Dataset Information

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

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.

SUBMITTER: Chen SY

PROVIDER: S-EPMC6591556 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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EP<sub>4</sub> Antagonist-Elicited Extracellular Vesicles from Mesenchymal Stem Cells Rescue Cognition/Learning Deficiencies by Restoring Brain Cellular Functions.

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

Stem cells translational medicine 20190319 7

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 E<sub>2 ...[more]

PMID: 30891948

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Project description:Mesenchymal stem cells (MSCs) have been used in clinical studies to treat neurological diseases and damage. However, implanted MSCs do not achieve their regenerative effects by differentiating into and replacing neural cells. Instead, MSC secretome components mediate the regenerative effects of MSCs. MSC-derived extracellular vesicles (EVs)/exosomes carry cargo responsible for rescuing brain damage. We previously showed that EP4 antagonist-induced MSC EVs/exosomes have enhanced regenerative potential to rescue hippocampal damage, compared with EVs/exosomes from untreated MSCs. Here we show that EP4 antagonist-induced MSC EVs/exosomes promote neurosphere formation in vitro and increase neurogenesis and neuritogenesis in damaged hippocampi; basal MSC EVs/exosomes do not contribute to these regenerative effects. 2',3'-Cyclic nucleotide 3'-phosphodiesterase (CNP) levels in EP4 antagonist-induced MSC EVs/exosomes are 20-fold higher than CNP levels in basal MSC EVs/exosomes. Decreasing elevated exosomal CNP levels in EP4 antagonist-induced MSC EVs/exosomes reduced the efficacy of these EVs/exosomes in promoting β3-tubulin polymerization and in converting toxic 2',3'-cAMP into neuroprotective adenosine. CNP-depleted EP4 antagonist-induced MSC EVs/exosomes lost the ability to promote neurogenesis and neuritogenesis in damaged hippocampi. Systemic administration of EV/exosomes from EP4 -antagonist derived MSC EVs/exosomes repaired cognition, learning, and memory deficiencies in mice caused by hippocampal damage. In contrast, CNP-depleted EP4 antagonist-induced MSC EVs/exosomes failed to repair this damage. Exosomal CNP contributes to the ability of EP4 antagonist-elicited MSC EVs/exosomes to promote neurogenesis and neuritogenesis in damaged hippocampi and recovery of cognition, memory, and learning. This experimental approach should be generally applicable to identifying the role of EV/exosomal components in eliciting a variety of biological responses.

Dataset Information

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

Publications

EP<sub>4</sub> Antagonist-Elicited Extracellular Vesicles from Mesenchymal Stem Cells Rescue Cognition/Learning Deficiencies by Restoring Brain Cellular Functions.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

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

Publications

EP<sub>4</sub> Antagonist-Elicited Extracellular Vesicles from Mesenchymal Stem Cells Rescue Cognition/Learning Deficiencies by Restoring Brain Cellular Functions.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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