Mesenchymal Stromal Cell–Derived Exosomes Contribute to Epithelial Regeneration in Experimental Inflammatory Bowel Disease

Barnhoorn, Marieke C.; Plug, L G; Jonge, E.S.M. Muller – de; Molenkamp, D.; Bos, Erik; Schoonderwoerd, Mark J.A.; Corver, Willem E.; Jong, Andrea E. van der Meulen–de; Verspaget, Hein W.; Hawinkels, Lukas J.A.C.

doi:10.1016/j.jcmgh.2020.01.007

Cited by 16 publications

(9 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Accumulating studies also revealed that the effects of anti-inflammatory and immunosuppression were mainly contributed by exosome secretion [ 28 , 29 ]. Currently, various animal experiments have shown that MSC-derived exosomes exert therapeutic effects in treating colitis [ 13 , 30 ], but only a single animal colitis model was used in most of these studies. The application of two different colitis models in our study reassured the anti-colitis effect of MSCs-Exo and suggested that the effect was strain-independent.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A novel therapeutic approach for inflammatory bowel disease by exosomes derived from human umbilical cord mesenchymal stem cells to repair intestinal barrier via TSG-6

et al. 2021

View full text Add to dashboard Cite

Background Exosomes as the main therapeutic vectors of mesenchymal stem cells (MSC) for inflammatory bowel disease (IBD) treatment and its mechanism remain unexplored. Tumor necrosis factor-α stimulated gene 6 (TSG-6) is a glycoprotein secreted by MSC with the capacities of tissue repair and immune regulation. This study aimed to explore whether TSG-6 is a potential molecular target of exosomes derived from MSCs (MSCs-Exo) exerting its therapeutic effect against colon inflammation and repairing mucosal tissue. Methods Two separate dextran sulfate sodium (DSS) and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced IBD mouse models were intraperitoneally administered MSCs-Exo extracted from human umbilical cord MSC (hUC-MSC) culture supernatant. Effects of MSCs-Exo on intestinal inflammation, colon barrier function, and proportion of T cells were investigated. We explored the effects of MSCs-Exo on the intestinal barrier and immune response with TSG-6 knockdown. Moreover, recombinant human TSG-6 (rhTSG-6) was administered exogenously and colon inflammation severity in mice was evaluated. Results Intraperitoneal injection of MSCs-Exo significantly ameliorated IBD symptoms and reduced mortality rate. The protective effect of MSCs-Exo on intestinal barrier was demonstrated evidenced by the loss of goblet cells and intestinal mucosa permeability, thereby improving the destruction of tight junctions (TJ) structures and microvilli, as well as increasing the expression of TJ proteins. Microarray analysis revealed that MSCs-Exo administration downregulated the level of pro-inflammatory cytokines and upregulated the anti-inflammatory cytokine in colon tissue. MSCs-Exo also modulated the response of Th2 and Th17 cells in the mesenteric lymph nodes (MLN). Reversely, knockdown of TSG-6 abrogated the therapeutic effect of MSCs-Exo on mucosal barrier maintenance and immune regulation, whereas rhTSG-6 administration showed similar efficacy to that of MSCs-Exo. Conclusions Our findings suggested that MSCs-Exo protected against IBD through restoring mucosal barrier repair and intestinal immune homeostasis via TSG-6 in mice.

show abstract

Section: Discussionmentioning

confidence: 99%

“…MSCs-Exo have been reported to stimulate the regeneration of epithelial cells in vitro [ 30 ], but its protective effect on the intestinal mucosal barrier in vivo remains unclear. The intestinal mucosal barrier includes mechanical, chemical, immune, and biological barrier.…”

Section: Discussionmentioning

confidence: 99%

A novel therapeutic approach for inflammatory bowel disease by exosomes derived from human umbilical cord mesenchymal stem cells to repair intestinal barrier via TSG-6

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Previous studies showed that when MSCs are administered intravenously, many are trapped in the lungs ( 41 , 44 ), undergo apoptosis, and are phagocytosed by macrophages that subsequently acquire an antiinflammatory phenotype ( 11 , 44 , 45 ). When locally administered, MSCs would be able to exert their immunosuppressive function and epithelial regenerative capacities by either direct cell-to-cell contact or through the local production of exosomes ( 46 , 47 ), chemokines, and cytokines ( 48 ). Our group previously showed that MSCs could be detected up to 6 days after local injection in mice with experimental colitis ( 21 ).…”

Section: Discussionmentioning

confidence: 99%

Local administration of mesenchymal stromal cells is safe and modulates the immune compartment in ulcerative proctitis

Ouboter¹,

Barnhoorn²,

Verspaget³

et al. 2023

JCI Insight

View full text Add to dashboard Cite

BackgroundDue to their immunoregulatory and tissue regenerative features, mesenchymal stromal cells (MSCs) are a promising novel tool for the management of ulcerative proctitis (UP). Here we report on a phase IIa clinical study to evaluate the impact of local MSC therapy in UP. MethodsThirteen refractory UP patients, with endoscopic Mayo score (EMS) 2 or 3, were included. Seven patients received 20-40 x 10 6 allogeneic MSCs (cohort 1), while six patients received 40-80 x 10 6 MSCs (cohort 2). Adverse events (AEs) were assessed at baseline and week 2, 6, 12, and 24. Clinical, endoscopic, and biochemical parameters were assessed at baseline, week 2 and 6. Furthermore, we evaluated the engraftment of MSCs, presence of donor-specific human leukocyte antigen (HLA) antibodies (DSAs), and we determined the impact of MSC therapy on the local immune compartment. ResultsNo serious AEs were observed. The clinical Mayo score was significantly improved at week 2 and 6, and the EMS was significantly improved at week 6, compared to baseline. At week 6, donor MSCs were still detectable in rectum biopsies of 4/9 patients and DSAs against both HLA-class I and -class II were found. Mass cytometry showed a reduction of activated CD8 + T cells and CD16 + monocytes and an enrichment in mononuclear phagocytes and natural killer cells in biopsies after local MSC therapy. ConclusionLocal administration of allogeneic MSCs is safe, tolerable, and feasible for treatment of refractory UP and shows encouraging signs of clinical efficacy and modulation of local immune responses. This sets the stage for larger clinical trials.

show abstract

“…Evidence from small animal models tends to indicate a potentially beneficial effect of systemic, intra-peritoneal or local stem cells-derivedEVs administration for luminal Crohn's disease [150][151][152]. Thus, in view of emerging experimental data on the use of EVs for post-surgical gastrointestinal fistula treatment [57,58], we consider that EV therapy for perianal and non-perianal fistulizing Crohn's disease could constitute an interesting future preclinical research axis.…”

Section: Extracellular Vesicles Therapy For Fistulizing Crohn 'S Disease -A Future Direction?mentioning

confidence: 99%

Regenerative medicine for digestive fistulae therapy: Benefits, challenges and promises of stem/stromal cells and emergent perspectives via their extracellular vesicles

Sebbagh

Rosenbaum

Péré

et al. 2021

Advanced Drug Delivery Reviews

View full text Add to dashboard Cite

Mesenchymal Stromal Cell–Derived Exosomes Contribute to Epithelial Regeneration in Experimental Inflammatory Bowel Disease

Cited by 16 publications

References 11 publications

A novel therapeutic approach for inflammatory bowel disease by exosomes derived from human umbilical cord mesenchymal stem cells to repair intestinal barrier via TSG-6

A novel therapeutic approach for inflammatory bowel disease by exosomes derived from human umbilical cord mesenchymal stem cells to repair intestinal barrier via TSG-6

Local administration of mesenchymal stromal cells is safe and modulates the immune compartment in ulcerative proctitis

Regenerative medicine for digestive fistulae therapy: Benefits, challenges and promises of stem/stromal cells and emergent perspectives via their extracellular vesicles

Contact Info

Product

Resources

About