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

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

doi:10.3389/fnins.2021.725398

Hyo Jeong Kim, Jaesuk Lee + Show 3 more

Open Access

https://doi.org/10.3389/fnins.2021.725398

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Abstract

Rett syndrome (RTT) is a severe X-linked dominant neurodevelopmental disorder caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene; MeCP2 regulates the expression of brain-derived neurotrophic factor (BDNF) 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 MECP2 knockout and MECP2-deficient mice. BDNF-MSCs upregulated the expression of BDNF, pAKT, and pERK1/2 and downregulated that of pp38, both in vitro and in vivo. In our in vivo 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.

Highlights

Rett syndrome (RTT) is a severe X-linked dominant neurodevelopmental disorder that affects approximately 1 in 10,000 female infants
Animal models of RTT show that Brain-derived neurotrophic factor (BDNF) is downregulated in the brain, serum, and cerebrospinal fluid; BDNF deficiency leads to symptoms and outcomes similar to that of de novo mutations in the methyl-CpG-binding protein 2 (MECP2) gene
This study investigated whether BDNFsecreting mesenchymal stem cells (MSCs) generated by CRISPR/Cas9 could reverse the neuronal pathology in MECP2-deficient RTT mouse models and in neurons that underwent MECP2 knockdown

Summary

Introduction

Rett syndrome (RTT) is a severe X-linked dominant neurodevelopmental disorder that affects approximately 1 in 10,000 female infants. It is categorized into classical and atypical RTT. MECP2 gene mutations affect male more severely than female, leading to early fetal death or severe neonatal encephalopathy (Villard, 2007). Deficiency of MECP2, through phosphorylation of the MECP2 gene or epigenetic modifications, BDNF-MSC Treatment in Rett Syndrome leads to a reduction in the expression, translation, and stability of in vivo BDNF (Damen and Heumann, 2013). Animal models of RTT show that BDNF is downregulated in the brain, serum, and cerebrospinal fluid; BDNF deficiency leads to symptoms and outcomes similar to that of de novo mutations in the MECP2 gene. Overexpression of BDNF against MECP2 deficiency in RTT model mice suggests that BDNF could be an alternative therapeutic for RTT (Vanhala et al, 1998; Riikonen, 2003; Abuhatzira et al, 2007)

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