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Phosphatidylserine-deficient small extracellular vesicle is a major somatic cell-derived sEV subpopulation in blood.

ABSTRACT: Small extracellular vesicles (sEVs) are important mediators of intercellular communication with respect to diverse pathophysiological processes. Here, we determined novel phosphatidylserine (PS)-deficient sEV subpopulations as a major somatic cell-derived sEV subpopulation in blood because of long blood circulation half-life through escape from macrophage uptake. PS^(-)-sEVs were identified in various cultured cells as a minor population. However, as a result of rapid uptake of PS⁽⁺⁾-sEVs by macrophages, circulating somatic cell-derived sEVs in the blood were found to be mainly PS^(-)-sEVs. These results suggest that endogenous PS^(-)-sEVs could indeed be the key player in sEV-mediated intercellular communication, a good target for sEV-based diagnosis, and a potent candidate for sEV-based drug delivery. Our findings bring a paradigm shift in the understanding of the biology and translational applications of sEVs.

SUBMITTER: Matsumoto A

PROVIDER: S-EPMC8326202 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Phosphatidylserine-deficient small extracellular vesicle is a major somatic cell-derived sEV subpopulation in blood.

Matsumoto Akihiro A Takahashi Yuki Y Ogata Kosuke K Kitamura Shimpei S Nakagawa Naoki N Yamamoto Aki A Ishihama Yasushi Y Takakura Yoshinobu Y

iScience 20210710 8

Small extracellular vesicles (sEVs) are important mediators of intercellular communication with respect to diverse pathophysiological processes. Here, we determined novel phosphatidylserine (PS)-deficient sEV subpopulations as a major somatic cell-derived sEV subpopulation in blood because of long blood circulation half-life through escape from macrophage uptake. PS<sup>(-)</sup>-sEVs were identified in various cultured cells as a minor population. However, as a result of rapid uptake of PS<sup> ...[more]

PMID: 34368655

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Project description:Toxoplasma gondii uracil phosphoribosyltransferase (UPRT) converts 4-thiouracil (4TUc) into 4-thiouridine (4TUd), which is incorporated into nascent RNAs and can be biotinylated, then labelled with streptavidin conjugates or isolated via streptavidin-affinity methods. Here, we generated mice that expressed T. gondii UPRT only in cardiomyocytes (CM UPRT mice) and tested our hypothesis that CM-derived miRNAs (CM miRs) are transferred into remote organs after myocardial infarction (MI) by small extracellular vesicles (sEV) that are released from the heart into the peripheral blood (PB sEV). We found that 4TUd was incorporated with high specificity and sensitivity into RNAs isolated from the hearts and PB sEV of CM UPRT mice 6 h after 4TUc injection. In PB sEV, 4TUd was incorporated into CM-specific/enriched miRs including miR-208a, but not into miRs with other organ or tissue-type specificities. 4TUd-labelled miR208a was also present in lung tissues, especially lung endothelial cells (ECs), and CM-derived miR-208a (CM miR-208a) levels peaked 12 h after experimentally induced MI in PB sEV and 24 h after MI in the lung. Notably, miR-208a is expressed from intron 29 of α myosin heavy chain (αMHC), but αMHC transcripts were nearly undetectable in the lung. When PB sEV from mice that underwent MI (MI-PB sEV) or sham surgery (Sham-PB sEV) were injected into intact mice, the expression of Tmbim6 and NLK, which are suppressed by miR-208a and cooperatively regulate inflammation via the NF-κB pathway, was lower in the lungs of MI-PB sEV-treated animals than the lungs of animals treated with Sham-PB sEV or saline. In MI mice, Tmbim6 and NLK were downregulated, whereas endothelial adhesion molecules and pro-inflammatory cells were upregulated in the lung; these changes were significantly attenuated when the mice were treated with miR-208a antagomirs prior to MI surgery. Thus, CM UPRT mice enables us to track PB sEV-mediated transport of CM miRs and identify an miR-208a-mediated mechanism by which myocardial injury alters the expression of genes and inflammatory response in the lung.

Project description:BackgroundTumor-derived small extracellular vesicles (sEVs) can promote tumorigenic and metastatic capacities in less aggressive recipient cells mainly through the biomolecules in their cargo. However, despite recent advances, the specific molecules orchestrating these changes are not completely defined. Lactadherin is a secreted glycoprotein typically found in the milk fat globule membrane. Its overexpression has been associated with increased tumorigenesis and metastasis in breast cancer (BC) and other tumors. However, neither its presence in sEVs secreted by BC cells, nor its role in sEV-mediated intercellular communication have been described. The present study focused on the role of lactadherin-containing sEVs from metastatic MDA-MB-231 triple-negative BC (TNBC) cells (sEV-MDA231) in the promotion of pro-metastatic capacities in non-tumorigenic and non-metastatic recipient cells in vitro, as well as their pro-metastatic role in a murine model of peritoneal carcinomatosis.ResultsWe show that lactadherin is present in sEVs secreted by BC cells and it is higher in sEV-MDA231 compared with the other BC cell-secreted sEVs measured through ELISA. Incubation of non-metastatic recipient cells with sEV-MDA231 increases their migration and, to some extent, their tumoroid formation capacity but not their anchorage-independent growth. Remarkably, lactadherin blockade in sEV-MDA231 results in a significant decrease of those sEV-mediated changes in vitro. Similarly, intraperitoneally treatment of mice with MDA-MB-231 BC cells and sEV-MDA231 greatly increase the formation of malignant ascites and tumor micronodules, effects that were significantly inhibited when lactadherin was previously blocked in those sEV-MDA231.ConclusionsAs to our knowledge, our study provides the first evidence on the role of lactadherin in metastatic BC cell-secreted sEVs as promoter of: (i) metastatic capacities in less aggressive recipient cells, and ii) the formation of malignant ascites and metastatic tumor nodules. These results increase our understanding on the role of lactadherin in sEVs as promoter of metastatic capacities which can be used as a therapeutic option for BC and other malignancies.

Dataset Information

Phosphatidylserine-deficient small extracellular vesicle is a major somatic cell-derived sEV subpopulation in blood.

Publications

Phosphatidylserine-deficient small extracellular vesicle is a major somatic cell-derived sEV subpopulation in blood.

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