Matrix-Bound Nanovesicles Recapitulate Extracellular Matrix Effects on Macrophage Phenotype

Abstract

The early macrophage response to biomaterials has been shown to be a critical and predictive determinant of downstream outcomes. When properly prepared, bioscaffolds composed of mammalian extracellular matrix (ECM) have been shown to promote a transition in macrophage behavior from a proinflammatory to a regulatory/anti-inflammatory phenotype, which in turn has been associated with constructive and functional tissue repair. The mechanism by which ECM bioscaffolds promote this phenotypic transition, however, is poorly understood. The present study shows that matrix-bound nanovesicles (MBV), a component of ECM bioscaffolds, are capable of recapitulating the macrophage activation effects of the ECM bioscaffold from which they are derived. MBV isolated from two different source tissues, porcine urinary bladder and small intestinal submucosa, were found to be enriched in miRNA125b-5p, 143-3p, and 145-5p. Inhibition of these miRNAs within macrophages was associated with a gene and protein expression profile more consistent with a proinflammatory rather than an anti-inflammatory/regulatory phenotype. MBV and their associated miRNA cargo appear to play a significant role in mediating the effects of ECM bioscaffolds on macrophage phenotype.

Extracellular Matrix Bioscaffolds for Building Gastrointestinal Tissue

“…Application of the SIS hydrogel showed restoration of colonic epithelial barrier function and mitigation of the proinflammatory macrophage phenotype. Overall, results from this study, and others, 33 , 80 , 137 , 138 , 139 have shown that ECM possesses immunomodulatory properties, a process shown to be a critical determinant of downstream constructive and functional tissue-remodeling outcomes.…”

“… 69 , 70 , 71 , 72 Additional degradation products of ECM bioscaffolds include growth factors stored within the matrix 73 , 74 , 75 , 76 ; structural molecules such as collagen, 9 , 77 laminin, 77 fibronectin, 78 and glycosaminoglycans 79 ; and matrix-bound nanovesicles (MBV), nanometer-sized membranous vesicles that are similar in size and structure to exosomes. 80 , 81 Although exosomes exist exclusively in body fluids, MBV are bound within the collagen network of the ECM. 81 MBV were shown to be sufficient (ie, in an ECM-independent manner) to recapitulate phenotypical and functional effects attributed to ECM bioscaffolds, as assessed by in vitro cell culture studies.…”

“… 81 MBV were shown to be sufficient (ie, in an ECM-independent manner) to recapitulate phenotypical and functional effects attributed to ECM bioscaffolds, as assessed by in vitro cell culture studies. 80 , 81 …”

Harnessing Inorganic Nanoparticles to Direct Macrophage Polarization for Skeletal Muscle Regeneration

“…The immunomodulatory effect of decellularized ECM (dECM) mainly depends on scaffold structure and composition. Huleihel and colleagues, for example, recently demonstrated that matrix-bound vesicles (MBVs) present in urinary bladder matrix are responsible for macrophage polarization towards the anti-inflammatory phenotype, via three miRs (miR125b-5p, miR143-3p, and miR145-5p) carried within the vesicles [ 26 ]. The authors hypothesized that, during degradation of the ECM-based scaffold, the released MBVs are internalized by macrophages, eliciting their polarization.…”

Extracellular Matrix Mimicking Nanofibrous Scaffolds Modified With Mesenchymal Stem Cell-Derived Extracellular Vesicles for Improved Vascularization

“…It is also known that physiologically native EVs actively interact with the ECM (Buzas et al, 2018 ) and the EV-ECM complexes are mediating significant biological functions of both ECMs and EVs (Sung et al, 2015 ). Recently, matrix-bound vesicles (MBVs) are identified to play a significant role in mediating the regenerative functions of ECM scaffolds (Huleihel et al, 2016 , 2017 ; van der Merwe et al, 2017 ; Rilla et al, 2019 ), which highlights the biological functions of the EV-ECM structural complexes. Therefore, designing and constructing biomaterial scaffolds to mimic the structure of the EV-ECM complex and the physiological interactions between the ECM and EVs, represents an attractive and promising novel approach for tissue engineering applications.…”