EP4 Antagonist-Elicited Extracellular Vesicles from Mesenchymal Stem Cells Rescue Cognition/Learning Deficiencies by Restoring Brain Cellular Functions

Author:

Chen Shih-Yin1,Lin Meng-Chieh1,Tsai Jia-Shiuan1,He Pei-Lin1,Luo Wen-Ting1,Herschman Harvey234,Li Hua-Jung1

Affiliation:

1. Institute of Cellular and System Medicine National Health Research Institutes, Miaoli, Taiwan, Republic of China

2. Department of Molecular & Medical Pharmacology University of California, Los Angeles, Los Angeles, California, USA

3. Department of Biological Chemistry University of California, Los Angeles, Los Angeles, California, USA

4. Molecular Biology Institute University of California, Los Angeles, Los Angeles, California, USA

Abstract

Abstract 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

Funder

Ministry of Science and Technology

National Health Research Institutes

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,General Medicine

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