Compensatory release of pro-inflammatory factors and recruitment of immune cells are key processes activated to preserve the structural and functional integrity of the heart following myocardial infarction (MI). It is essential that phagocytic clearance of dying cardiac cells occurs efficiently to ensure that inflammation resolves in a timely manner. Failure to do so leads to adverse remodelling and impaired cardiac function, which progresses to heart failure. Thus, therapeutic strategies promoting resolution of inflammation, or protecting/preventing cardiac cells from enduring further damage are a key focus for improving overall outcomes. To this end, mesenchymal stem cells (MSCs) have gained traction for their potential to repair the fibrotic heart. A growing body of evidence indicates MSCs exert their effects via secretion of paracrine factors which stimulate angiogenesis or cardiomyogenesis, and prevent further cell death. A primary secreted component of MSCs, exosomes, are believed to be a driving force of MSC mediated repair.
In the current study, Patil and co-workers demonstrate that MSC derived exosomes exert their effect via MFGE8 (milk fat globule epidermal growth factor-factor VIII)/ integrin αvβ3 signalling via several key experiments. First, they determine these exosomes are an active source of MFGE8 and can opsonise dying cells – a process in which they bind to cells to make them more susceptible to phagocytosis. Furthermore, they trigger phagocytic signalling in resident or recruited phagocytes following ischaemia, and increased phagocytosis of dying cells both in vitro and in vivo.
Secondly, pre-incubating macrophages with exosomes, led to the discovery that macrophages not only uptake these exosomes, but also increased their tendency to phagocytose, activated the integrin αvβ3 signalling pathway, and exhibited a trend towards M2 shift in polarisation. Contrarily, pre-incubation with exosomes derived from MFGE8 deficient MSCs (MFGE8-MSCs) resulted in the exact opposite effect; that is a diminished capacity for resolving inflammation overall. This shift in macrophage polarisation from an pro-inflammatory M1 profile to an immunosuppressive and reparative M2 profile with exosome incubation is in concordance with data demonstrating a similar shift in macrophages co-cultured with MSCs themselves.
Finally, the authors convincingly demonstrated the protective role these exosomes play by delivering them directly to the infarcted heart. An increased ability to engulf and clear dying cardiomyocytes was present in a mouse MI model. This data was further solidified by a corresponding reduction in proinflammatory signalling, increased vascularisation, and improvements in fibrosis, and overall cardiac function. Interestingly, the in vitro observations of MFGE8-MSC exosomes were somewhat mimicked in the mouse model of MI as well, with a drastic reduction in survival rate and increase in inflammatory signalling in mice receiving these exosomes.
With this study, the authors present compelling evidence for the role MSC derived exosomes play in promoting the clearance of apoptotic cells and reducing the length of inflammation. In doing so, the authors add to the growing knowledge of mechanisms by which MSCs and their secreted cargo may promote cardiac repair.