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鉴定编码慢骨骼肌肌钙蛋白 T 的基因作为视网膜色素上皮细胞永生化的新型标志物。

Identification of a Gene Encoding Slow Skeletal Muscle Troponin T as a Novel Marker for Immortalization of Retinal Pigment Epithelial Cells.

机构信息

Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Tokyo, Japan.

Foundation for Biomedical Research and Innovation, Kobe, Japan.

出版信息

Sci Rep. 2017 Aug 15;7(1):8163. doi: 10.1038/s41598-017-08014-w.

DOI:10.1038/s41598-017-08014-w
PMID:28811571
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5557831/
Abstract

Human pluripotent stem cells (hPSCs) are leading candidate raw materials for cell-based therapeutic products (CTPs). In the development of hPSC-derived CTPs, it is imperative to ensure that they do not form tumors after transplantation for safety reasons. Because cellular immortalization is a landmark of malignant transformation and a common feature of cancer cells, we aimed to develop an in vitro assay for detecting immortalized cells in CTPs. We employed retinal pigment epithelial (RPE) cells as a model of hPSC-derived products and identified a gene encoding slow skeletal muscle troponin T (TNNT1) as a novel marker of immortalized RPE cells by comprehensive microarray analysis. TNNT1 mRNA was commonly upregulated in immortalized RPE cells and human induced pluripotent stem cells (hiPSCs), which have self-renewal ability. Additionally, we demonstrated that TNNT1 mRNA expression is higher in several cancer tissues than in normal tissues. Furthermore, stable expression of TNNT1 in ARPE-19 cells affected actin filament organization and enhanced their migration ability. Finally, we established a simple and rapid qRT-PCR assay targeting TNNT1 transcripts that detected as low as 3% of ARPE-19 cells contained in normal primary RPE cells. Purified hiPSC-derived RPE cells showed TNNT1 expression levels below the detection limit determined with primary RPE cells. Our qRT-PCR method is expected to greatly contribute to process validation and quality control of CTPs.

摘要

人多能干细胞（hPSCs）是细胞治疗产品（CTPs）的主要候选原料。在开发 hPSC 衍生的 CTP 时，出于安全原因，必须确保它们在移植后不会形成肿瘤。由于细胞永生化是恶性转化的标志，也是癌细胞的共同特征，我们旨在开发一种体外检测 CTP 中永生化细胞的方法。我们使用视网膜色素上皮 (RPE) 细胞作为 hPSC 衍生产品的模型，并通过综合微阵列分析确定编码慢骨骼肌肌钙蛋白 T (TNNT1) 的基因是 RPE 细胞永生化的新型标志物。TNNT1 mRNA 在永生化 RPE 细胞和具有自我更新能力的人诱导多能干细胞 (hiPSC) 中普遍上调。此外，我们证明 TNNT1 mRNA 表达在几种癌症组织中高于正常组织。此外，TNNT1 在 ARPE-19 细胞中的稳定表达影响肌动蛋白丝的组织并增强其迁移能力。最后，我们建立了一种针对 TNNT1 转录本的简单快速 qRT-PCR 检测方法，可检测到正常初级 RPE 细胞中低至 3%的 ARPE-19 细胞。纯化的 hiPSC 衍生的 RPE 细胞显示 TNNT1 表达水平低于用初级 RPE 细胞确定的检测限。我们的 qRT-PCR 方法有望为 CTP 的工艺验证和质量控制做出重大贡献。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cec/5557831/8fbe0c4378b2/41598_2017_8014_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cec/5557831/041171750ea4/41598_2017_8014_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cec/5557831/3a5efb553c64/41598_2017_8014_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cec/5557831/86acf9b180dd/41598_2017_8014_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cec/5557831/c520d369a34d/41598_2017_8014_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cec/5557831/ccf70afa3d59/41598_2017_8014_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cec/5557831/8fbe0c4378b2/41598_2017_8014_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cec/5557831/041171750ea4/41598_2017_8014_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cec/5557831/3a5efb553c64/41598_2017_8014_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cec/5557831/86acf9b180dd/41598_2017_8014_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cec/5557831/c520d369a34d/41598_2017_8014_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cec/5557831/ccf70afa3d59/41598_2017_8014_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cec/5557831/8fbe0c4378b2/41598_2017_8014_Fig6_HTML.jpg

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