Study shows more effective, safer way to develop stem cells for treating brain damage

When it comes to regenerating damaged brain cells, mesenchymal stem cells (MSCs) induced using an EP4 antagonist are superior to MSCs induced without the antagonist, according to a new study released today in the STEM CELLS Translational Medicine journal. The study, conducted on mice by researchers at the Institute of Cellular and System Medicine, National Health Research Institutes (NHRI), Taiwan, and the University of California, Los Angeles, provides information that could be used to develop new treatments for brain damage, including those caused by stroke and Parkinson’s disease.

Several clinical studies have shown the promise of MSCs in repairing neurological damage, but MSCs also present challenges such as complications of cell implantation and the possibility of ectopic tissue formation.

“However,” said the study’s lead investigator, Hua-Jung Li, Ph.D., “MSC-derived extracellular vesicles (EVs)/exosomes – which shuttle proteins and genetic information between cells – do not cause many of these difficulties. Consequently, the use of MSC-derived EVs/exosomes for therapy may attenuate many of the safety concerns related to the use of living stem cells.”

Previous studies by Dr. Li’s team focused on EP4, a protein-coupled receptor found to promote tumor proliferation and invasion. They demonstrated that inducing the MSC EV/exosomes in culture treated with an EP4 antagonist resulted in MSCs superior to those from basal (untreated) culture for rescuing cognition and learning deficiencies in the hippocampus. This is the area of the brain where cognition, spatial learning and memory occur.

“Consequently, we suspected increases in specific EP4 antagonist-induced MSC EVs/exosome cargo components might be behind these regenerative effects,” Dr. Li said.

In the new study – a follow-up to their previous work – the researchers further demonstrate the effects of EV/exosomes released from EP4 antagonist treated MSCs. “We show that they contain increased levels of CNP – a myelin-associated enzyme necessary for rescuing cognition and learning deficiencies – and they suppress astrogliosis and inflammation. The systemic administration of EP4 antagonist-elicited MSC EVs/exosomes also promote the growth of new neurons and neurites in damaged hippocampi,” Dr. Li said.

In contrast, CNP-depleted EP4 antagonist-induced MSC EVs/exosomes failed to repair the damage.

“Taken together, these data indicate that EP4 antagonist-elicited MSC EVs may be useful for therapies of central nervous system disease and damage,” Dr. Li concluded.

“The data from this line of research show enhanced regenerative potential for therapies that could someday treat brain damage and neural degeneration diseases,” said Anthony Atala, M.D., Editor-in-Chief of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine. “We look forward to seeing the successful advancement of this work.”

EP4 antagonist‐induced MSC EVs increase DCX‐positive
neuronal precursor cells in damaged hippocampi


(A) Schematic depiction of the brain sections representing the anatomic region analyzed by immunostaining. The blue box in (A‐i) represents the anatomic regions analyzed in (B). The blue box in (A‐ii) represents the anatomic regions analyzed in (C). The purple arrow indicates the direction of the x‐axis of the histogram in (C). B,C, Expression of β3‐tubulin (green) and DCX (red) in the hippocampi of UC and DC mice treated with PBS, and DC mice treated with MSC EVs and with MSC GWEVs at 5 days after EV/GWEV treatment. Cell nuclei were stained with DAPI. Quantification of DCX, DAPI, and β3‐tubulin signals along the purple arrow in (A‐ii) is shown in the histograms of (C). pVZ, periventricular zone. Scale bar, 50 μm. D, DCX quantification in stratum pyramidale (soma of CA1 neurons) and stratum radiatum (apical neurites of CA1 neurons), data from (C). Data are means ± SEM (n = 3). ***P  ≤ .001. DCX, doublecortin; EV, extracellular vesicle; GWEV, GW EP4 antagonist‐induced MSC EVs/exosome; MSC, mesenchymal stem cell; PBS, phosphate‐buffered saline

Source – PR Web

Chen SY, Lin MC, Tsai JS, et al. (2020) Exosomal 2′,3′-CNP from mesenchymal stem cells promotes hippocampus CA1 neurogenesis/neuritogenesis and contributes to rescue of cognition/learning deficiencies of damaged brain. Stem Cells Transl Med 9(4):499-517. [article]

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