Local administration of porcine immunomodulatory, chemotactic and angiogenic extracellular vesicles using engineered cardiac scaffolds for myocardial infarction

The administration of extracellular vesicles (EV) from mesenchymal stromal cells (MSC) is a promising cell-free nanotherapy for tissue repair after myocardial infarction (MI). However, the optimal EV delivery strategy remains undetermined. Here, we designed a novel MSC-EV delivery, using 3D scaffolds engineered from decellularised cardiac tissue as a cell-free product for cardiac repair. EV from porcine cardiac adipose tissue-derived MSC (cATMSC) were purified by size exclusion chromatography (SEC), functionally analysed and loaded to scaffolds. cATMSC-EV markedly reduced polyclonal proliferation and pro-inflammatory cytokines production (IFNγ, TNFα, IL12p40) of allogeneic PBMC. Moreover, cATMSC-EV recruited outgrowth endothelial cells (OEC) and allogeneic MSC, and promoted angiogenesis. Fluorescently labelled cATMSC-EV were mixed with peptide hydrogel, and were successfully retained in decellularised scaffolds. Then, cATMSC-EV-embedded pericardial scaffolds were administered in vivo over the ischemic myocardium in a pig model of MI. Six days from implantation, the engineered scaffold efficiently integrated into the post-infarcted myocardium. cATMSC-EV were detected within the construct and MI core, and promoted an increase in vascular density and reduction in macrophage and T cell infiltration within the damaged myocardium. The confined administration of multifunctional MSC-EV within an engineered pericardial scaffold ensures local EV dosage and release, and generates a vascularised bioactive niche for cell recruitment, engraftment and modulation of short-term post-ischemic inflammation

Local administration of porcine immunomodulatory, chemotactic and angiogenic extracellular vesicles using engineered cardiac scaffolds for myocardial infarction

Ingeniería de tejido cardíaco; Exosomas; InfiltraciónEnginyeria de teixits cardíacs; Exosomes; InfiltracióCardiac tissue engineering; Exosomes; InfiltrationThe administration of extracellular vesicles (EV) from mesenchymal stromal cells (MSC) is a promising cell-free nanotherapy for tissue repair after myocardial infarction (MI). However, the optimal EV delivery strategy remains undetermined. Here, we designed a novel MSC-EV delivery, using 3D scaffolds engineered from decellularised cardiac tissue as a cell-free product for cardiac repair. EV from porcine cardiac adipose tissue-derived MSC (cATMSC) were purified by size exclusion chromatography (SEC), functionally analysed and loaded to scaffolds. cATMSC-EV markedly reduced polyclonal proliferation and pro-inflammatory cytokines production (IFNγ, TNFα, IL12p40) of allogeneic PBMC. Moreover, cATMSC-EV recruited outgrowth endothelial cells (OEC) and allogeneic MSC, and promoted angiogenesis. Fluorescently labelled cATMSC-EV were mixed with peptide hydrogel, and were successfully retained in decellularised scaffolds. Then, cATMSC-EV-embedded pericardial scaffolds were administered in vivo over the ischemic myocardium in a pig model of MI. Six days from implantation, the engineered scaffold efficiently integrated into the post-infarcted myocardium. cATMSC-EV were detected within the construct and MI core, and promoted an increase in vascular density and reduction in macrophage and T cell infiltration within the damaged myocardium. The confined administration of multifunctional MSC-EV within an engineered pericardial scaffold ensures local EV dosage and release, and generates a vascularised bioactive niche for cell recruitment, engraftment and modulation of short-term post-ischemic inflammation.This work was supported in part by grants from Fundació la Marató de TV3 (201516-10, 201502-30), the PERIS (SLT002/16/00234) and SGR programmes (2017-SGR-301 REMAR Group, 2017-SGR-1427 and 2017-SGR-483 ICREC Group) from the Generalitat de Catalunya, the Spanish Ministry of Economy and Competitiveness-MICINN (SAF2017-84324-C2-1-R; PID2019-110137RB-I00; PID2019-107145RB-I00), Instituto de Salud Carlos III (PI17/01487, PIC18/00014, ICI19/00039, PI18/00256, PI18/01227, and ICI20/00135), ISCIII-REDinREN (RD16/0009 Feder Funds), Red de Terapia Celular-TerCel (RD16/0011/0006), CIBER Cardiovascular (CB16/11/00403) projects as a part of the Plan Nacional de I + D + I, and it was co-funded by ISCIII-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER), AGAUR (2019PROD00122), Sociedad Española de Cardiología, Societat Catalana de Cardiologia, PCMR[C] and EoI Collaborative Projects on Regenerative Medicine 2019, and Institut Català de Salut (ICS). PG is sponsored by the PERIS (SLT002/16/00209) from the Generalitat de Catalunya. AR is supported by the Miguel Servet program (CPII15/00003) and research grants (PI16/00981) from the Instituto de Salud Carlos III, and co-financed by the European Regional Development Fund. FEB is a researcher from Fundació Institut de Recerca en Ciències de la Salut Germans Trias i Pujol, supported by the Health Department of the Catalan Government (Generalitat de Catalunya)

Local administration of porcine immunomodulatory, chemotactic and angiogenic extracellular vesicles using engineered cardiac scaffolds for myocardial infarction

Altres ajuts: This work was supported in part by grants from Fundació la Marató de TV3 (201516-10, 201502-30).The administration of extracellular vesicles (EV) from mesenchymal stromal cells (MSC) is a promising cell-free nanotherapy for tissue repair after myocardial infarction (MI). However, the optimal EV delivery strategy remains undetermined. Here, we designed a novel MSC-EV delivery, using 3D scaffolds engineered from decellularised cardiac tissue as a cell-free product for cardiac repair. EV from porcine cardiac adipose tissue-derived MSC (cATMSC) were purified by size exclusion chromatography (SEC), functionally analysed and loaded to scaffolds. cATMSC-EV markedly reduced polyclonal proliferation and pro-inflammatory cytokines production (IFNγ, TNFα, IL12p40) of allogeneic PBMC. Moreover, cATMSC-EV recruited outgrowth endothelial cells (OEC) and allogeneic MSC, and promoted angiogenesis. Fluorescently labelled cATMSC-EV were mixed with peptide hydrogel, and were successfully retained in decellularised scaffolds. Then, cATMSC-EV-embedded pericardial scaffolds were administered in vivo over the ischemic myocardium in a pig model of MI. Six days from implantation, the engineered scaffold efficiently integrated into the post-infarcted myocardium. cATMSC-EV were detected within the construct and MI core, and promoted an increase in vascular density and reduction in macrophage and T cell infiltration within the damaged myocardium. The confined administration of multifunctional MSC-EV within an engineered pericardial scaffold ensures local EV dosage and release, and generates a vascularised bioactive niche for cell recruitment, engraftment and modulation of short-term post-ischemic inflammation