Human amniotic epithelial cell transplantation promotes neurogenesis and ameliorates social deficits in BTBR mice

Ruiyu Zhang,Yulong Cai,Lihe Guo,Haiwei Xu,Xin Li,Xiaotang Fan,Rui Xiao,Hongyu Zhong

doi:10.1186/s13287-019-1267-0

Abstract

BackgroundAutism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social interactions and communication and stereotypical patterns of behaviors, interests, or activities. Even with the increased prevalence of ASD, there is no defined standard drug treatment for ASD patients. Currently, stem cells, including human amniotic epithelial cell (hAEC) transplantation, seem to be a promising treatment for ASD, but the effectiveness needs to be verified, and the mechanism has not been clarified.MethodsWe intraventricularly transplanted hAECs into a 2-month-old BTBR T+tf/J (BTBR) mouse model of ASD. Behavior tests were detected 1 month later; hippocampal neurogenesis, neuroprogenitor cell (NPC) pool, and microglia activation were analyzed with immunohistochemistry and immunofluorescence; the levels of pro-inflammatory cytokines, brain-derived neurotrophic factor (BDNF), and TrkB in the hippocampus were determined by real-time PCR or western blotting.ResultsAfter intraventricular injection of hAECs into adult males, social deficits in BTBR mice were significantly ameliorated. In addition, hAEC transplantation restored the decline of neurogenesis and NPCs in the hippocampus of BTBR mice by expanding the stem cell pool, and the decreased levels of BDNF and TrkB were also rescued in the hippocampus of the hAEC-injected BTBR mice. Meanwhile, the transplantation of hAECs did not induce microglial overactivation or excessive production of pro-inflammatory cytokines in the hippocampus of BTBR mice.ConclusionsBased on these results, we found that hAEC transplantation ameliorated social deficits and promoted hippocampal neurogenesis in BTBR mice. Our study indicates a promising therapeutic option that could be applied to ASD patients in the future.

Highlights

Autism spectrum disorder (ASD) is a heterogeneous developmental disability characterized by impairments in social interaction, communication, and repetitive behaviors [1]
Results human amniotic epithelial cell (hAEC) injection ameliorated social deficits in the threechambered social approach task of BTBR T+tf/J (BTBR) mice, but not the repetitive behavior Sociability was defined as a preference for the novel mouse over the novel object
We found that BTBR mice with vehicle treatment had more Iba1+ microglia in the hippocampal subgranular zone (SGZ) compared to C57 mice (Fig. 3a, b, d, e, i, P < 0.001), and there was no significant difference in the number of Iba1+ microglia in the SGZ between the BTBR mice treated with vehicle and hAECs (Fig. 3b–f, i, NS)

Summary

Introduction

Autism spectrum disorder (ASD) is a heterogeneous developmental disability characterized by impairments in social interaction, communication, and repetitive behaviors [1]. Evidence has indicated that deficits in hippocampal neurogenesis contribute to ASD pathogenesis both in humans and in mouse models of ASD [8, 10,11,12]. Approaches to promote hippocampal neurogenesis effectively alleviate ASD-like behaviors. It seems that hippocampal neurogenesis could be considered a target for treating ASD. Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social interactions and communication and stereotypical patterns of behaviors, interests, or activities. Stem cells, including human amniotic epithelial cell (hAEC) transplantation, seem to be a promising treatment for ASD, but the effectiveness needs to be verified, and the mechanism has not been clarified

Methods

Results

Discussion

Conclusion