AUTHOR=Kim Hyo Jeong , Bayarsaikhan Delger , Lee Jaesuk , Bayarsaikhan Govigerel , Lee Bonghee 

TITLE=Brain-Derived Neurotrophic Factor Secreting Human Mesenchymal Stem Cells Improve Outcomes in Rett Syndrome Mouse Models

JOURNAL=Frontiers in Neuroscience

VOLUME=15

YEAR=2021

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2021.725398

DOI=10.3389/fnins.2021.725398

ISSN=1662-453X

ABSTRACT=<p>Rett syndrome (RTT) is a severe X-linked dominant neurodevelopmental disorder caused by mutations in the methyl-CpG-binding protein 2 (<italic>MECP2</italic>) gene; <italic>MeCP2</italic> regulates the expression of brain-derived neurotrophic factor (<italic>BDNF</italic>) and increasing BDNF levels ameliorates RTT symptoms. However, the clinical application of BDNF is limited, because of its short half-life and low penetrance across the blood-brain barrier. In this study, we generated BDNF-secreting mesenchymal stem cells (MSCs) from the human umbilical cord cells, using CRISPR-Cas9. We studied the effects of BDNF-MSCs in <italic>MECP2</italic> knockout and <italic>MECP2</italic>-deficient mice. BDNF-MSCs upregulated the expression of BDNF, pAKT, and pERK1/2 and downregulated that of pp38, both <italic>in vitro</italic> and <italic>in vivo</italic>. In our <italic>in vivo</italic> experiments, BDNF-MSCs increased the body and brain weights in mice. BDNF-MSCs increased the neuronal cell numbers in the hippocampus, cortex, and striatum; in addition, they increased the number of synapses. BDNF-MSCs upregulated BDNF and the activity of BDNF downstream effectors, such as pAKT and pERK 1/2; this upregulation was persistent. In conclusion, BDNF-MSCs generated using CRISPR-Cas9 could be a therapeutic strategy for treating RTT.</p>