Role of mesenchymal stem cells‐derived exosomes on inflammation, apoptosis, fibrosis and telocyte modulation in doxorubicin‐induced cardiotoxicity: A closer look at the structural level

Cardiotoxicity induced by doxorubicin (Dox) is a major complication in cancer patients. Exosomes (Ex) derived from mesenchymal cells could be a promising therapeutic for various heart diseases. This study investigated the role of Ex in Dox-induced cardiotoxicity and its mechanistic insights, using Sacubitril/valsartan (S/V) as a reference drug widely recommended in heart failure management. The study involved 24 Wistar rats, divided into a control, Dox, Dox + S/V, and Dox + Ex groups. The rats were assessed for cardiac enzymes, inflammatory and oxidative stress markers. Immunohistochemical expression of caspase-1, nuclear factor erythroid 2-related factor 2 (NrF2), E-Cadherin, CD117/c-kit, and Platelet-derived growth factor-α (PDGFα) was evaluated. P53 and Annexin V were assessed by PCR. Histological examination was performed using hematoxylin and eosin and Sirius red stains. Ex ameliorated the adverse cardiac pathological changes and significantly decreased the cardiac enzymes and inflammatory and oxidative stress markers. Ex also exerted antifibrotic and antiapoptotic effect in heart tissue. Ex treatment also improved NrF2 immunohistochemistry, up-regulated E-Cadherin immune expression, and restored the telocyte markers CD117/c-kit and PDGFα. Ex can mitigate Dox-induced cardiotoxicity by acting as an anti-inflammatory, antioxidant, antiapoptotic, and antifibrotic agents, restoring telocytes and modulating epithelial mesenchymal transition. RESEARCH HIGHLIGHTS: Exosomes exhibit positive expression for CD90 and CD105 whereas showing -ve expression for CD 34 by flow cytometry. Exosomes restore the immunohistochemical expression of the telocytes markers CD117/c-kit and PDGFα. Exosomes alleviate myocardial apoptosis, oxidative stress and fibrosis.