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

Fecha de publicación: 19/10/2021 Fecha Ahead of Print: 19/10/2021

Autores de IIS La Fe

Marta Gómez Ferrer

Autor
Akaitz Dorronsoro González

Autor
Pilar Sepúlveda Sanchis

Autor

Participantes ajenos a IIS La Fe

Amaro-Prellezo E
Sánchez-Sánchez R
Vicente Á
Cosín-Roger J
Barrachina MD
Baquero MC
Valencia J

Grupos

Regeneración y Trasplante Cardíaco

Leader

Pilar Sepúlveda Sanchis

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 (EV MSC-T-HIF C ) with potent immunomodulatory activity. We tested the efficacy of EV MSC-T-HIF C to repolarize M1 macrophages (Mf1) to M2-like macrophages (Mf2-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 EV MSC-T-HIF C to dampen the inflammatory response of activated endothelium and modulate fibrosis. Finally, we tested the therapeutic capacity of EV MSC-T-HIF C in an acute colitis model. EV MSC-T-HIF c induced the repolarization of monocytes from Mf1 to an Mf2-like phenotype, which was accompanied by reduced inflammatory cytokine release. EV MSC-T-HIF c -treated Mf1 had similar effects of immunosuppression on activated peripheral blood mononuclear cells (PBMC) as Mf2, and reduced the adhesion of PBMCs to activated endothelium. EV MSC-T-HIF c also prevented myofibroblast differentiation of TGF-ß-treated fibroblasts. Finally, administration of EV MSC-T-HIF c promoted healing in a TNBS-induced mouse colitis model in terms of preserving colon length and intestinal mucosa architecture and altering the ratio of Mf1/ Mf2 infiltration. In conclusion, EV MSC-T-HIF C 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.

Datos de la publicación

ISSN/ISSNe:: 1661-6596, 1661-6596
Tipo:: Article
Páginas:: -
DOI:: 10.3390/ijms222011269
Factor de Impacto:: 1,176 SCImago ℠
Cuartil:: Q1 SCImago ℠

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Métricas

Filiaciones

Gómez-Ferrer M:: Instituto de Investigación. Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain
Amaro-Prellezo E:: Instituto de Investigación. Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain
Dorronsoro A:: Instituto de Investigación. Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain
Sánchez-Sánchez R:: Instituto de Investigación. Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain
Vicente Á:: Sección Departamental de Biología Celular, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain

Instituto de Investigación Sanitaria, Hospital Clínico San Carlos, 28040 Madrid, Spain
Cosín-Roger J:: Hospital Dr Peset, FISABIO, 46017 Valencia, Spain
Barrachina MD:: Departamento de Farmacología, Facultad de Medicina, University of Valencia, 46010 Valencia, Spain
Baquero MC:: Servicio de Cirugía Oral y Maxilofacial, Hospital Universitari I Politècnic La Fe, Avenida Fernando Abril Martorell, 106, 46026 Valencia, Spain
Valencia J:: Sección Departamental de Biología Celular, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain

Instituto de Investigación Sanitaria, Hospital Clínico San Carlos, 28040 Madrid, Spain
Sepúlveda P:: Instituto de Investigación. Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain