Long-term cultured mesenchymal stem cells frequently develop genomic mutations but do not undergo malignant transformation.
Long-term cultured mesenchymal stem cells frequently develop genomic mutations but do not undergo malignant transformation.
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长期培养的间充质干细胞经常发生基因组突变，但不会发生恶性转化
DOI：
10.1038/cddis.2013.480
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发表时间：
2013-12-05
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
培养的人脐带间充质干细胞（hUC-MSCs）正在一些临床试验中进行测试，并观察到令人鼓舞的结果。为了确定体外扩增是否影响hUC-MSC的基因组稳定性，我们在长期培养中维持了9个hUC-MSC克隆，并在传代早期和后期对其进行了比较分析。所有克隆在培养中都出现衰老，表现出端粒酶活性降低和端粒缩短。两个无性系在第30代（P30）没有DNA拷贝数变异（CNVs）。7个无性系在P30位点与P3位点相比CNVs≥1，其中1个无性系在传代后期出现10号染色体三体。在注射hUC-MSCs的免疫缺陷小鼠中，无论细胞在传代后期是否具有CNVs，均未发生肿瘤。mRNA-Seq分析表明，在基因组不稳定的hUC-MSC克隆中，细胞周期控制和DNA损伤应答通路在体外培养过程中下调，而在基因组稳定性较好的克隆中，这些通路则上调。这些结果表明，hUC-MSCs可以进行多次传代培养并获得大量细胞，但大多数培养的hUC-MSCs发生基因组改变。虽然具有基因组改变的hUC-MSCs不会发生恶性转化，但在这些细胞用于临床应用之前，建议定期进行基因组监测和关注基因组稳定性的供体管理。
Cultured human umbilical cord mesenchymal stem cells (hUC-MSCs) are being tested in several clinical trials and encouraging outcomes have been observed. To determine whether in vitro expansion influences the genomic stability of hUC-MSCs, we maintained nine hUC-MSC clones in long-term culture and comparatively analyzed them at early and late passages. All of the clones senesced in culture, exhibiting decreased telomerase activity and shortened telomeres. Two clones showed no DNA copy number variations (CNVs) at passage 30 (P30). Seven clones had≥ 1 CNVs at P30 compared with P3, and one of these clones appeared trisomic chromosome 10 at the late passage. No tumor developed in immunodeficient mice injected with hUC-MSCs, regardless of whether the cells had CNVs at the late passage. mRNA-Seq analysis indicated that pathways of cell cycle control and DNA damage response were downregulated during in vitro culture in hUC-MSC clones that showed genomic instability, but the same pathways were upregulated in the clones with good genomic stability. These results demonstrated that hUC-MSCs can be cultured for many passages and attain a large number of cells, but most of the cultured hUC-MSCs develop genomic alterations. Although hUC-MSCs with genomic alterations do not undergo malignant transformation, periodic genomic monitoring and donor management focusing on genomic stability are recommended before these cells are used for clinical applications.
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