Abstract
Simple SummaryAnthracyclines, such as doxorubicin (Dox), are an important class of chemotherapeutic drugs. However, their use is hampered by the risk of developing heart failure. The aim of this study was to assess and compare the cardioprotective effects exerted by a set of factors, collectively named secretomes, secreted by either adult or fetal human stem cells. Both secretome formulations were effective in counteracting Dox-induced apoptosis and mitochondrial impairment in cardiomyocytes and cardiac fibroblasts. In vivo experiments in a mouse model of Dox-induced cardiomyopathy (DIC) indicated that early administration of both secretomes during Dox treatment exerted beneficial long-term effects, preserving cardiac function and body mass. These findings suggest that the stem cell secretome could represent a feasible option for future paracrine cardioprotective therapy against Dox-related cardiotoxicity during cancer treatment.Cardiovascular side effects are major shortcomings of cancer treatments causing cardiotoxicity and late-onset cardiomyopathy. While doxorubicin (Dox) has been reported as an effective chemotherapy agent, unspecific impairment in cardiomyocyte mitochondria activity has been documented. We demonstrated that the human fetal amniotic fluid-stem cell (hAFS) secretome, namely the secreted paracrine factors within the hAFS-conditioned medium (hAFS-CM), exerts pro-survival effects on Dox-exposed cardiomyocytes. Here, we provide a detailed comparison of the cardioprotective potential of hAFS-CM over the secretome of mesenchymal stromal cells from adipose tissue (hMSC-CM). hAFS and hMSC were preconditioned under hypoxia to enrich their secretome. The cardioprotective effects of hAFS/hMSC-CM were evaluated on murine neonatal ventricular cardiomyocytes (mNVCM) and on their fibroblast counterpart (mNVFib), and their long-term paracrine effects were investigated in a mouse model of Dox-induced cardiomyopathy. Both secretomes significantly contributed to preserving mitochondrial metabolism within Dox-injured cardiac cells. hAFS-CM and hMSC-CM inhibited body weight loss, improved myocardial function, reduced lipid peroxidation and counteracted the impairment of mitochondrial complex I activity, oxygen consumption, and ATP synthesis induced by Dox. The hAFS and hMSC secretomes can be exploited for inhibiting cardiotoxic detrimental side effects of Dox during cancer therapy, thus ensuring cardioprotection via combinatorial paracrine therapy in association with standard oncological treatments.
Highlights
Good communication and networking capacities are mandatory skills to ensure efficient performance
Here we demonstrated that the Human adipose tissue-derived mesenchymal stromal cells (hMSC) secretome and, most of all the human fetal amniotic fluid-stem cell (hAFS)
While the present study offers encouraging results in suggesting the application of the fetal and adult stem cell secretomes as a paracrine, cell-free cardioprotective strategy in combination with standard chemotherapy, some limitations must be acknowledged and need to be addressed with further research
Summary
Good communication and networking capacities are mandatory skills to ensure efficient performance. Several independent preclinical studies have provided evidence that the transplanted cells can release trophic paracrine factors which activate endogenous pathways, leading to the significant improvement of tissue repair [1]. In this perspective, the stem/progenitor cell secretome, i.e., the whole of the cell-secreted paracrine factors, including both soluble individual molecules and membrane-bound extracellular vesicles, has gained increasing interest as a novel curative booster in regenerative medicine [2]. As a matter of fact, multiple studies have suggested harnessing the stem/progenitor cell secretome as a therapeutic agent for cardiac disease and myocardial dysfunction and have provided proof of principle of the paracrine therapy [5,6,7]
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