhanced osteogenesis potential compared with PD-BMSCs. PIK3CA knockdown by shRNA or BYL719 treatment significantly reduced osteogenic differentiation capacity of MAC-BMSCs. RNA-Seq and qRT-PCR revealed the upregulation of distal-less homeobox 5 (DLX5) in MAC-BMSCs compared with PD-BMSCs. The osteogenic potential of MAC-BMSCs was inhibited by DLX5 knockdown, indicating that DLX5 is a downstream target of PIK3CA activation-mediated osteogenesis. This study revealed that osteogenic differentiation in MAC-BMSCs is enhanced by PIK3CA activation mutation through PI3K/AKT/mTOR signaling pathway and can be reversed by PIK3CA knockdown or drug inhibition.

| S-EPMC7338441 | biostudies-literature

Activating PIK3CA mutation promotes osteogenesis of bone marrow mesenchymal stem cells in macrodactyly

Project description:Comparison of differential expression between macrodactyly BMSC and polydactyly BMSC

2020-07-13 | GSE147823 | GEO

Activating Mutations in PIK3CA result in Widespread Modulation of the Tyrosine Phosphoproteome

Project description:The human oncogene PIK3CA is frequently mutated in human cancers. The two hotspot mutations in PIK3CA, E545K and H1047R, have been shown to regulate widespread signaling events downstream of AKT. However, the impact of these activating mutations on the tyrosine phosphorylation signaling in the cell has not been studied. Here, we performed a global phosphotyrosine profiling using isogenic knockin cell lines containing these activating mutations. We identified 824 unique phosphopeptides from 308 proteins. We found a surprisingly widespread modulation of tyrosine phosphorylation levels of proteins in the knockin mutant cells, with many of the regulated proteins involved in important biological processes, including those in the cytoskeletal migration pathways and kinase regulated signaling. We observed a widespread modulation of the tyrosine kinome, with 24 of the tyrosine kinases showing either upregulation or downregulation in phosphorylation levels. Many of the regulated phosphosites that we identified were located in the kinase domain or the canonical activating sites, indicating that the kinases were active and hence their downstream signaling pathways. Our study thus shows that the activating mutations in PIK3CA result in widespread tyrosine signaling regulation, in addition to the serine/threonine signaling pathways activated by the canonical PI3K-AKT axis.

2018-10-24 | PXD001460 | Pride

Fgf9 promotes adipogenesis and reduces osteogenesis by regulating mesenchymal stromal cells differentiation in adult bone marrow

Project description:In this study, we found that Fgf9 regulates the bone-fat balance by modulating the cell fate determination of BMSCs. Histology and micro-CT analysis demonstrate that Fgf9 S99N mutation (loss-of-function) significantly inhibited the formation of bone marrow adipose tissue (BMAT) in adult mice and alleviated the ovariectomized (OVX) induced bone loss and BMAT accumulation. In vitro cytodifferentiation assays unveiled that the Fgf9 S99N mutation hindered adipogenesis while promoting osteogenesis in BMSCs. Furthermore, recombinant FGF9 stimulation and Fgf9 overexpression in BMSCs demonstrated that Fgf9 significantly promoted adipocyte formation and inhibited osteogenesis in vitro and in vivo. Cytodifferentiation assays at various stages of BMSC differentiation indicated that FGF9 altered the osteogenic and adipogenic potential of BMSCs, particularly during the early stages of differentiation. Transcriptomic and gene expression analyses demonstrated that FGF9 significantly upregulated the expression of adipogenic genes while downregulating osteogenic gene expression at both mRNA and protein levels. KEEG analysis revealed and in vitro differentiation assays with specific inhibitors confirmed that FGF9 modulated bone-fat balance by inhibiting osteogenesis via the MAPK/ERK pathway and promoting adipogenesis by activating the PI3K/AKT and Hippo pathways.

2024-07-17 | GSE252394 | GEO

Spinal tuberculosis infection induces osteopenia by reducing the migration and osteogenesis of bone marrow mesenchymal stem cells

Project description:Objectives: Bone marrow mesenchymal stem cells (BMSC) play an important role in osteogenesis. However, the role of BMSC in osteopenia in spinal tuberculosis (STB) patients is unclear. Methods: Bone mineral density (BMD) of 53 STB patients and 55 controls was measured. The migration and osteogenesis of BMSC were assessed by wound healing assays and alizarin red staining, and osteoclast marker expression was measured. RNA-seq was performed on BMSC and the enriched signaling pathways were verified. Results:BMD of STB patients was significantly decreased and BMSC migration and osteogenesis were significantly reduced. After verification, we found that the B-cell receptor signaling pathway, tuberculosis, osteoclast differentiation, Th17-cell differentiation, Ras signaling pathway and PI3K-Akt signaling pathway were affected.And of these pathways, the B-cell receptor signaling, Th17-cell differentiation, Ras signaling pathway and PI3K-Akt signaling pathway were not previously known to be involved in osteopenia. The MAPK signaling pathway and ECM-receptor interactions were correlated with STB prognosis. Conclusion: STB infection can significantly reduce BMSC migration and osteogenesis, decreasing BMD. This process is regulated by multiple pathways and is associated with STB prognosis. Our study suggests that reduced BMSC migration and osteogenesis play important roles in osteopenia in STB patients, and BMSC may be a therapeutic target.

2023-12-01 | GSE222013 | GEO

Transcriptome expression of human bone marrow mesenchymal stem cell (hBMSCs) during osteogenesis

Project description:Transcriptome expression of human bone marrow mesenchymal stem cell (hBMSCs) during osteogenesis

| PRJNA740003 | ENA

Activating AKT1 and PIK3CA mutations in metastatic castration-resistant prostate cancer

Project description:Activating mutations in AKT1 and PIK3CA are under-characterised in metastatic castration-resistant prostate cancer (mCRPC), but in other cancers are linked to PI3K signaling activation and sensitivity to pathway inhibitors. Our objective was to determine the prevalence, genomic context, and clinical associations of AKT1/PIK3CA activating mutations in mCRPC.

| EGAS00001004328 | EGA

eHSP70 promotes osteogenesis of hMSCs through activating ERK signaling pathway

Project description:Heat shock proteins are highly conserved proteins that, when produced intracellularly, protect stress exposed cells. It has been suggested that extracellular Hsp70 has both protective and deleterious effects. Our study showed eHSP70 increased the ALP activity, promoted mineralization and up-regulated osteogenesis-related markers. We used microarrays to determine the differentially expressed genes and identify revelant pathways through pathway enrichment analysis. hMSCs were selected for RNA extraction and hybridization on Affymetrix microarrays after 3-day culture. The experimental group was treated with HSP70 (200ng/ml) during osteogenic differentiation and control group without it.

2016-07-03 | E-GEOD-71080 | biostudies-arrayexpress

Transcriptome analysis of mouse tumors driven by PIK3CA mutation variants

Project description:The RTK/RAS/PI3K pathway is a key driver of tumorigenesis across all cancers, with 90% of Glioblastoma (GBM) tumors exhibiting alterations in this pathway. Among the specific genes in this pathway mutations in PI3K’s catalytic subunit, PIK3CA, are found in 11% of GBM tumors. Sequencing of GBM samples has revealed several known hotspot mutations that drive tumorigenesis in several cancers (E545K, H1047R), as well as a series of 63 in frame mutations (as indexed in COSMIC) that remain largely unclassified. To decode which of these PIK3CA variants function as drivers of GBM, we established an in vivo complementation screening platform for GBM. Our mouse GBM model relies on in utero electroporation (IUE) and CRISPR-Cas9 mediated knockout of NF1, p53, and PTEN (termed 3xCR). Because PTEN catalyzes the reverse reaction of PIK3CA, phosphorylation of PIP2 to PIP3, we complemented loss of PTEN with overexpression of E545K or H1047R, two bona fide hot spot driver mutations of PIK3CA. Both these variants accelerated tumor associated death, demonstrating that known PIK3CA drivers can complement PTEN loss in our system.

2019-10-09 | GSE123519 | GEO

Gene expression of human bone marrow mesenchymal stem cell (hBMSCs) during osteogenesis with or without TNF-alpha

Project description:In our previous study, we found that TNF-alpha (100ng/mL) different treatment times have opposing effects on BMSC osteogenesis. To investigate the roles of TNF-alpha in the osteogenic differentiation of hBMSCs, we performed gene microarray to detected the gene expression of hBMSCs with or without TNF-alpha during osteogenesis on days 3 and 4.

2021-06-04 | GSE176086 | GEO

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