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WJMSC-derived small extracellular vesicle enhance T cell suppression through PD-L1.

ABSTRACT: Both mesenchymal stem cells (MSCs) and their corresponding small extracellular vesicles (sEVs, commonly referred to as exosomes) share similar immunomodulatory properties that are potentially beneficial for the treatment of acute graft versus host disease (aGvHD). We report that clinical grade Wharton's Jelly-derived MSCs (WJMSCs) secrete sEVs enriched in programmed death-ligand 1 (PD-L1), an essential ligand for an inhibitory immune checkpoint. A rapid increase in circulating sEV-associated PD-L1 was observed in patients with aGvHD and was directly associated with the infusion time of clinical grade WJMSCs. In addition, in vitro inhibitory antibody mediated blocking of sEV-associated PD-L1 restored T cell activation (TCA), suggesting a functional inhibitory role of sEVs-PD-L1. PD-L1-deficient sEVs isolated from WJMSCs following CRISPR-Cas9 gene editing fail to inhibit TCA. Furthermore, we found that PD-L1 is essential for WJMSC-derived sEVs to modulate T cell receptors (TCRs). Our study reveals an important mechanism by which therapeutic WJMSCs modulate TCR-mediated TCA through sEVs or sEV-carried immune checkpoints. In addition, our clinical data suggest that sEV-associated PD-L1 may be not only useful in predicting the outcomes from WJMSC clinical administration, but also in developing cell-independent therapy for aGvHD patients.

SUBMITTER: Li M

PROVIDER: S-EPMC7869022 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Osteosarcoma (OS) is the most common primary bone cancer characterized by an aggressive phenotype with bone destruction. The prognosis of OS patients remains unoptimistic with the current treatment strategy. Recently, osteoclasts are believed to play a crucial role in cancer bone metastasis. Thus, osteoclast could be a target both in bone destruction and cancer progression in OS. However, mechanisms governing osteoclastogenesis in OS remain poorly understood. miRNA delivered by small extracellular vesicles (sEVs) could mediate cellular communications. In this study, we investigated the effects of sEVs on osteoclastogenesis and osteoclast function, also clarified the underlying mechanism. We herein found that sEVs promoted pre-osteoclast migration, osteoclastogenesis and resorption by exposing RAW264.7 cells to sEVs derived from OS cells. Bioinformatics analysis showed that phosphatase tension homologue (PTEN), and miR-19a-3p were involved in OS progression. Overexpression of miR-19a-3p or sEVs' miR-19a-3p promoted osteoclast formation and function through PTEN/PI3K/AKT signaling pathway, while inhibition of miR-19a-3p showed the contrary results. The bone marrow macrophages (BMMs) were used to verify the results. OS mice, which were established by subcutaneous injection of OS cells, exhibited increased levels of sEVs' miR-19a-3p in blood. Moreover, micro-computed tomography (CT) and histomorphometry analysis demonstrated that OS mice exhibited osteopenia with increased number of osteoclasts. In conclusion, miR-19a-3p delivery via OS cell-derived sEVs promotes osteoclast differentiation and bone destruction through PTEN/phosphatidylinositol 3 -kinase (PI3K)/protein kinase B (AKT) signaling pathway. These findings highlight sEVs packaging of miR-19a-3p as a potential target for prevention and treatment of bone destruction and cancer progression in OS patients. And this finding provides a novel potentially therapeutic target for the bone metastasis.

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WJMSC-derived small extracellular vesicle enhance T cell suppression through PD-L1.

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