Adipocytes signal to recruit specific mRNAs from surrounding cells to restore expression deficits [scRNA-Seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE319159 | GEO | 2026/03/03
REPOSITORIES: GEO
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Project description:Extracellular vesicles (EVs) are nano-sized, membrane-delimited, particles released by cells that carry signaling macromolecules. A major pathway of EV production is potentiated by neutral sphingomyelinase 2 (SMPD3/nSMAse2), an enzyme that generates ceramide from sphingomyelin. In our attempt to study this pathway in adipocytes of male mice, we discovered that the elimination of SMPD3 from adipocytes in vivo triggers a signal to surrounding immune cell-like preadipocytes to release EVs that carry SMPD3 mRNA. This results in a widespread increase in SMPD3 mRNA in purified null adipocytes without a change in the transcripts of other enzymes involved in ceramide metabolism. These results point to a fundamental, novel, and selective mechanism by which specific mRNA molecules are acquired from the microenvironment to a level that can restore expression of mRNA and protein in a cell that is depleted of the corresponding genetic information.
2026-03-03 | GSE319160 | GEO
Project description:Metabolic dysfunction-associated steatohepatitis (MASH) remains a significant health challenge. Herein, we identify sphingomyelin phosphodiesterase 3 (SMPD3) as a key driver of hepatic ceramide accumulation through increasing sphingomyelin hydrolysis at the cell membrane. Hepatocyte-specific Smpd3 gene disruption and pharmacological inhibition of SMPD3 alleviate MASH, whereas reintroducing SMPD3 reverses the resolution of MASH. While healthy livers express low-level SMPD3, lipotoxicity-induced DNA damage suppresses SIRT1, triggering an upregulation of SMPD3 during MASH. This disrupts membrane sphingomyelin-ceramide balance and promotes MASH progression by enhancing caveolae-dependent lipid uptake in hepatocytes and extracellular vesicle secretion from steatotic hepatocytes to worsen inflammation and fibrosis. Thus, SMPD3 acts as a central hub integrating key MASH hallmarks. Notably, we discovered a bifunctional agent that simultaneously activates SIRT1 and inhibits SMPD3, which shows significant therapeutic potential in MASH treatment. These findings suggest that inhibition of hepatic SMPD3 restores membrane sphingolipid balance and holds great promise for developing novel MASH therapies.
2025-02-26 | GSE271336 | GEO
Project description:Metabolic dysfunction-associated steatohepatitis (MASH) remains a significant health challenge. Herein, we identify sphingomyelin phosphodiesterase 3 (SMPD3) as a key driver of hepatic ceramide accumulation through increasing sphingomyelin hydrolysis at the cell membrane. Hepatocyte-specific Smpd3 gene disruption and pharmacological inhibition of SMPD3 alleviate MASH, whereas reintroducing SMPD3 reverses the resolution of MASH. While healthy livers express low-level SMPD3, lipotoxicity-induced DNA damage suppresses SIRT1, triggering an upregulation of SMPD3 during MASH. This disrupts membrane sphingomyelin-ceramide balance and promotes MASH progression by enhancing caveolae-dependent lipid uptake in hepatocytes and extracellular vesicle secretion from steatotic hepatocytes to worsen inflammation and fibrosis. Thus, SMPD3 acts as a central hub integrating key MASH hallmarks. Notably, we discovered a bifunctional agent that simultaneously activates SIRT1 and inhibits SMPD3, which shows significant therapeutic potential in MASH treatment. These findings suggest that inhibition of hepatic SMPD3 restores membrane sphingolipid balance and holds great promise for developing novel MASH therapies.
2025-02-26 | GSE271335 | GEO
Project description:Metabolic dysfunction-associated steatohepatitis (MASH) remains a significant health challenge. Herein, we identify sphingomyelin phosphodiesterase 3 (SMPD3) as a key driver of hepatic ceramide accumulation through increasing sphingomyelin hydrolysis at the cell membrane. Hepatocyte-specific Smpd3 gene disruption and pharmacological inhibition of SMPD3 alleviate MASH, whereas reintroducing SMPD3 reverses the resolution of MASH. While healthy livers express low-level SMPD3, lipotoxicity-induced DNA damage suppresses SIRT1, triggering an upregulation of SMPD3 during MASH. This disrupts membrane sphingomyelin-ceramide balance and promotes MASH progression by enhancing caveolae-dependent lipid uptake in hepatocytes and extracellular vesicle secretion from steatotic hepatocytes to worsen inflammation and fibrosis. Thus, SMPD3 acts as a central hub integrating key MASH hallmarks. Notably, we discovered a bifunctional agent that simultaneously activates SIRT1 and inhibits SMPD3, which shows significant therapeutic potential in MASH treatment. These findings suggest that inhibition of hepatic SMPD3 restores membrane sphingolipid balance and holds great promise for developing novel MASH therapies.
2025-02-26 | GSE286433 | GEO
Project description:Metabolic dysfunction-associated steatohepatitis (MASH) remains a significant health challenge. Herein, we identify sphingomyelin phosphodiesterase 3 (SMPD3) as a key driver of hepatic ceramide accumulation through increasing sphingomyelin hydrolysis at the cell membrane. Hepatocyte-specific Smpd3 gene disruption and pharmacological inhibition of SMPD3 alleviate MASH, whereas reintroducing SMPD3 reverses the resolution of MASH. While healthy livers express low-level SMPD3, lipotoxicity-induced DNA damage suppresses SIRT1, triggering an upregulation of SMPD3 during MASH. This disrupts membrane sphingomyelin-ceramide balance and promotes MASH progression by enhancing caveolae-dependent lipid uptake in hepatocytes and extracellular vesicle secretion from steatotic hepatocytes to worsen inflammation and fibrosis. Thus, SMPD3 acts as a central hub integrating key MASH hallmarks. Notably, we discovered a bifunctional agent that simultaneously activates SIRT1 and inhibits SMPD3, which shows significant therapeutic potential in MASH treatment. These findings suggest that inhibition of hepatic SMPD3 restores membrane sphingolipid balance and holds great promise for developing novel MASH therapies.
2025-02-26 | GSE271333 | GEO
Project description:Purpose: The goals of this study are to compare next generation sequencing-derived brain cortex transcriptome profiling (RNA-seq) to study the role of neutral sphingomyelinase 2 (smpd3) in brain aging. Methods: Brain cortex mRNA profiles of 10 month old (fro/+) and smpd3 total knockout (fro/fro) mice were generated by deep sequencing, in duplicate, using Illumina NovaSeq 6000. (https://en.novogene.com) Results:A total of 1462 transcripts differed between genotypes, with 891 transcripts increased and 571 transcripts decreased. Conclusions: Transcriptome differences link decreased oxidative stress and astrocyte activation in brain cortex to nSMase2 deficiency, while synaptic signaling transcripts increased in ways consistent with increased cognitive function previously demonstrated in nSMase2-deficient mice.
2022-04-27 | GSE179045 | GEO
Project description:We have used human umbilical vein endothelial cell line (HUVEC) as a model to investigate the effect of ultrasound (US) activated micro-bubbles on sensitizing the tumour response to radiation and to check the implication of this approach on gene expression. The use of micro-bubbles in cancer therapy is a novel approach that is being recently investigated, and patterns of gene expressions were not yet characterized. Gene analysis has identified about 19,264 genes; where, 239 – 517 genes have shown more than two folds up-regulation in response to the different treatments. This included a number of genes that are known to be involved in apoptosis and ceramide-induced apoptosis pathways, such as Sphingomyelin phosphodiesterase 2, neutral sphingomyelinase (SMPD2), sphingomyelin phosphodiesterase 1, acid lysosomal (ASM; SMPD1), UDP-galactose ceramide galactosyltransferase (UGT8), cytochrome c oxidase (COX6B1), Caspase-9 and mitogen-activated protein kinase kinase 1 (MAP2K1). To verify these results, we have performed Real time RT-PCR, which indicated an up-regulation that ranged from 2 to 200 folds, specifically in the combined treatment of US, 3.3% micro-bubbles and 8 Gy. The observed higher levels of expression of UGT8, SMPD2 and Caspase 9-alpha when compared to the control or to radiation only indicated the involvement of ceramide, which possibly induces apoptosis . These results support the hypothesis that micro-bubbles play a role in increasing sensitization to radiation, and can prove to be an effective cancer therapeutic approach. Gene analysis has identified about 19,264 genes; where, 239 – 517 genes have shown more than two folds up-regulation in response to the different treatments. This included a number of genes that are known to be involved in apoptosis and ceramide-induced apoptosis pathways, such as Sphingomyelin phosphodiesterase 2, neutral sphingomyelinase (SMPD2), sphingomyelin phosphodiesterase 1, acid lysosomal (ASM; SMPD1), UDP-galactose ceramide galactosyltransferase (UGT8), cytochrome c oxidase (COX6B1), Caspase-9 and mitogen-activated protein kinase kinase 1 (MAP2K1). To verify these results, we have performed Real time RT-PCR, which indicated an up-regulation that ranged from 2 to 200 folds, specifically in the combined treatment of US, 3.3% micro-bubbles and 8 Gy. The observed higher levels of expression of UGT8, SMPD2 and Caspase 9-alpha when compared to the control or to radiation only indicated the involvement of ceramide, which possibly induces apoptosis . These results support the hypothesis that micro-bubbles play a role in increasing sensitization to radiation, and can prove to be an effective cancer therapeutic approach.
2009-08-27 | E-GEOD-17525 | biostudies-arrayexpress
Project description:RNA transfer via extracellular vesicles (EVs) influences cell phenotypes; however, lack of information regarding biogenesis of RNA-containing EVs has limited progress in the field. Here, we identify endoplasmic reticulum membrane contact sites (ER MCS) as platforms for generation of RNA-containing EVs. We identify a subpopulation of small EVs that is highly enriched in RNA and regulated by the ER MCS linker protein VAP-A. Functionally, VAP-A-regulated EVs are critical for miR-100 transfer between cells and in vivo tumor formation. Lipid analysis of VAP-A-knockdown EVs revealed reductions in the EV biogenesis lipid ceramide. Knockdown of the VAP-A-binding ceramide transfer protein CERT led to similar defects in EV RNA content. Imaging experiments revealed that VAP-A promotes lumenal filling of multivesicular bodies (MVBs). CERT localizes to MVBs, and the ceramide-generating enzyme neutral sphingomyelinase 2 colocalizes with VAP-A-positive ER. We propose that ceramide transfer via VAP-A-CERT linkages drives biogenesis of a select RNA-containing population.
2022-04-05 | GSE188223 | GEO
Project description:Mesenchymal stromal cells (MSCs) are multipotent stromal cells with regenerative, immunomodulatory, and anti-inflammatory properties, making them a promising tool in cell-based therapies. Increasing evidence suggests the therapeutic effects of MSCs are largely mediated by secreted paracrine factors and extracellular vesicles (EVs), which facilitate extracellular communication by transferring bioactive molecules such as proteins, lipids, and nucleic acids to target cells. The lipid composition of EVs is critical for their stability, uptake, and functional activity. Sphingomyelinase (SMase), an enzyme that hydrolyzes sphingomyelin into ceramide, plays a key role in EV biogenesis by influencing membrane curvature allowing for invagination and budding of multivesicular bodies (MVBs). However, the impact of SMase treatment on the characteristics and therapeutic potential of MSC-derived EVs remains largely unexplored. In this study, human MSCs were cultured with SMase for 24 hours and EVs were isolated via ultracentrifugation. EV size distribution was analyzed using nanoparticle tracking analysis (NTA), microRNA (miRNA) profile was determined using RNA-sequencing, while lipidomic and proteomic profiling were assessed using mass spectrometry. Functional assays were conducted to assess changes in bioactivity. NTA revealed a shift in EV production, with a higher vesicle concentration in SMase induced MSCs compared to untreated cells. SMase treatment significantly altered MSC-EV composition, leading to increased ceramide and glycosphingolipids. In addition, the modifications in protein and miRNA EV cargo were found to be associated with pathways involving TNF-α signaling, vesicle trafficking, wound healing, and angiogenesis. Functional assays indicated greater suppression of TNF-α in activated macrophages and greater tubular network formation in HUVECS. These findings provide new insights into distinct biophysical and biochemical changes in MSC-derived EVs following SMase stimulation, potentially enhancing their therapeutic properties and may inform strategies for optimizing future EV-based therapies.
2025-09-03 | GSE306908 | GEO
Project description:We have used human umbilical vein endothelial cell line (HUVEC) as a model to investigate the effect of ultrasound (US) activated micro-bubbles on sensitizing the tumour response to radiation and to check the implication of this approach on gene expression. The use of micro-bubbles in cancer therapy is a novel approach that is being recently investigated, and patterns of gene expressions were not yet characterized. Gene analysis has identified about 19,264 genes; where, 239 – 517 genes have shown more than two folds up-regulation in response to the different treatments. This included a number of genes that are known to be involved in apoptosis and ceramide-induced apoptosis pathways, such as Sphingomyelin phosphodiesterase 2, neutral sphingomyelinase (SMPD2), sphingomyelin phosphodiesterase 1, acid lysosomal (ASM; SMPD1), UDP-galactose ceramide galactosyltransferase (UGT8), cytochrome c oxidase (COX6B1), Caspase-9 and mitogen-activated protein kinase kinase 1 (MAP2K1). To verify these results, we have performed Real time RT-PCR, which indicated an up-regulation that ranged from 2 to 200 folds, specifically in the combined treatment of US, 3.3% micro-bubbles and 8 Gy. The observed higher levels of expression of UGT8, SMPD2 and Caspase 9-alpha when compared to the control or to radiation only indicated the involvement of ceramide, which possibly induces apoptosis . These results support the hypothesis that micro-bubbles play a role in increasing sensitization to radiation, and can prove to be an effective cancer therapeutic approach.
2009-08-27 | GSE17525 | GEO