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Exosomes from mesenchymal stromal cells reduce murine colonic inflammation via a macrophage-dependent mechanism.

ABSTRACT: Conventional treatments for inflammatory bowel disease (IBD) have multiple potential side effects. Therefore, alternative treatments are desperately needed. This work demonstrated that systemic administration of exosomes from human bone marrow-derived mesenchymal stromal cells (MSC-Exos) substantially mitigated colitis in various models of IBD. MSC-Exos treatment downregulated inflammatory responses, maintained intestinal barrier integrity, and polarized M2b macrophages but did not favor intestinal fibrosis. Mechanistically, infused MSC-Exos acted mainly on colonic macrophages, and macrophages from colitic colons acquired obvious resistance to inflammatory restimulation when prepared from mice treated with MSC-Exos versus untreated mice. The beneficial effect of MSC-Exos was blocked by macrophage depletion. Also, the induction of IL-10 production from macrophages was partially involved in the beneficial effect of MSC-Exos. MSC-Exos were enriched in proteins involved in regulating multiple biological processes associated with the anticolitic benefit of MSC-Exos. Particularly, metallothionein-2 in MSC-Exos was required for the suppression of inflammatory responses. Taken together, MSC-Exos are critical regulators of inflammatory responses and may be promising candidates for IBD treatment.

SUBMITTER: Liu H

PROVIDER: S-EPMC6975270 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Exosomes from mesenchymal stromal cells reduce murine colonic inflammation via a macrophage-dependent mechanism.

Liu Huashan H Liang Zhenxing Z Wang Fengwei F Zhou Chi C Zheng Xiaobin X Hu Tuo T He Xiaowen X Wu Xianrui X Lan Ping P

JCI insight 20191219 24

Conventional treatments for inflammatory bowel disease (IBD) have multiple potential side effects. Therefore, alternative treatments are desperately needed. This work demonstrated that systemic administration of exosomes from human bone marrow-derived mesenchymal stromal cells (MSC-Exos) substantially mitigated colitis in various models of IBD. MSC-Exos treatment downregulated inflammatory responses, maintained intestinal barrier integrity, and polarized M2b macrophages but did not favor intesti ...[more]

PMID: 31689240

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Project description:The study: Bone marrow-derived mesenchymal stromal cells (MSC) can be triggered to enhance the expression of repair associated factors by certain stimuli. The purpose of this study was to perform a transcriptome-wide analysis of the effect of macrophage-derived inflammation on MSC and evaluate the repair potential of the conditioned cells. To validate the results, we compared the condition of interest to three control conditions, described bellow. Methods: MSC were cultured in baseline conditions (D10 medium) until reaching passage 4. In parallel, monocytes were differentiated to macrophages and polarized to pro-inflammatory (M1) or non-polarized (M0). After 24h of polarization, the supernatants were collected to produce M1CM and M0CM, respectively. The medium used for macrophage polarization (Pol1) was included in the conditions for MSC culture as a control. The medium of all MSC cultures was changed into fresh D10, M1CM, M0CM or Pol1, and they were cultured for 24h (conditioning). Then, MSC were trypsinized and their RNA was extracted. We worked with Novogene Inc. USA for the RNAsequencing, which they performed based on the Illumina platform. Novogene performed the sequencing, data processing and preliminary analysis. We then did the downstream analysis and data interpretation. Results: Dowstream analysis, after data processing was completed for all samples and groups, was focused on the comparison M1CM vs D10. This is because the effect of M0CM and Pol1 on MSC was minor compared to the effect of M1CM, based on correlation and Venn diagram analysis. M1CM induced 1721 upregulated DEG and 1487 downregulated DEG in MSC compared to D10. Among those genes, the GO and KEGG analyses showed enrichment in GO terms and pathways associated to the enhancement of angiogenesis, immunomodulation, paracrine cell survival, tissue development and regeneration, indicating increased therapeutic potential. Additionally, genes associated with programmed cell death were upregulated, while cell cycle and motility associated genes were downregulated, indicating compromised cell viability and motility. Conclusions: We found that macrophage-derived inflammation induces a transcriptomic makeover on MSC, enhancing their reparative potential. These results reveal the possibility to use inflammation as a priming method for MSC before transplantation, which could potentiate the transplant's efficacy. Further pre-clinical studies are necessary to determine the effects of the beneficial outcomes in tissue, as well as the implications of compromised viability and motility.

Dataset Information

Exosomes from mesenchymal stromal cells reduce murine colonic inflammation via a macrophage-dependent mechanism.

Publications

Exosomes from mesenchymal stromal cells reduce murine colonic inflammation via a macrophage-dependent mechanism.

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