Bioactive factors secreted from mesenchymal stromal cells protect the intestines from experimental colitis in a three-dimensional culture

Gonçalves, Fabiany da Costa; Serafini, Michele Aramburu; Mello, Helena Flores; Pfaffenseller, Bianca; Araújo, Anelise Bergmann; Visioli, Fernanda; Paz, Ana Helena da Rosa

doi:10.1016/j.jcyt.2018.06.007

Cited by 11 publications

(7 citation statements)

References 67 publications

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“…MSC-derived exosomes have suppressive effects on innate immune cells like dendritic cells (DCs), monocytes, and macrophages and alleviate colonic inflammation [ 12 ]. A number of published researches indicate that MSC-derived exosomes can alleviate colonic inflammation [ 13 – 16 ]. Liu et al reported that MSC-derived exosomes downregulated colonic inflammatory responses, maintained intestinal barrier integrity, and polarized macrophages to M2b phenotype to reduce murine experimental colitis [ 14 ], offering a feasible and promising cell-free therapeutic strategy for IBD.…”

Section: Introductionmentioning

confidence: 99%

hucMSC-derived exosomes attenuate colitis by regulating macrophage pyroptosis via the miR-378a-5p/NLRP3 axis

et al. 2021

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Background Human umbilical cord mesenchymal stem cell (hucMSC)-derived exosomes are recognized as novel cell-free therapeutic agents for inflammatory bowel disease (IBD), a condition caused by dysregulated intestinal mucosal immunity. In this event, macrophage pyroptosis, a process of cell death following the activation of NLRP3 (NOD-like receptor family, pyrin domain-containing 3) inflammasomes, is believed to partially account for inflammatory reactions. However, the role of macrophage pyroptosis in the process of hucMSC-derived exosomes alleviating colitis remains unknown. This study aimed at exploring the therapeutic effect and mechanism of hucMSC-derived exosomes on colitis repair. Methods In vivo, we used BALB/c mice to establish a dextran sulfate sodium (DSS)-induced colitis model and administrated hucMSC-derived exosomes intravenously to estimate its curative effect. Human myeloid leukemia mononuclear (THP-1) cells and mouse peritoneal macrophages (MPMs) were stimulated with lipopolysaccharides (LPS) and Nigericin to activate NLRP3 inflammasomes, which simulated an inflammation environment in vitro. A microRNA mimic was used to verify the role of miR-378a-5p/NLRP3 axis in the colitis repair. Results hucMSC-derived exosomes inhibited the activation of NLRP3 inflammasomes in the mouse colon. The secretion of interleukin (IL)-18, IL-1β, and Caspase-1 cleavage was suppressed, resulting in reduced cell pyroptosis. The same outcome was observed in the in vitro cell experiments, where the co-culture of THP-1 cells and MPMs with hucMSC-derived exosomes caused decreased expression of NLRP3 inflammasomes and increased cell survival. Furthermore, miR-378a-5p was highly expressed in hucMSC-derived exosomes and played a vital function in colitis repair. Conclusion hucMSC-derived exosomes carrying miR-378a-5p inhibited NLRP3 inflammasomes and abrogated cell pyroptosis to protect against DSS-induced colitis.

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Section: Introductionmentioning

confidence: 99%

hucMSC-derived exosomes attenuate colitis by regulating macrophage pyroptosis via the miR-378a-5p/NLRP3 axis

et al. 2021

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“…The above researches suggested us that secretom of MSCs might play an important role in cellular immunity or tissue damage repair processes. Previous studies have indicated that mesenchymal stem cellsconditioned medium could ameliorate colitis in the DSS induced models (Gonçalves et al, 2018;Heidari et al, 2018). Preconditioning could enhance the immunomodulatory functions of MSCs and increase the secretion of paracrine factors (Ankrum et al, 2014;Saparov et al, 2016;Hu and Li, 2018;Yang et al, 2018;Lee and Kang, 2020).…”

Section: Discussionmentioning

confidence: 99%

The Therapeutic Efficacy of Adipose Tissue-Derived Mesenchymal Stem Cell Conditioned Medium on Experimental Colitis Was Improved by the Serum From Colitis Rats

Fan

Mao

et al. 2021

Front. Bioeng. Biotechnol.

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Adipose derived mesenchymal stem cells (AD-MSCs) have shown therapeutic potential in treatments of inflammatory bowel disease (IBD). Due to the harsh host environment and poor survival of the cells, controversy concerning the homing, proliferation and differentiation of MSCs in lesion tissue still remains. It has been reported that conditioned media from MSCs could improve the colitis, whereas the therapeutic efficiency could be significantly elevated by the stimulation of pro-cytokines. In this study, we pre-treated the adipose derived MSCs with the serum from colitis rats and then the activated conditioned media (CM-AcMSC) were collected. To compare the therapeutic effects of CM-MSC and CM-AcMSC on IBD, we constructed dextran sodium sulphate (DSS)-induced colitis rat models. The colitis was induced in rats by administrating 5% DSS in drinking water for 10 days, and the disease symptoms were recorded daily. The colon histopathological changes were observed by different staining methods (H&E and PAS). The expression levels of MUC2 and tight junctions (TJs) were determined by RT-qPCR. The levels of inflammatory cytokines were analyzed by ELISA and western blot analysis. Our findings suggested that CM-AcMSC was more effective in ameliorating the clinical features and histological damage scores. Treatment with CM-AcMSC significantly increased the expression of MUC2 and TJs and suppressed the production of pro-inflammatory cytokines in colonic tissues of colitis rats. The inhibitory effects of CM-AcMSC on inflammatory responses of colitis rats were mediated by NF-κB signaling pathway. These results suggested that pre-activation of MSCs with serum from colitis rats could promote the production of paracrine factors and improve the therapeutic effects of conditioned medium on colitis rats.

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“…In our previous study, we investigated the paracrine role of MSC in DSS-induced colitis of colon organ culture. Our results have shown that colonic inflammation is alleviated by MSC-CM, and this effect is independent of cell contact[119]. Also, CM has been evaluated in several other conditions and diseases, such as myocardial infarction[120], bone defect[121], hepatic insufficiency[122], and spinal cord injury[123].…”

Section: Therapy Based On the Immunomodulatory Properties Of Mscmentioning

confidence: 99%

“…In our previous study, we have shown that MSC stimulated with IFN-γ decreased lymphocyte population in colonic organ culture of DSS-treated mice, but no effect of CM treatment was observed. That could be explained by the fact that T cell immunosuppression has a partial dependence on the cell-cell contact mechanism[119]. Furthermore, Fan et al[143] showed that IL-1β primed MSC have enhanced immunosuppressive capacities and migration ability, and Cheng et al[144] demonstrated that IL-25 primed MSC inhibited Th17 immune response and induced regulatory T cell phenotyping in DSS-induced colitis[143,144].…”

Section: Therapy Based On the Immunomodulatory Properties Of Mscmentioning

confidence: 99%

Cell membrane and bioactive factors derived from mesenchymal stromal cells: Cell-free based therapy for inflammatory bowel diseases

Gonçalves¹,

Paz²

2019

WJSC

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Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract associated with multifactorial conditions such as ulcerative colitis and Crohn's disease. Although the underlying mechanisms of IBD remain unclear, growing evidence has shown that dysregulated immune system reactions in genetically susceptible individuals contribute to mucosal inflammation. However, conventional treatments have been effective in inducing remission of IBD but not in preventing the relapse of them. In this way, mesenchymal stromal cells (MSC) therapy has been recognized as a promising treatment for IBD due to their immunomodulatory properties, ability to differentiate into several tissues, and homing to inflammatory sites. Even so, literature is conflicted regarding the location and persistence of MSC in the body after transplantation. For this reason, recent studies have focused on the paracrine effect of the biofactors secreted by MSC, especially in relation to the immunomodulatory potential of soluble factors (cytokines, chemokines, and growth factors) and extracellular vehicles that are involved in cell communication and in the transfer of cellular material, such as proteins, lipids, and nucleic acids. Moreover, treatment with interferon-γ, tumor necrosis factor-α, and interleukin-1β causes MSC to express immunomodulatory molecules that mediate the suppression via cell-contact dependent mechanisms. Taken together, we present an overview of the role of bioactive factors and cell membrane proteins derived from MSC as a cell-free therapy that can improve IBD treatment.

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Bioactive factors secreted from mesenchymal stromal cells protect the intestines from experimental colitis in a three-dimensional culture

Cited by 11 publications

References 67 publications

hucMSC-derived exosomes attenuate colitis by regulating macrophage pyroptosis via the miR-378a-5p/NLRP3 axis

hucMSC-derived exosomes attenuate colitis by regulating macrophage pyroptosis via the miR-378a-5p/NLRP3 axis

The Therapeutic Efficacy of Adipose Tissue-Derived Mesenchymal Stem Cell Conditioned Medium on Experimental Colitis Was Improved by the Serum From Colitis Rats

Cell membrane and bioactive factors derived from mesenchymal stromal cells: Cell-free based therapy for inflammatory bowel diseases

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