(175j) Anti-Senescence Effects of Human Blood Vessel Organoid-Derived Extracellular Vesicles

Extracellular vesicles (EVs) are small phospholipid bound particles derived from cells used for intercommunication with each other through the delivery of various cargo such as proteins, nucleic acid, lipids, and growth factors. EVs derived from induced pluripotent stem cells (iPSCs) have been shown to possess anti-senescent properties due to the cargo they possess. Cell senescence occurs when cells stop dividing and undergo irreversible growth suspension. Age has been shown to play a large factor in cell senescence along with other variables such as DNA damage, telomere shortening, and stress. As cell senescence matures, changes in gene expression and EV cargo can be observed; It is thought that these changes can impact neighboring cell activity. These changes can cascade into tissue aging and age-related diseases such as Alzheimer’s and Blood Brain Barrier degradation. This study focuses on the effects senescence has on blood brain barrier cell types and the potential therapeutic effects of EVs from healthy cells. Not much is known about how differentiation of iPSCs into neural cell type affects the anti-aging properties of the EVs secreted. To induce senescence, D-galactose was utilized on multiple neural cell types differentiated from iPSCs. iPSC-derived pericytes (iPC), neural progenitor cells (iNPC) and blood vessel organoids (iBVO) had senescence induced via D-galactose at various concentrations. The EVs of Alzheimer’s disease patient-derived brain organoids were also evaluated. The influences of various types of EVs on oxidative stress, inflammation, and mitochondrial disfunction were investigated in this study. This study showed a concentration dependence on D-galactose to influence common senescent genes Sirt-1 and Sirt-3 activity, reactive oxidative stress, metabolic activity, inflammation and apoptosis. This study also tests the anti-aging ability of the respective EVs produced from multiple neural differentiations from iPSCs relative to undifferentiated iPSC-EVs. The results show that differentiation path, EV dosage and cargo all serve as key factors in the anti-aging effects of differentiated iPSC-EVs. This study has significance in understanding key markers that affect aging and neurogenerative diseases that can occur as a by-product as well as development of potential non-invasive EV therapeutics.