HIF-Overexpression and Pro-Inflammatory Priming in Human Mesenchymal Stromal Cells Improves the Healing Properties of Extracellular Vesicles in Experimental Crohn’s Disease

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Gómez Ferrer, Marta and Amaro Prellezo, Elena and Dorronsoro, Akaitz and Sánchez Sánchez, Rafael and Vicente López, Ángeles and Cosín Roger, Jesús and Barrachina, María Dolores and Baquero, María Carmen and Valencia Mahón, Jaris and Sepúlveda, Pilar (2021) HIF-Overexpression and Pro-Inflammatory Priming in Human Mesenchymal Stromal Cells Improves the Healing Properties of Extracellular Vesicles in Experimental Crohn’s Disease. International Journal of Molecular Sciences, 22 (20). p. 11269. ISSN 1422-0067

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Official URL: https://doi.org/10.3390/ijms222011269




Abstract

Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) have therapeutic potential in the treatment of several immune disorders, including ulcerative colitis, owing to their regenerative and immunosuppressive properties. We recently showed that MSCs engineered to overexpress hypoxia-inducible factor 1-alpha and telomerase (MSC-T-HIF) and conditioned with pro-inflammatory stimuli release EVs (EVMSC-T-HIFC) with potent immunomodulatory activity. We tested the efficacy of EVMSC-T-HIFC to repolarize M1 macrophages (Mφ1) to M2-like macrophages (Mφ2-like) by analyzing surface markers and cytokines and performing functional assays in co-culture, including efferocytosis and T-cell proliferation. We also studied the capacity of EVMSC-T-HIFC to dampen the inflammatory response of activated endothelium and modulate fibrosis. Finally, we tested the therapeutic capacity of EVMSC-T-HIFC in an acute colitis model. EVMSC-T-HIFc induced the repolarization of monocytes from Mφ1 to an Mφ2-like phenotype, which was accompanied by reduced inflammatory cytokine release. EVMSC-T-HIFc-treated Mφ1 had similar effects of immunosuppression on activated peripheral blood mononuclear cells (PBMC) as Mφ2, and reduced the adhesion of PBMCs to activated endothelium. EVMSC-T-HIFc also prevented myofibroblast differentiation of TGF-β-treated fibroblasts. Finally, administration of EVMSC-T-HIFc promoted healing in a TNBS-induced mouse colitis model in terms of preserving colon length and intestinal mucosa architecture and altering the ratio of Mφ1/ Mφ2 infiltration. In conclusion, EVMSC-T-HIFC have effective anti-inflammatory properties, making them potential therapeutic agents in cell free-based therapies for the treatment of Crohn’s disease and likely other immune-mediated inflammatory diseases.


Item Type:Article
Uncontrolled Keywords:mesenchymal stromal cells; extracellular vesicles; hypoxia-inducible factor 1-alpha; immunomodulation; macrophage repolarization; Crohn’s disease
Subjects:Medical sciences > Medicine > Gastroenterology and Hepatology
ID Code:71675
Deposited On:05 Apr 2022 15:01
Last Modified:06 Apr 2022 08:48

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