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Myocardial ischemia-reperfusion (MIR) injury drives adverse remodeling and heart failure after ST-elevation myocardial infarction (STEMI), yet no therapy directly targets the fibrotic response. Here, we developed a good manufacturing practice-compatible extracellular vesicle (EV)-enriched secretome from bone marrow mesenchymal stromal cells and identified a laminin-521-based production strategy suitable for clinical translation. The EV-enriched secretome exhibited in vitro immunomodulatory activity, and in murine MIR-injury models, treatment preserved left ventricular ejection fraction, reduced platelet-derived growth factor receptor beta (PDGFR beta)-associated myofibroblast activation quantified by positron emission tomography (PET) imaging, attenuated fibrosis, and promoted reparative macrophage polarization. In a clinically relevant porcine ischemia-reperfus ion model, intracoronary administration was cardioprotective. We further developed a clinically approved PDGFR beta-targeted PET-imaging platform for longitudinal assessment of fibrotic activity in STEMI patients, where preliminary observations suggest that myofibroblast activation persists for up to 2 months after STEMI in selected patients. Together, these findings establish a translational therapeutic-diagnostic framework for individualized management of MIR injury.

Recent developments in mass spectrometry-based proteomics have established it as a robust tool for system-wide analyses essential for pathophysiological research. While post-mortem samples are a critical source for these studies, our understanding of how body decomposition influences the proteome remains limited. Here, we have revisited published data and conducted a clinically relevant time-course experiment in mice, revealing organ-specific proteome regulation after death, with only a fraction of these changes linked to protein autolysis. The liver and spleen exhibit significant proteomic alterations within hours post-mortem, whereas the heart displays only modest changes. Additionally, subcellular compartmentalization leads to an unexpected surge in proteome alterations at the earliest post-mortem interval (PMI). Additionally, we have conducted a comprehensive analysis of semi-tryptic peptides, revealing distinct consensus motifs for different organs, indicating organ-specific post-mortem protease activity. In conclusion, our findings emphasize the critical importance of considering PMI effects when designing proteomics studies, as these effects may significantly overshadow the impacts of diseases. Preferably, the samples should be taken in the operation room, especially for studies including subcellular compartmentalization or trans-organ comparison. In single-organ studies, the planning should involve careful control of PMI.

Extracellular vesicles (EVs) derived from corneal epithelial cells have shown great promise in promoting corneal wound healing and stromal regeneration, but they face challenges with rapid clearance from the eye. This study addresses these challenges by developing a biocompatible collagen-hydrogel sustained delivery system. We successfully isolated, purified, and characterized corneal epithelial EVs (CE-EVs), assessed their efficacy in corneal epithelial healing in vitro, and demonstrated their sustained delivery over 10 days followed by an on-demand release through enzymatic degradation of the hydrogel, which mimics the in vivo scenario. To develop a microscale understanding of the EV diffusion inside the hydrogel matrix, we probed the hydrogel network with several model compounds and nanoparticles by using advanced confocal microscopy analyses, followed by fitting our results to established diffusion models. Our findings suggest this innovative approach offers a safe and effective strategy to promote corneal wound healing. This technology has the potential to revolutionize corneal injury treatment and improve patient outcomes. Moreover, the possibility to tailor EV-release kinetics broadens the scope of EV research in clinical practices, as varying short- and long-term release profiles will be required for diverse medical applications.