Mapping developmental trajectories and subtype diversity of normal and glaucomatous human retinal ganglion cells by single-cell transcriptome analysis.
Mapping developmental trajectories and subtype diversity of normal and glaucomatous human retinal ganglion cells by single-cell transcriptome analysis.
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DOI：
10.1002/stem.3238
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发表时间：
2020-10-01
期刊：
影响因子：
--
通讯作者：
Ahmad I
中科院分区：
文献类型：
--
作者：
Teotia P;Niu M;Ahmad I
青光眼的特征是视网膜神经节细胞（RGC）进行性退化，导致不可逆的视力丧失。目前，RGC变性尚无有效治疗方法。我们使用培养皿中的疾病干细胞模型来检查 RGC 对青光眼变性的发育敏感性，这可能为治疗方法的制定提供信息。在这里，我们使用 SIX6 风险等位基因（SIX6 风险等位基因）原发性开角型青光眼患者特异性和对照 hRGC 的单细胞转录组分析来比较谱系和阶段特异性转录特征方面的发育轨迹，以识别失调的阶段/基因，并使用亚型组成来估计 RGC 退化的相对脆弱性，因为它们再生轴突的能力是亚型特异性的。 SIX6 风险等位基因和对照 RGC 的发育轨迹（从神经干细胞开始到 RGC）相似。然而，与对照组相比，SIX6 风险等位基因 RGC 的分化在视网膜祖细胞阶段相对停滞，损害了成熟表型和亚型组成的获得，这可能是由于 mTOR 和 Notch 信号通路失调所致。此外，与对照相比，SIX6 风险等位基因 RGC 表达的与优先抵抗变性的 RGC 亚型相对应的基因较少。 SIX6 风险等位基因 RGC 的不成熟表型以及代表性不足的抗变性亚型可能使它们容易发生青光眼变性。基于单细胞转录组的发育轨迹揭示了青光眼患者特异性视网膜神经节细胞（RGC）的发育异常。根据沿 RGC 谱系区分青光眼患者（SIX6 风险等位基因）特异性和对照诱导多能干细胞的谱系和阶段特异性转录特征，对发育轨迹进行比较，结果表明 SIX6 风险等位基因 RGC 在成熟表型和亚型组成方面受到损害，包括与对照相比具有抗变性的 RGC。
Glaucoma is characterized by a progressive degeneration of retinal ganglion cells (RGCs), leading to irreversible vision loss. Currently, there is no effective treatment for RGC degeneration. We used a disease‐in‐a‐dish stem cell model to examine the developmental susceptibility of RGCs to glaucomatous degeneration, which may inform on the formulation of therapeutic approaches. Here, we used single‐cell transcriptome analysis of SIX6 risk allele (SIX6 risk allele) primary open angle glaucoma patient‐specific and control hRGCs to compare developmental trajectories in terms of lineage‐ and stage‐specific transcriptional signature to identify dysregulated stages/genes, and subtype composition to estimate the relative vulnerability of RGCs to degeneration because their ability to regenerate axons are subtype‐specific. The developmental trajectories, beginning from neural stem cells to RGCs, were similar between SIX6 risk allele and control RGCs. However, the differentiation of SIX6 risk allele RGCs was relatively stalled at the retinal progenitor cell stage, compromising the acquisition of mature phenotype and subtype composition, compared with controls, which was likely due to dysregulated mTOR and Notch signaling pathways. Furthermore, SIX6 risk allele RGCs, as compared with controls, expressed fewer genes corresponding to RGC subtypes that are preferentially resistant to degeneration. The immature phenotype of SIX6 risk allele RGCs with underrepresented degeneration‐resistant subtypes may make them vulnerable to glaucomatous degeneration. Single‐cell transcriptome‐based developmental trajectories reveal developmental abnormalities in glaucoma patient‐specific retinal ganglion cells (RGCs). A comparison of the developmental trajectories, based on lineage‐ and stage‐specific transcriptional signature of differentiating glaucoma patient (SIX6 risk allele)‐specific and control induced pluripotent stem cells along the RGC lineage, revealed that the SIX6 risk allele RGCs are compromised in mature phenotype and subtype composition, including those that are degeneration‐resistant vs controls.
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