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Proteomic analysis of small extracellular vesicles derived from human iPSC-MSCs

ABSTRACT: Human mesenchymal stem cell-derived small extracellular vesicles(MSC-sEVs) have exhibited immunomodulatory and pro-regenerative properties. However, the absence of quantifiable and specific markers for defining and qualifying human MSC-sEVs impedes their translation into clinical practice. Here, we ranked the relative abundances of proteins representing unique signature for MSCs in the proteomic datasets of MSC-sEVs and chose several proteins with high relative abundances as candidate markers for MSC-sEVs. This work would facilitate the establishment of quantifiable, reproducible and standardized assays for defining MSC-sEV preparations, ultimately accelerating the translation of MSC-sEVs into clinical practice.

ORGANISM(S): Homo Sapiens

SUBMITTER: Yang Wang

PROVIDER: PXD054232 | iProX | Thu Jul 25 00:00:00 BST 2024

REPOSITORIES: iProX

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Project description:Background: Allergic asthma is one of the chronic inflammatory diseases and is generally induced by CD4+ T helper 2 cells (Th2) in the context of persistent inhaled stimuli. Dendritic cells (DCs) are essential to mounting the Th2-mediated airway inflammation by presenting inhaled antigens to prime CD4+ T cells. Small extracellular vesicles (sEV) derived from mesenchymal stem cells (MSCs) exhibited great interest in intractable diseases. However, whether MSC-sEV play a role on DCs in airway inflammation is still unclear. Methods: We isolate MSC-sEV using anion-exchange chromatography. Mouse bone marrow-derived DCs (BMDCs) and human monocyte-derived DCs (moDCs) were used to study the effects of MSC-sEV on dendritic cell surface molecules and their cytokine release. Mice were sensitized with house dust mites (HDM) to induce airway inflammation, and treated with MSC-sEV, The effects of sEV on murine DCs were identified. Extracellular flux analysis techniques were used to study the effects of MSC-sEV on the metabolic state of dendritic cells. RNA sequencing to study altered gene expression in BMDCs after MSC-sEV treatment. Results: MSC-sEV mitigated the accumulation of Th2-associated moDCs in mouse lung in response to HDM. MSC-sEV also decreased the activation of moDCs induced in vitro including the expression of co-stimulatory molecules and cytokines secretion. Furthermore, we identified that DCs were able to take MSC-sEV in vitro and in vivo. Mechanistically, using bulk RNA-sequencing, we found that MSC-sEV played roles in the metabolic pathway of murine DCs. Using extracellular flux analysis, we found that MSC-sEV increased the requirement of oxidative phosphorylation on moDCs. Importantly, MSC-sEV displayed similar effects on human moDCs including decreased co-stimulatory molecular and cytokine production. Conclusions: MSC-sEV are able to alter the metabolic state of DCs, favoring DCs to maintain OXPHOS (oxidative phosphorylation) rather than glycolysis, thereby reducing DCs-initiated inflammatory responses and attenuating Th2 lung inflammation, suggesting MSC-sEV can be a potential clinical therapy for airway inflammation.

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Proteomic analysis of small extracellular vesicles derived from human iPSC-MSCs

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