将畸胎瘤定义为多谱系人类发育的模型。
Defining the Teratoma as a Model for Multi-lineage Human Development.
机构信息
Department of Bioengineering, University of California, San Diego, San Diego, CA 92093, USA; Biomedical Sciences Graduate Program, University of California, San Diego, San Diego, CA 92093, USA.
Department of Bioengineering, University of California, San Diego, San Diego, CA 92093, USA.
出版信息
Cell. 2020 Nov 25;183(5):1402-1419.e18. doi: 10.1016/j.cell.2020.10.018. Epub 2020 Nov 4.
We propose that the teratoma, a recognized standard for validating pluripotency in stem cells, could be a promising platform for studying human developmental processes. Performing single-cell RNA sequencing (RNA-seq) of 179,632 cells across 23 teratomas from 4 cell lines, we found that teratomas reproducibly contain approximately 20 cell types across all 3 germ layers, that inter-teratoma cell type heterogeneity is comparable with organoid systems, and teratoma gut and brain cell types correspond well to similar fetal cell types. Furthermore, cellular barcoding confirmed that injected stem cells robustly engraft and contribute to all lineages. Using pooled CRISPR-Cas9 knockout screens, we showed that teratomas can enable simultaneous assaying of the effects of genetic perturbations across all germ layers. Additionally, we demonstrated that teratomas can be sculpted molecularly via microRNA (miRNA)-regulated suicide gene expression to enrich for specific tissues. Taken together, teratomas are a promising platform for modeling multi-lineage development, pan-tissue functional genetic screening, and tissue engineering.
我们提出，畸胎瘤是验证干细胞多能性的公认标准，它可能成为研究人类发育过程的一个很有前途的平台。对来自 4 个细胞系的 23 个畸胎瘤中的 179632 个细胞进行单细胞 RNA 测序（RNA-seq），我们发现畸胎瘤在所有 3 个胚层中可重现地包含大约 20 种细胞类型，其肿瘤间细胞类型异质性与类器官系统相当，并且畸胎瘤肠道和脑细胞类型与类似的胎儿细胞类型很好地对应。此外，细胞条形码技术证实，注射的干细胞可强有力地植入并有助于所有谱系。通过 pooled CRISPR-Cas9 knockout 筛选，我们表明畸胎瘤可以同时对所有胚层的遗传扰动效应进行检测。此外，我们还证明，通过 microRNA（miRNA）调控的自杀基因表达可以对畸胎瘤进行分子修饰，从而富集特定组织。总之，畸胎瘤是一个很有前途的平台，可以用于多谱系发育、泛组织功能遗传筛选和组织工程。
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