Dissecting the secretome of amniotic mesenchymal stromal cells to find new therapies for cardiac diseases

The high worldwide incidence of cardiovascular diseases has driven the development of novel therapeutic approaches. Mesenchymal stromal cells (MSCs) have been widely investigated in preclinical models of heart diseases, showing significant therapeutic benefits. It is well-established that MSCs primarily exert their therapeutic effects through paracrine mechanisms mediated by their secretome. However, MSCs derived from elderly donors or individuals with chronic conditions exhibit reduced regenerative potential, as they tend to lose therapeutic efficacy with age due to the depletion of key paracrine factors. Vice versa, MSCs of fetal origin isolated from the amniotic membrane of the human placenta (hAMSCs), produce high number of secreted factors that have demonstrated significant cardio-protective and cardio-reparative effects in animal models. The secretome contains a wide array of bioactive molecules, including proteins, nucleic acids, and extracellular vesicles (EVs), which are critical for its paracrine benefits. Notably, recent findings suggest that EVs alone may replicate the therapeutic effects of the whole secretome. This study aimed to characterize the secretome and EVs derived from hAMSCs for the treatment of cardiac diseases. The cytoprotective and pro-angiogenic properties of hAMSC-derived secretome and EVs were evaluated in models of ischemia and chronic hypoxia, demonstrating their ability to reduce ischemic damage and promote angiogenesis. Additionally, key paracrine bioactive molecules potentially responsible for the cardioprotective effects mediated by hAMSCs were identified. Our results confirm that hAMSC-derived secretome is cardioprotective and suggest that the EVs isolated from the same secretome replicate, at least partly, the same beneficial effects, thus offering a promising alternative to cell-based therapies due to their ease of standardization. This study underscores the essential role of the hAMSC secretome in cardioprotection and paves new avenues for therapeutic strategies in the treatment of cardiovascular diseases.