Dataset Information

Accumulation of kynurenine elevates oxidative stress and alters microRNA profile in human bone marrow stromal cells.

ABSTRACT: Kynurenine, a metabolite of tryptophan breakdown, has been shown to increase with age, and plays a vital role in a number of age-related pathophysiological changes, including bone loss. Accumulation of kynurenine in bone marrow stromal cells (BMSCs) has been associated with a decrease in cell proliferation and differentiation, though the exact mechanism by which kynurenine mediates these changes is poorly understood. MiRNAs have been shown to regulate BMSC function, and accumulation of kynurenine may alter the miRNA expression profile of BMSCs. The aim of this study was to identify differentially expressed miRNAs in human BMSCs in response to treatment with kynurenine, and correlate miRNAs function in BMSCs biology through bioinformatics analysis. Human BMSCs were cultured and treated with and without kynurenine, and subsequent miRNA isolation was performed. MiRNA array was performed to identify differentially expressed miRNA. Microarray analysis identified 50 up-regulated, and 36 down-regulated miRNAs in kynurenine-treated BMSC cultures. Differentially expressed miRNA included miR-1281, miR-330-3p, let-7f-5p, and miR-493-5p, which are important for BMSC proliferation and differentiation. KEGG analysis found up-regulated miRNA targeting glutathione metabolism, a pathway critical for removing oxidative species. Our data support that the kynurenine dependent degenerative effect is partially due to changes in the miRNA profile of BMSCs.

SUBMITTER: Dalton S

PROVIDER: S-EPMC6998036 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Accumulation of kynurenine elevates oxidative stress and alters microRNA profile in human bone marrow stromal cells.

Dalton Sherwood S Smith Kathryn K Singh Kanwar K Kaiser Helen H Kolhe Ravindra R Mondal Ashis K AK Khayrullin Andrew A Isales Carlos M CM Hamrick Mark W MW Hill William D WD Fulzele Sadanand S

Experimental gerontology 20191130

Kynurenine, a metabolite of tryptophan breakdown, has been shown to increase with age, and plays a vital role in a number of age-related pathophysiological changes, including bone loss. Accumulation of kynurenine in bone marrow stromal cells (BMSCs) has been associated with a decrease in cell proliferation and differentiation, though the exact mechanism by which kynurenine mediates these changes is poorly understood. MiRNAs have been shown to regulate BMSC function, and accumulation of kynurenin ...[more]

PMID: 31790802

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Project description:FK506 (also known as tacrolimus) is a potent immunosuppressive agent that is widely used in the treatment of graft-rejection and autoimmune diseases. FK506 has attracted additional attention owing to its potential role in osteogenic differentiation and bone formation. MicroRNAs (miRNAs) have been demonstrated to serve important roles in the regulation of osteogenic differentiation; however, identification of specific miRNAs and their roles in regulating FK506‑induced osteogenic differentiation have been poorly examined. In the present study, osteodifferentiation of rat bone marrow stromal cells (BMSCs) was induced with varying concentrations of FK506 (5‑5,000 nM) for 3, 7 and 14 days. Differentially expressed miRNAs were profiled using miRNA array, verified by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and subjected to gene ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Results from the present study identified a subset of miRNAs that were differentially expressed, of which five upregulated miRNAs (miR‑106b‑5p, miR‑101b‑3p, miR‑193a‑3p, miR‑485‑3p and miR‑142‑3p) and four downregulated miRNAs (miR‑27a‑3p, miR‑207, miR‑218a‑2‑3p and let‑7a‑5p) were confirmed by RT‑qPCR. GO and KEGG analysis revealed that the predicted target genes of these miRNAs are involved in multiple biological processes and signaling pathways, including cell differentiation and the mitogen‑activated protein kinase (MAPK) signaling pathway. Verification of the miRNA‑target genes revealed that Smad5, Jagged 1 and MAPK9 were significantly upregulated, whereas Smad7, BMP and activin membrane‑bound inhibitor, and dual‑specificity phosphatase 2 were significantly downregulated during FK506‑induced osteodifferentiation. The present study may provide an experimental basis for further research on miRNA functions during FK506‑induced osteogenic differentiation in rat BMSCs.

Project description:Background and Aims: MicroRNAs (miRNAs) play important roles in hepatocyte differentiation from human bone marrow mesenchymal stem cells (hBMSCs) and the therapeutic application in vivo. However, the mechanisms of miRNA regulation are still unknown. This study aimed to profile the miRNA basis for improving the function of hBMSC-differentiated hepatocyte-like cells (hBMSC-Heps). Methods: Characteristic miRNAs of hBMSC-Heps were identified by transcriptome sequencing and validated by quantitative real-time polymerase chain reaction (qRT-PCR). An in vivo hBMSC transplantation model was used to assess the regulatory effects of miRNAs on liver regeneration during hBMSC therapy in pigs with fulminant hepatic failure (FHF). The biological functions of significant miRNA molecules were confirmed by transfection of miRNA activators or inhibitors into hBMSCs during hepatogenic differentiation. Results: The transcriptome of hBMSC-Heps showed characteristics distinct from those of undifferentiated hBMSCs. A total of 77 miRNAs were significantly differentially expressed in hBMSC-Heps at day 10 and day 20 after hBMSC differentiation that were directly related to the functions of hepatocytes. Among the top 10 significantly differentially expressed and the top 10 most abundant miRNAs, nine miRNAs that exhibited a pattern of gradual change were chosen for further analysis. The expression of nine miRNAs was confirmed by qRT-PCR in vitro and showed the same changing trends in vivo in an hBMSC transplantation model in pigs. Functional experiments with these miRNAs showed that activators of hsa-miR-26b-5p and hsa-miR-148a-3p and an inhibitor of hsa-miR-423-3p were sufficient to improve the differentiation of hBMSCs into hepatocyte-like cells. Conclusions: Transcriptome profiles of miRNA revealed the basis of the differentiation and development of hBMSC-Heps. Manipulation of three miRNAs (hsa-miR-26b-5p, hsa-miR-148a-3p and hsa-miR-423-3p) significantly improved hepatocyte generation and liver regeneration, indicating the potential of these miRNAs for future clinical applications.

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Accumulation of kynurenine elevates oxidative stress and alters microRNA profile in human bone marrow stromal cells.

Publications

Accumulation of kynurenine elevates oxidative stress and alters microRNA profile in human bone marrow stromal cells.

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