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Effects of Autophagy Modulators Tamoxifen and Chloroquine on the Expression Profiles of Long Non-Coding RNAs in MIAMI Cells Exposed to IFNg

ABSTRACT: Effects of Autophagy Modulators Tamoxifen and Chloroquine on the Expression Profiles of Long Non-Coding RNAs in MIAMI Cells Exposed to IFNg

PROVIDER: PRJNA809705 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18115969_1.fastq.gz	Fastqsanger.gz
	SRR18115969_2.fastq.gz	Fastqsanger.gz
	SRR18115970_1.fastq.gz	Fastqsanger.gz
	SRR18115970_2.fastq.gz	Fastqsanger.gz
	SRR18115971_1.fastq.gz	Fastqsanger.gz

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Project description:Mesenchymal stromal cells (MSCs) can be utilized clinically for treatment of conditions that result from excessive inflammation. In a pro-inflammatory environment, MSCs adopt an anti-inflammatory phenotype resulting in immunomodulation. A sub-type of MSCs referred to as “marrow-isolated adult multilineage inducible” (MIAMI) cells, which were isolated from bone marrow, were utilized to show that the addition of autophagy modulators, tamoxifen (TX) or chloroquine (CQ), can alter how MIAMI cells respond to IFNg exposure in vitro resulting in an increased immunoregulatory capacity of the MIAMI cells. Molecularly, it was also shown that TX and CQ each alter both the levels of immunomodulatory genes and microRNAs which target such genes. However, the role of other non-coding RNAs (ncRNAs) such as long non-coding RNAs (lncRNAs) in regulating the response of MSCs to inflammation has been poorly studied. Here, we utilized transcriptomics and data mining to analyze the putative roles of various differentially regulated lncRNAs in MIAMI cells exposed to IFNg with (or without) TX or CQ. The aim of this study was to investigate how the addition of TX and CQ alters lncRNA levels and evaluate how such changes could alter previously observed TX- and CQ-driven changes to the immunomodulatory properties of MIAMI cells. Data analysis revealed 693 long intergenic non-coding RNAS (lincRNAs), 480 pseudogenes, and 642 antisense RNAs that were differentially regulated with IFNg, IFNg+TX and IFNg+CQ treatments. Further analysis of these RNA species based on the existing literature data revealed 6 antisense RNAs, 2 pseudogenes, and 5 lincRNAs that have the potential to modulate MIAMI cell’s response to IFNg treatment. Functional analysis of these genomic species based on current literature linking inflammatory response and ncRNAs indicated their potential for regulation of several key pro- and anti-inflammatory responses, including NFkB signaling, cytokine secretion and auto-immune responses. Overall, this work found potential involvement of multiple pro-and anti-inflammatory pathways and molecules in modulating MIAMI cells’ response to inflammation.

Project description:Bone marrow mesenchymal stromal cells (MSCs) are therapeutic cells which adopt an immunomodulatory phenotype when exposed to pro-inflammatory cytokines and thus can be used for treatment of conditions associated with excessive inflammation. It was suggested recently that many therapeutic benefits of MSCs can be attributed to the secretion of exosomes, small membrane vesicles of endocytic origin. Exosome formation and release are impacted by the autophagy pathway, a homeostatic quality control mechanism that recycles proteins and organelles via lysosomal degradation. We hypothesized that the exposure of MSCs to autophagy modulators in the presence of a pro-inflammatory cytokine IFN may impact on exosome RNA content and immunomodulatory properties. To address this hypothesis, we treated MSCs with either tamoxifen (TX) or chloroquine (CQ) to stimulate or inhibit autophagy, respectively, in the presence of pro-inflammatory cytokine, IFN. Subsequently, we characterized exosomes from such cells and determined their functional and molecular properties. Exosomes’ immunoregulatory properties were evaluated ex-vivo using activated CD4 T cells and subsequent flow cytometry analysis to assess the effects of exosomes on CD4 T cell proliferation. We also performed small RNA sequencing to determine exosomal microRNA content. Subsequently, we performed functional analysis to determine potential effects of exosomal microRNAs on the expression of genes in target cells. Our data indicate that the exosomes isolated from MSCs treated with CQ+IFN possess higher capacity to decrease T cell proliferation. Small RNA sequencing of exosomal RNA revealed that, although similar microRNAs were found to be expressed in exosomes isolated from all treated cells, the treatments did affect the levels of multiple microRNAs. Analysis of putative gene targets revealed that most microRNA-target genes belong to either cancer or inflammation-related biological pathways. Overall, we conclude that the pre-treatment of MSCs with small molecules, in addition to pro-inflammatory cytokines, has a potential to additionally modulate biological targets of exosomes and thus biological effects of the latter.

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Effects of Autophagy Modulators Tamoxifen and Chloroquine on the Expression Profiles of Long Non-Coding RNAs in MIAMI Cells Exposed to IFNg

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