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

Abstract

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.

Embryonic Trophectoderm Secretomics Reveals Chemotactic Migration and Intercellular Communication of Endometrial and Circulating MSCs in Embryonic Implantation

“…We aimed to build an in vitro model of cell-to-cell communication through EVs and soluble proteins. To demonstrate the functional transfer between embryonic trophectoderm and maternal MSC of protein-containing secretome, we first confirmed that EVs isolated from conditioned media of BBT cells previously labeled with PKH26 were successfully uptaken by maternal eMSC and pbMSC during a chemotaxis experiment in an agarose spot assay following the procedures of Calle et al [ 11 , 15 ] and Monguió-Tortajada et al [ 16 ] as described in materials and methods ( Figure S5 ).…”

Regenerative Neurology and Regenerative Cardiology: Shared Hurdles and Achievements

“…In many congenital heart diseases neonatal ventricles demonstrate a number of intrinsic pathologic modifications, including relative immaturity of the extra-cellular matrix, inappropriately low transcription factor expression and increased myocyte apoptosis, this should open the way for the evaluation of treatments associating tissue engineering with cells implants. The main mechanisms by which cell transplantation and tissue engineering can bring functional benefits in myocardial diseases is the combination of cells and scaffolds, which limit the spread of the pathologic area, preventing excessive remodeling and dilatation of the ventricle [ 143 , 144 , 145 , 146 ].…”

Mesenchymal Stem Cell Immunomodulation: A Novel Intervention Mechanism in Cardiovascular Disease

“…MSCs and their derived materials are emerging in the treatment of MI as well. Exosomes of porcine cardiac adipose tissue-derived MSCs (cATMSC) loaded onto a three-dimensional scaffold designed from decellularized heart tissue and injected into pigs after MI, found to reduce macrophage and T cell infiltration in the damaged myocardium and increase vascular density and tissue remodeling ( Monguió-Tortajada et al, 2021 ). Researchers coated the cell membrane of MSCs on PLGA particles loaded with MSCs secretions to create a particle called synMSCs and injected it into mice with acute myocardial infarction (AMI), and found that synMSCs-treated mice were able to express MHC I molecules that allowed them to avoid allogeneic recognition by the immune system, thereby modulating the body’s innate immune response and enhancing their attachment to cardiomyocytes and promoting their survival by secreting adhesion factors (such as SDF1) ( Luo et al, 2017 ).…”