Extracellular vesicles containing miR-146a-5p activate hepatocytic progenitor cells in regenerating retrorsin-treated rat livers
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PROVIDER: PRJNA644882 | ENA |
REPOSITORIES: ENA
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Project description:BackgroundSmall hepatocyte-like progenitor cells (SHPCs) appear to form transient clusters in rat livers treated with retrorsine (Ret) and 70% partial hepatectomy (PH). We previously reported that the expansion of SHPCs was amplified in Ret/PH-treated rat livers transplanted with Thy1+ cells derived from D-galactosamine-treated injured livers. Extracellular vesicles (EVs) produced by hepatic Thy1+ donor cells activated SHPCs via interleukin (IL)-17 receptor B signaling. As bone marrow-derived mesenchymal cells (BM-MCs) also express Thy1, we aimed to determine whether BM-MCs could also promote the growth of SHPCs.MethodsBM-MCs were isolated from dipeptidyl-peptidase IV (DPPIV)-positive rats. BM-MCs or BM-MC-derived EVs were administered to DPPIV-negative Ret/PH rat livers, and the growth and the characteristics of SHPC clusters were evaluated 14 days post-treatment. miRNA microarrays and cytokine arrays examined soluble factors within EVs. Small hepatocytes (SHs) isolated from an adult rat liver were used to identify factors enhancing hepatocytic progenitor cells growth.ResultsThe recipient's livers were enlarged at 2 weeks post-BM-MC transplantation. The number and the size of SHPCs increased remarkably in livers transplanted with BM-MCs. BM-MC-derived EVs also stimulated SHPC growth. Comprehensive analyses revealed that BM-MC-derived EVs contained miR-146a-5p, interleukin-6, and stem cell factor, which could enhance SHs' proliferation. Administration of EVs derived from the miR-146a-5p-transfected BM-MCs to Ret/PH rat livers remarkably enhanced the expansion of SHPCs.ConclusionsmiR-146a-5p involved in EVs produced by BM-MCs may play a major role in accelerating liver regeneration by activating the intrinsic hepatocytic progenitor cells.
| S-EPMC8164814 | biostudies-literature
Project description:We found that the transplantation of bone marrow mesenchymal cells (BM-MCs) transiently increased the liver mass by expanding resident small hepatocy-like progenitor cells (SHPCs). We used microarrays to detail the gene expression of SHPCs clusters with and without BM-MCs transplantation.
2020-07-09 | GSE154022 | GEO
Project description:Small hepatocyte-like progenitor cells (SHPCs) are hepatocytic progenitor cells that transiently form clusters in rat livers treated with retrorsine and with 70% partial hepatectomy (PH). We previously reported that transplantation of Thy1+ cells derived from D-galactosamine-treated livers promotes SHPC expansion, resulting in the acceleration of liver regeneration. Extracellular vesicles (EVs) produced by Thy1+ cells act on sinusoidal endothelial cells (SECs) and Kupffer cells to secrete IL17B and IL25, respectively, resulting in SHPC activation through IL17 receptor B (RB) signaling. Our aim is to identify factors in Thy1-EVs that activate IL17RB signaling. Thy1+ cells isolated from rats with D-galactosamine-induced liver injury were cultured for one week. Although some liver stem/progenitor cells proliferated into colonies, others maintained as mesenchymal cells (MCs). Thy1-MCs or Thy1-liver stem/progenitor cells were transplanted into retrorsine/PHtreated livers to examine their effects on SHPCs. SHs isolated from adult rat livers were used to validate factors regulating growth induction. The number and size of SHPCs remarkably increased in livers transplanted with Thy1-MCs. Comprehensive analysis of Thy1-MC-EVs revealed that miR-199a-5p, CINC-2, and MCP-1 are candidates for stimulating SHPC growth. Administration of the miR-199a-5p mimic, and not CINC-2, promoted SH growth. SECs treated with CINC-2 induced IL17b expression and their conditioned medium promoted SH growth. Thy1-MC transplantation may accelerate liver regeneration due to SHPCs expansion, which is stimulated by CINC-2/IL17RB signaling and miR-199a-5p.
2023-04-07 | PXD039384 | Pride
Project description:Analysis of human mesenchymal stem cells (MSC) from bone marrow and the Wharton's jelly of the umbilical cord after manupulating miR-146a-5p expression. miR-146a-5p is involved in controlling the proliferation and migration of MSCs. Results provide miR-146a-5p-regulating genes in MSCs. In this study, BM-MSCs transduced with miR-146a-5p expression vector or pCDH-CMV-MCS-EF1-copGFP vector only, as well as two WJ-MSCs transfected with short interfering RNAs targeting miR-146a or a GFP control.
2013-09-05 | E-GEOD-44186 | biostudies-arrayexpress
Project description:Analysis of human mesenchymal stem cells (MSC) from bone marrow and the Wharton's jelly of the umbilical cord after manupulating miR-146a-5p expression. miR-146a-5p is involved in controlling the proliferation and migration of MSCs. Results provide miR-146a-5p-regulating genes in MSCs.
2013-09-05 | GSE44186 | GEO
Project description:We established stable miR-146a-5p overexpression T24 cells, then performed transcriptome profiling of miR-146a-5p overexpressing cells compared to control T24 cells to detect the molecular mechanisms of the miR-146a-5p’s effect on bladder cancer cells.
2024-02-03 | GSE166139 | GEO
Project description:MicroRNAs (miRNAs) are small non-coding RNAs that function as modulators of gene expression. We previously showed that miR-146a-5p is upregulated in pancreatic islets treated with pro-inflammatory cytokines and in pancreatic sections from organ donors with type 1 diabetes (T1D). Other studies have associated overexpression of miR-146a-5p with β cell apoptosis and impaired insulin secretion; however, the molecular mechanisms mediating these effects remain elusive. To investigate the role of miR-146a-5p in β cell function, we developed stable MIN6 cell lines transduced with lentiviral vectors to either overexpress or inhibit the expression of miR-146a-5p. Monoclonal cell populations were treated with pro-inflammatory cytokines (IL1β, IFNg, and TNFα) to model T1D in vitro. We found that overexpression of miR-146a-5p increased the cell death of MIN6 cells under inflammatory stress, whereas inhibition of miR-146a-5p reversed these effects. Additionally, inhibition of miR-146a-5p increased mitochondrial DNA copy number, respiration rate, and ATP production, suggesting that miR-146a-5p inhibition improves mitochondrial function. In support of this finding, we also observed that miR-146a-5p is enriched in the mitochondria of MIN6 cells treated with cytokines. Consistently, bioinformatic analysis of RNA sequencing data using MIN6 stable cells showed enrichment of pathways related to insulin secretion, apoptosis, and mitochondrial function when the expression levels of miR-146a-5p were altered. Overall, the findings from our study show for the first time that miR-146a-5p upregulation during inflammatory stress may promote β cell dysfunction and death by suppressing mitochondrial function.
2024-04-10 | GSE255756 | GEO
Project description:We analyzed gene expression of hepatocytic parental progenitor cells in a population of small hepatocytes. The hepatocytic parental progenitor cells possess self-renewal capability. These cells maintain the ability to differentiate into mature hepatocytes.
2016-09-08 | GSE86523 | GEO
Project description:Oncogenic mutations in BRAF and NRAS occur in 70% of melanomas. Here we identify a microRNA, miR-146a, that is highly upregulated by oncogenic BRAF and NRAS. Expression of miR-146a increases the ability of human melanoma cells to proliferate in culture and form tumors in mice, whereas knockdown of miR-146a has the opposite effects. We show these oncogenic activities are due to miR-146a targeting the NUMB mRNA, a repressor of Notch signaling. Previous studies have shown that pre-miR-146a contains a single nucleotide polymorphism (C>G rs2910164). We find that the ability of pre-miR-146a/G to activate Notch signaling and promote oncogenesis is substantially higher than that of pre-miR-146a/C. Analysis of melanoma cell lines and matched patient samples indicates that during melanoma progression pre-miR-146a/G is enriched relative to pre-miR-146a/C, resulting from a C-to-G somatic mutation in pre-miR-146a/C. Collectively, our results reveal a central role for miR-146a in the initiation and progression of melanoma.
2014-02-18 | GSE39983 | GEO
Project description:Oncogenic mutations in BRAF and NRAS occur in 70% of melanomas. Here we identify a microRNA, miR-146a, that is highly upregulated by oncogenic BRAF and NRAS. Expression of miR-146a increases the ability of human melanoma cells to proliferate in culture and form tumors in mice, whereas knockdown of miR-146a has the opposite effects. We show these oncogenic activities are due to miR-146a targeting the NUMB mRNA, a repressor of Notch signaling. Previous studies have shown that pre-miR-146a contains a single nucleotide polymorphism (C>G rs2910164). We find that the ability of pre-miR-146a/G to activate Notch signaling and promote oncogenesis is substantially higher than that of pre-miR-146a/C. Analysis of melanoma cell lines and matched patient samples indicates that during melanoma progression pre-miR-146a/G is enriched relative to pre-miR-146a/C, resulting from a C-to-G somatic mutation in pre-miR-146a/C. Collectively, our results reveal a central role for miR-146a in the initiation and progression of melanoma.
2014-02-18 | GSE39294 | GEO