EP4 Antagonist-Elicited Extracellular Vesicles from Mesenchymal Stem Cells Rescue Cognition/Learning Deficiencies by Restoring Brain Cellular Functions.
Adult brains have limited regenerative capacity. Consequently, both brain damage and neurodegenerative diseases often cause functional impairment for patients. Mesenchymal stem cells (MSCs), one type of adult stem cells, can be isolated from various adult tissues. MSCs have been used in clinical trials to treat human diseases and the therapeutic potentials of the MSC-derived secretome and extracellular vesicles (EVs) have been under investigation. We found that blocking the prostaglandin E2 /prostaglandin E2 receptor 4 (PGE2 /EP4 ) signaling pathway in MSCs with EP4 antagonists increased EV release and promoted the sorting of specific proteins, including anti-inflammatory cytokines and factors that modify astrocyte function, blood-brain barrier integrity, and microglial migration into the damaged hippocampus, into the EVs. Systemic administration of EP4 antagonist-elicited MSC EVs repaired deficiencies of cognition, learning and memory, inhibited reactive astrogliosis, attenuated extensive inflammation, reduced microglial infiltration into the damaged hippocampus, and increased blood-brain barrier integrity when administered to mice following hippocampal damage. Stem Cells Translational Medicine 2019.
['Chen|Shih-Yin|SY|', 'Lin|Meng-Chieh|MC|', 'Tsai|Jia-Shiuan|JS|', 'He|Pei-Lin|PL|', 'Luo|Wen-Ting|WT|', 'Herschman|Harvey|H|', 'Li|Hua-Jung|HJ|0000-0002-6041-3873']
D000328:Adult D000818:Animals D001812:Blood-Brain Barrier D003071:Cognition D000067128:Extracellular Vesicles D006624:Hippocampus D006801:Humans D054833:Isoindoles D007858:Learning D008297:Male D059630:Mesenchymal Stem Cells D051379:Mice D008822:Mice, Transgenic D058309:Receptors, Prostaglandin E, EP4 Subtype D020127:Recovery of Function D013449:Sulfonamides
Extracellular vesicle Mesenchymal stem cell Astrocyte Inflammation Cognition and memory Exosome PGE2/EP4 signaling