HDAC1 Silence Promotes Neuroprotective Effects of Human Umbilical Cord-Derived Mesenchymal Stem Cells in a Mouse Model of Traumatic Brain Injury via PI3K/AKT Pathway.

Ling Xu,Qu Xing,Yaping Wang,Xinkui Zhou,Tian Cheng,Jiankang Zhou,Yuanbo Cui,Tuanjie Huang,Greta Luyuan Yang,Bo Yang,Jiewen Zhang,Tengfei Liu,Shanshan Ma,Fangxia Guan,Xingxing Zang

doi:10.3389/fncel.2018.00498

Abstract

Stem cell transplantation is a promising therapy for traumatic brain injury (TBI), but low efficiency of survival and differentiation of transplanted stem cells limits its clinical application. Histone deacetylase 1 (HDAC1) plays important roles in self-renewal of stem cells as well as the recovery of brain disorders. However, little is known about the effects of HDAC1 on the survival and efficacy of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in vivo. In this study, our results showed that HDAC1 silence promoted hUC-MSCs engraftment in the hippocampus and increased the neuroprotective effects of hUC-MSCs in TBI mouse model, which was accompanied by improved neurological function, enhanced neurogenesis, decreased neural apoptosis, and reduced oxidative stress in the hippocampus. Further mechanistic studies revealed that the expressions of phosphorylated PTEN (p-PTEN), phosphorylated Akt (p-Akt), and phosphorylated GSK-3β (p-GSK-3β) were upregulated. Intriguingly, the neuroprotective effects of hUC-MSCs with HDAC1 silence on behavioral performance of TBI mice was markedly attenuated by LY294002, an inhibitor of the PI3K/AKT pathway. Taken together, our findings suggest that hUC-MSCs transplantation with HDAC1 silence may provide a potential strategy for treating TBI in the future.

Highlights

Traumatic brain injury (TBI) is a common brain disorder with high mortality and disability (Reis et al, 2015)
We found that silencing histone deacetylase 1 (HDAC1) through siRNA could promote the engraftment of hUC-mesenchymal stem cells (MSCs) in the hippocampus and improve the efficacy of hUC-MSCs transplantation in a TBI mouse model as indicated by improved neurological function, enhanced neurogenesis, decreased neural apoptosis, and reduced oxidative stress in the hippocampus; and, the underlying mechanism of these neuroprotective effects of hUC-MSCs with silenced HDAC1 might involve in the activation of PI3K/AKT pathway
These results indicate that HDAC1 silence enhances the survival and migration of hUC-MSCs in the hippocampus of TBI mice after transplantation via tail vein

Summary

Introduction

Traumatic brain injury (TBI) is a common brain disorder with high mortality and disability (Reis et al, 2015). Despite the considerable advances in the treatment and nursing of patients, effective therapy to attenuate the pathological process of TBI remain to be explored extensively. Emerging evidence shows that mesenchymal stem cells (MSCs) transplantation can improve the neurologic function following TBI (Kota et al, 2016), which imply MSCs-based therapy is promising for TBI. Human umbilical cord-derived MSCs (hUC-MSCs) have high self-renewal ability, and multidirectional differentiation potential (Xu et al, 2012). Many studies reported that only a small fraction of transplanted MSCs could migrate, survive and differentiate into neural-like cells in the injured area, which limits its clinical application (Juliandi et al, 2010; Kang et al, 2016). It is imperative to develop new strategies to overcome these problems in preclinical studies

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