Studies on Biodistribution of CDC-Exosomes and their Immunomodulatory Effects on Macrophages

Abstract

Myocardial infarctions (MIs) commonly result from coronary artery disease leading to an obstruction of coronary blood flow. This can cause irreversible myocardial necrosis and a reduction in heart function. Cardiosphere-Derived Cells (CDCs) have been shown to have regenerative capacity largely attributed to paracrine effects mediated by exosomes. Additional studies are needed to better understand the mechanisms by which exosomes impart their benefit post-MI. As such, we sought to develop a method of tracking physiological exosome uptake in vivo. Exosomes play a critical role in intracellular communication and orchestrating sequential inflammatory events resulting in anti-inflammatory, cardioprotective effects following myocardial infarction (MI). Nr4a1/Nur77/NGFI-B-orphan nuclear receptor is a master regulator involved in the inflammatory response and immune homeostasis. It suppresses inflammatory genes through inhibition of NF-κB signaling pathways and is known to be upregulated by multiple substrates including TNFα and oxidized lipids like lipopolysaccharides (LPS). We hypothesized that the anti-inflammatory effects of CDC-exos are mediated by Nr4a1 induction in macrophages which regulates the expression of inflammatory genes.