Radio-detoxified LPS alters bone marrow-derived extracellular vesicles and endothelial progenitor cells

Abstract

Stem cell-based therapies raise hope for cell replacement and provide opportunity for cardiac regenerative medicine and tumor therapy. Extracellular vesicles are a membrane-enclosed intercellular delivery system with the potential to improve the therapeutic efficacy of the treatment of a variety of disorders. As the incidence of breast cancer continues to rise, radiotherapy has emerged as a leading treatment modality. Radiotherapy also increases the risk of coronary heart disease and cardiac mortality. In a chest-irradiated mouse model of cardiac injury, we investigated the effects of local irradiation. We found an increased lethality after 16 Gy irradiation. Importantly, radio-detoxified LPS (RD-LPS) treatment prolonged the survival significantly. By flow cytometry, we demonstrated that upon administration of RD-LPS, the number of bone marrow-derived endothelial progenitor cells increased in the bone marrow and, in particular, in the circulation. Furthermore, mass spectrometry analysis showed that RD-LPS altered the proteomic composition of bone marrow cell-derived small extracellular vesicles (sEVs). RD-LPS treatment increased interferon-induced transmembrane protein-3 (IFITM3) expression markedly both in bone marrow cells and in bone marrow cell-derived small extracellular vesicles. This is the first study to demonstrate that radio-detoxified LPS treatment induces an increase of circulating endothelial progenitor cells (EPCs) in parallel with a reduced radiotherapy-related mortality. While the total number of bone marrow-derived extracellular vesicles was significantly increased 24 h after treatment in the RD-LPS groups, the number of endothelial progenitor cells was reduced in animals injected with GW4896 (a chemical inhibitor of exosome biogenesis) as compared with controls. In contrast to these in vivo results, in vitro experiments did not support the effect of sEVs on EPCs. Our data raise the intriguing possibility that IFITM3 may serve as a marker of the radio-detoxified LPS treatment.

Recent Advances of Using Exosomes as Diagnostic Markers and Targeting Carriers for Cardiovascular Disease

“…Lipopolysaccharides, nitric oxide, deferoxamine, interferon, and tumor necrosis factor enhance the efficacy of exosomes. Similar enhancement was reported for stimulation with cytokines, such as ILs and hypoxia-inducible factors. , Several miRNAs and ultraviolet induction also enhance the efficacy of exosomes . Gene transfection and cell surface modification of stem cells enhance the treatment effect of exosomes (Figure ).…”

“…62,63 Several miRNAs and ultraviolet induction also enhance the efficacy of exosomes. 64 Gene transfection and cell surface modification of stem cells enhance the treatment effect of exosomes 65 (Figure 2).…”

Announcing the ISEV2020 special achievement award recipients: Andrew Hill and Edit Buzás; and the recipient of the ISEV2020 special education award: Carolina Soekmadji

“…Edit Buzás is Professor and Chair of the Department of Genetics, Cell‐ and Immunobiology at Semmelweis University in Budapest, Hungary. With a background in immunology, Edit has furthered our understanding of EV subtypes (Crescitelli et al., 2013; Osteikoetxea, Balogh, et al., 2015; Valcz et al., 2019), EVs in inflammation and cardiology (Giricz et al., 2014; Hegyesi et al., 2019; Marton et al., 2017; Osteikoetxea et al., 2016), and the roles that EVs play in the complex menagerie of blood and other biofluids, interacting with lipoproteins and protein complexes (Osteikoetxea, Sódar, et al., 2015; Sódar et al., 2016). Already in 2011, she published a highly influential review article on extracellular vesicles, emphasizing the diversity of EVs and endorsing “extracellular vesicle” as a collective term to encompass this diversity (Gyorgy et al., 2011).…”

Circulating cardiomyocyte-derived extracellular vesicles reflect cardiac injury during systemic inflammatory response syndrome in mice

“…Recently, outstanding interest has been attracted by EVs as a potential next-generation biomarker. EVs have been shown to cross biological barriers and serve as promising complex diagnostic and prognostic tools [ 2 ]. Secreted by various types of cells, EVs carry important biomolecules originating from their parent cells.…”