Transdifferentiation of periodontal ligament-derived stem cells into retinal ganglion-like cells and its microRNA signature.
Transdifferentiation of periodontal ligament-derived stem cells into retinal ganglion-like cells and its microRNA signature.
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DOI：
10.1038/srep16429
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发表时间：
2015-11-09
影响因子：
4.6
通讯作者：
Pang CP
中科院分区：
文献类型：
--
作者：
Ng TK;Yung JS;Choy KW;Cao D;Leung CK;Cheung HS;Pang CP
在发达国家，视网膜疾病是导致不可逆视力损害和失明的主要原因。人类视网膜的再生能力有限，无法取代细胞损失。干细胞替代疗法已被提出作为一种可行的选择。在此之前，我们已经诱导成人牙周膜干细胞（PDLSCs）的视网膜谱系。在这项研究中，我们修改了我们的诱导方案，以指导人类成人PDLSC进入视网膜神经节样细胞，并确定了这种转分化过程的microRNA（miRNA）签名。分化的PDLSC表现出功能性神经元的特征，因为它们表达神经元和视网膜神经节细胞标志物（ATOH 7、POU 4F 2、β-III微管蛋白、MAP 2、TAU、NEUROD 1和SIX 3），形成突触，并显示谷氨酸诱导的钙反应以及自发电活动。在视网膜诱导后，总体miRNA表达谱鉴定出44种上调和27种下调的人miRNA。对预测的miRNA靶基因进行基因本体分析，证实转分化与神经元分化过程密切相关。此外，在诱导过程中，2种miRNA靶向候选物VEGF和PTEN的表达显著上调。这项研究确定了人类成体干细胞向视网膜神经节样细胞的转分化过程，并揭示了遗传和miRNA调控机制的参与。
Retinal diseases are the leading causes of irreversible visual impairment and blindness in the developed countries. Human retina has limited regenerative power to replace cell loss. Stem cell replacement therapy has been proposed as a viable option. Previously, we have induced human adult periodontal ligament stem cells (PDLSCs) to the retinal lineage. In this study, we modified our induction protocol to direct human adult PDLSCs into retinal ganglion-like cells and determined the microRNA (miRNA) signature of this transdifferentiation process. The differentiated PDLSCs demonstrated the characteristics of functional neurons as they expressed neuronal and retinal ganglion cell markers (ATOH7, POU4F2, β-III tubulin, MAP2, TAU, NEUROD1 and SIX3), formed synapses and showed glutamate-induced calcium responses as well as spontaneous electrical activities. The global miRNA expression profiling identified 44 upregulated and 27 downregulated human miRNAs after retinal induction. Gene ontology analysis of the predicted miRNA target genes confirmed the transdifferentiation is closely related to neuronal differentiation processes. Furthermore, the expressions of 2 miRNA-targeted candidates, VEGF and PTEN, were significantly upregulated during the induction process. This study identified the transdifferentiation process of human adult stem cells into retinal ganglion-like cells and revealed the involvement of both genetic and miRNA regulatory mechanisms.