The shift towards secretome-based therapies, particularly those involving extracellular vesicles (EVs) or exosomes, represents a transformative advance in regenerative medicine. Unlike cell-based therapies, which entail complexities associated with cell preparation, engraftment, survival, and inconsistent therapeutic efficacy, secretome/EV therapies offer several advantages. EVs encapsulate a wide array of bioactive molecules capable of modulating multiple reparative pathways simultaneously, potentially leading to synergistic therapeutic effects. Their small size and protective lipid bilayer enhance their stability and extend their half-life, making the production and preparation of these biologics logistically easier, with the additional possibility of cryopreservation. In addition, EVs can be administered intramyocardially or intravenously, allowing for repeated dosing. Illustrating these advantages, the SECRET-HF phase 1 trial, the first-in-man clinical trial, demonstrated the feasibility and safety of repeated intravenous injections of an EV-enriched secretome derived from induced pluripotent stem cell-derived cardiac progenitor cells (CPC).
Identifying the most effective EV source for cardiac repair is crucial. Preclinical work, such as that conducted by González-King et al., is essential in providing insights into these aspects. Using functional in vitro assays, the study compared EVs from several cell sources, including human primary and immortalized bone marrow mesenchymal stromal cells, EVs from embryonic stem cells (ESC), ESC-derived CPC, ESC-derived cardiomyocytes, and primary ventricular cardiac fibroblasts. The authors identified that ESC-EVs exhibited superior cardioprotective, pro-angiogenic, and anti-fibrotic properties and influenced macrophage polarization in vitro.
In vivo, human ESC-EVs significantly enhanced cardiac function, angiogenesis, and modulated fibrosis in a murine cardiac ischemic reperfusion model. The study highlighted significant variability in EV composition depending on the cell source, emphasizing the importance of thorough preclinical evaluation to determine the most effective sEVs for therapeutic use. Nevertheless, the embryonic origin of the cells raises ethical considerations, and induced pluripotent stem cell-derived cells were not investigated in this study.
As we advance, rigorous quality control and preclinical functional tests are essential to fully harness the potential of secretome/EV therapies for cardiac repair. The journey of EVs from bench to bedside has begun and will pursue with sustained scientific investigation and clinical validation.
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