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Atoh7通过抑制Notch信号通路促进源自穆勒细胞的视网膜干细胞分化为视网膜神经节细胞。

Atoh7 promotes the differentiation of retinal stem cells derived from Müller cells into retinal ganglion cells by inhibiting Notch signaling.

作者信息

Song Wei-tao, Zhang Xue-yong, Xia Xiao-bo

出版信息

Stem Cell Res Ther. 2013 Aug 14;4(4):94. doi: 10.1186/scrt305.

DOI:10.1186/scrt305
PMID:23945288
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3854761/
Abstract

INTRODUCTION

Retinal Müller cells exhibit the characteristics of retinal progenitor cells, and differentiate into ganglion cells under certain conditions. However, the number of ganglion cells differentiated from retinal Müller cells falls far short of therapeutic needs. This study aimed to develop a novel protocol to promote the differentiation of retinal Müller cells into ganglion cells and explore the underlying signaling mechanisms.

METHODS

Müller cells were isolated and purified from rat retina and induced to dedifferentiate into retinal stem cells. Next the stem cells were transfected with lentivirus PGC-FU-GFP or lentivirus PGC-FU-Atoh7-GFP. In addition, the stem cells were transfected with Brn-3b siRNA or Isl-1 siRNA or treated with Notch inhibitor gamma-secretase inhibitor (GSI).

RESULTS

The proportion of ganglion cells differentiated from Atoh7-tranfected stem cells was significantly higher than that of controls. Knockdown of Brn-3b or Isl-1 inhibited, while GSI promoted, the differentiation into retinal ganglion cells. Atoh7 promoted the expression of Brn-3b and Isl-1 but inhibited the expression of Notch1.

CONCLUSIONS

Atoh7 promotes the differentiation of Müller cells-derived retinal stem cells into retinal ganglion cells by inhibiting Notch signaling, thus opening up a new avenue for gene therapy and optic nerve regeneration in glaucoma.

摘要

引言

视网膜穆勒细胞具有视网膜祖细胞的特征，并在特定条件下分化为神经节细胞。然而，从视网膜穆勒细胞分化而来的神经节细胞数量远远不能满足治疗需求。本研究旨在开发一种新方法来促进视网膜穆勒细胞向神经节细胞的分化，并探索其潜在的信号传导机制。

方法

从大鼠视网膜中分离并纯化穆勒细胞，诱导其去分化为视网膜干细胞。接下来，用慢病毒PGC-FU-GFP或慢病毒PGC-FU-Atoh7-GFP转染干细胞。此外，用Brn-3b siRNA或Isl-1 siRNA转染干细胞，或用Notch抑制剂γ-分泌酶抑制剂（GSI）处理。

结果

Atoh7转染的干细胞分化为神经节细胞的比例显著高于对照组。敲低Brn-3b或Isl-1会抑制向视网膜神经节细胞的分化，而GSI则会促进这种分化。Atoh7促进Brn-3b和Isl-1的表达，但抑制Notch1的表达。

结论

Atoh7通过抑制Notch信号促进穆勒细胞来源的视网膜干细胞向视网膜神经节细胞的分化，从而为青光眼的基因治疗和视神经再生开辟了一条新途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01bc/3854761/229e9374293b/scrt305-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01bc/3854761/10cbe4a24f16/scrt305-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01bc/3854761/0f7f489aa699/scrt305-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01bc/3854761/c04ee24c4539/scrt305-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01bc/3854761/67ed7929f977/scrt305-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01bc/3854761/229e9374293b/scrt305-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01bc/3854761/10cbe4a24f16/scrt305-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01bc/3854761/0f7f489aa699/scrt305-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01bc/3854761/c04ee24c4539/scrt305-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01bc/3854761/67ed7929f977/scrt305-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01bc/3854761/229e9374293b/scrt305-5.jpg

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