Predictive Markers Guide Differentiation to Improve Graft Outcome in Clinical Translation of hESC-Based Therapy for Parkinson's Disease.
Predictive Markers Guide Differentiation to Improve Graft Outcome in Clinical Translation of hESC-Based Therapy for Parkinson's Disease.
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预测标记指导分化以改善基于hESC的帕金森氏病疗法的临床翻译中的移植结果。
DOI：
10.1016/j.stem.2016.09.004
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发表时间：
2017-01-05
期刊：
影响因子：
23.9
通讯作者：
Parmar M
中科院分区：
文献类型：
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作者：
Kirkeby A;Nolbrant S;Tiklova K;Heuer A;Kee N;Cardoso T;Ottosson DR;Lelos MJ;Rifes P;Dunnett SB;Grealish S;Perlmann T;Parmar M
神经退行性疾病的干细胞治疗有望很快进入临床试验。目前正在开发的大多数方法涉及移植未成熟的祖细胞，随后在体内经历表型和功能成熟，并且预测已经在祖细胞阶段的长期移植结果仍然是一个挑战。在此，我们采用无偏的方法，通过对> 30批移植的人胚胎干细胞（hESC）衍生祖细胞的基因表达分析，鉴定在帕金森病动物模型中与移植结果相关的多巴胺神经元祖细胞中表达的预测标志物。我们发现许多常用的标记物不能准确预测体内亚型特异性成熟。相反，我们确定了一组特定的标记物与尾侧中脑相关，与体内移植后多巴胺能产量高。使用这些标记物，我们开发了一个良好的生产规范（GMP）分化方案，用于从hESC高效和可重复地生产可移植的多巴胺祖细胞。hESC衍生的DA祖细胞的常见标志物与移植物结果相关性差RNA-seq揭示了尾侧中脑标志物与体内DA神经元产量的相关性FGF8b模式hESC衍生的祖细胞向尾侧VM命运的分阶段应用使用该方法的GMP分化适应改善了移植结果Kirkeby等人显示一组预测标记物鉴定和应用可以帮助改进分化方案并改善基于hESC的帕金森病治疗的临床前模型中的移植结果。
Stem cell treatments for neurodegenerative diseases are expected to reach clinical trials soon. Most of the approaches currently under development involve transplantation of immature progenitors that subsequently undergo phenotypic and functional maturation in vivo, and predicting the long-term graft outcome already at the progenitor stage remains a challenge. Here, we took an unbiased approach to identify predictive markers expressed in dopamine neuron progenitors that correlate with graft outcome in an animal model of Parkinson’s disease through gene expression analysis of >30 batches of grafted human embryonic stem cell (hESC)-derived progenitors. We found that many of the commonly used markers did not accurately predict in vivo subtype-specific maturation. Instead, we identified a specific set of markers associated with the caudal midbrain that correlate with high dopaminergic yield after transplantation in vivo. Using these markers, we developed a good manufacturing practice (GMP) differentiation protocol for highly efficient and reproducible production of transplantable dopamine progenitors from hESCs. Common markers of hESC-derived DA progenitors correlate poorly with graft outcome RNA-seq reveals correlation of caudal midbrain markers with DA neuron yield in vivo Staged application of FGF8b patterns hESC-derived progenitors to a caudal VM fate GMP adaptation of differentiation using this approach improves transplant outcome Kirkeby et al. show that identification and application of a set of predictive markers can help refine differentiation protocols and improve transplant outcome in a preclinical model for hESC-based treatment of Parkinson’s disease.