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Effect of PI3K/mTOR dual-target inhibitor WX390 on adipose-derived stem cells isolated from facial infiltrating lipomatosis

ABSTRACT: Facial infiltrating lipomatosis (FIL) is a congenital disorder characterized by unilateral facial enlargement. Although next-generation sequencing has revealed that the pathogenesis of FIL is associated with phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) mutations, the underlying molecular mechanisms remain undetermined. We found that the adipose tissue in FIL patients demonstrated tissue infiltration accompanied by adipocytes hypertrophy and increased lipid accumulation. All FIL-ADSCs harboured PIK3CA mutations. Compared to ADSCs obtained from normal subcutaneous adipose tissue, FIL-ADSCs exhibited a greater capacity for adipogenesis. Suppression of PIK3CA resulted in a reduction in the adipogenic potential of FIL-ADSCs. Furthermore, WX390, a novel dual-target PI3K/mTOR inhibitor, was found to impede PIK3CA-mediated adipogenesis both in vivo and in vitro. RNA-seq revealed that the expression of transient receptor potential vanilloid subtype 1 (TRPV1) was upregulated after PI3K pathway inhibition, and overexpression and activation of TRPV1 both inhibited adipogenesis of FIL-ADSCs. Our study showed that PIK3CA mutations promoted adipogenesis in FIL-ADSCs and that this effect was achieved by suppressing the expression of TPRV1. Pathogenesis experiments suggested that WX390 may serve as an agent for the treatment of FIL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253170 | GEO | 2024/06/28

REPOSITORIES: GEO

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Project description:Adipogenesis occurs through a specific gene program in undifferentiated fat progenitors. We hypothesized that the properties of the fat progenitors are regulated by hox genes, the developmental genes essential in different tissue stem cells. Their biased expression in white and brown fat implies roles in distinguishing the two fat types. Among 39 Hox genes, Hoxc8 is highly enriched in undifferentiated adipose tissue stem cells (ADSCs) and down-regulated in differentiated adipocytes. Forced expression of Hoxc8 suppressed adipocyte differentiation of ADSCs. Using microarrays, we investigated the effect of Hoxc8 overexpression on global transcripts in ADSCs. We compared among four groups: untreated ADSCs, adipogenic induction media (MDI)-treated ADSCs, MDI-treated ADSC-vector and MDI-treated ADSC-Hoxc8. A number of, but not all, adipogenesis-related genes are suppressed by Hoxc8. This dataset illustrates the global effect of Hoxc8, a developmental transcription factor, on the expression of adipogenesis-related genes. Gene expression was compared among untreated ADSCs (control), adipogenic induction media-treated ADSCs, adipogenic induction media-treated ADSC-vector (ADSCs transduced with control vector), and adipogenic induction media-treated ADSC-Hoxc8 (ADSCs transduced with human Hoxc8). Total RNA was isolated from ADSCs using the Qiagen RNeasy kit (Qiagen). At NimbleGen, quality and yield were verified before cDNA synthesis and Cy3-end labeling. The labeled cDNA samples were hybridized to Homo sapiens 4-Plex arrays (Roche NimbleGen, A4487001-00-01) that represent 24,000 human genes. Raw data files for each sample were normalized and background-corrected using a Robust Multi-Array Analysis as implemented by NimbleScan software. Students’ two-tail t-tests were conducted among the samples for each transcript and fold-change was determined. Transcripts whose abundance was significantly altered (P < 0.05) and an absolute fold change greater than 2 were defined as differentially regulated.

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Effect of PI3K/mTOR dual-target inhibitor WX390 on adipose-derived stem cells isolated from facial infiltrating lipomatosis

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