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

Abstract

Ingeniería de tejido cardíaco; Exosomas; Infiltración

Enginyeria de teixits cardíacs; Exosomes; Infiltració

Cardiac tissue engineering; Exosomes; Infiltration

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.

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).