Extracellular Vesicles from Thapsigargin-Treated Mesenchymal Stem Cells Ameliorated Experimental Colitis via Enhanced Immunomodulatory Properties

Abstract

Therapeutic applications of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have attracted considerable attention because of their immunomodulatory properties against immune-mediated, inflammatory diseases. Here, we demonstrated enhanced immunomodulatory properties of EVs secreted from endoplasmic reticulum (ER) stress inducer thapsigargin (TSG)-primed human Wharton’s jelly-derived MSCs (WJ-MSCs). EVs from TSG-primed WJ-MSCs (TSG-EV) showed increased yield and expression of immunomodulatory factors, such as transforming growth factor-β1 (TGFβ), cyclooxygenase-2 (COX2), and especially indoleamine 2,3-dioxygenase (IDO), compared to control EVs. TSG-EV showed a significantly enhanced immunosuppressive effect on human peripheral blood-derived T cell proliferation and Th1 and Th17 differentiation, whereas Treg and M2-type macrophage were enriched compared to a control EV-treated group. Furthermore, TSG-EV substantially mitigated mouse experimental colitis by reducing the inflammatory response and maintaining intestinal barrier integrity. A significant increase of Tregs and M2-type macrophages in colitic colons of a TSG-EV-treated mouse suggests an anti-inflammatory effect of TSG-EV in colitis model, possibly mediated by Treg and macrophage polarization. These data indicate that TSG treatment promoted immunomodulatory properties of EVs from WJ-MSCs, and TSG-EV may provide a new therapeutic approach for treatment of colitis.

Diesel Exhaust Particles Impair Therapeutic Effect of Human Wharton's Jelly-Derived Mesenchymal Stem Cells against Experimental Colitis through ROS/ERK/cFos Signaling Pathway

“…All the mice were sacrificed on day 12 and their colon lengths and weights were measured. Myeloperoxidase (MPO) activity assay and histopathological evaluation were performed as previously described ( 11 ).…”

“…MSCs also inhibit pro-inflammatory M1 macrophages and activate anti-inflam-matory M2 macrophages ( 9 ). Previously, we have shown that the human MSC secretome, including transforming growth factor-beta (TGF-β), prostaglandin E2 (PGE2), indoleamine 2,3-dioxygenase (IDO), and extracellular vesicles (EVs), is responsible for the anti-inflammatory properties ( 10 , 11 ). The mechanisms and therapeutic effects of MSCs in autoimmune and DEP-induced diseases have been studied; however, neither the nature of direct interactions between DEP and MSCs nor the precise mechanism of DEP effects on MSCs have been elucidated ( 12 - 14 ).…”

Mesenchymal Stromal Cell Secretome for the Treatment of Immune-Mediated Inflammatory Diseases: Latest Trends in Isolation, Content Optimization and Delivery Avenues

“…Moreover, licensed EVs exerted direct immunomodulatory effects by suppressing T-cell proliferation and differentiation while increasing Treg proliferation and macrophage M2 polarization. Remarkably, these immunomodulatory effects of the EVs obtained by licensed MSCs were related to therapeutic outcomes observed in dextran sodium sulfate (DSS)-induced colitis mice models [146].…”

Improving the Efficacy of Mesenchymal Stem/Stromal-Based Therapy for Treatment of Inflammatory Bowel Diseases

“…These molecules carry out their effects by activation of the Toll-like receptor (TLR) pathways that ultimately activate NACHT, LRR, and PYD domains containing protein (NLRP3) inflammasome. Other molecules such as IL-25 (a member of the cytokine IL-17 family [ 79 ]) and thapsigargin (an endoplasmic reticulum stress inducer) showed increased yield and expression of immunomodulatory factors such as TGFβ, COX2, and IDO [ 80 ] and muramyl dipeptide that increased the production of PGE 2 via the NOD2–RIP2 pathway [ 53 ]. Interestingly, Xiao E et al [ 81 ] observed that normal microbiota is required to maintain immunomodulatory properties of MSCs.…”

“…Most of the beneficial effects of MSCs are mediated by paracrine pathways through the secretion of factors packaged in EVs. To confirm these effects of conditioned medium from MSCs (CM-MSCs), Joo H et al and Tian J et al observed that culture media from MSCs treated with GW4869 (inhibitor of EV secretion) [ 80 ] or with Pistop2 (cell membrane-permeable clathrin inhibitor) [ 57 ] inhibited the therapeutic effects of CM-MSCs or MSCs in a DSS-induced colitis model, suggesting that the most important factors responsible for the therapeutic effects of CM-MSCs are packaged and carried out within EVs. The large majority of studies conducted with CM-MSCs have observed similar therapeutic effects to MSCs [ 106 , 107 , 108 , 109 , 110 ] in DSS, as well as in TNBS-induced colitis models regardless of the tissue source, MHC context, or route of administration used ( Table 5 ).…”