Tumorigenicity analysis of heterogeneous dental stem cells and its self-modification for chromosome instability
Tumorigenicity analysis of heterogeneous dental stem cells and its self-modification for chromosome instability
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异质牙干细胞的致瘤性分析及其染色体不稳定性的自我修饰。
DOI：
10.1080/15384101.2015.1036204
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发表时间：
2015-11-02
期刊：
影响因子：
4.3
通讯作者：
Tian, Weidong
中科院分区：
文献类型：
--
作者：
Meng, Zhaosong;Chen, Guoqing;Tian, Weidong
异质性表明干细胞是由不同分化状态的几个亚克隆构成的。异质状态通过亚克隆间的相互作用得以维持，从而保证了干细胞的适应性。在本研究中，我们研究了异质性在遗传稳定性中的作用。从异质牙干细胞（DSCs）中分离到3个亚克隆（DF2、DF8和DF18），经长期扩增证实为染色体不稳定（CIN）。亚克隆未检测到细胞凋亡，表现出较强的成瘤倾向，且p53表达较弱，超微结构异常。然而，3个亚克隆在体内没有过表达肿瘤相关标志物或诱导肿瘤发生。混合培养研究表明，3-克隆混合培养细胞（DF1）的非整倍体比例明显降低。筛选实验进一步证明，3个亚克隆在此修饰过程中是单独发挥作用的，但只有将3个亚克隆混合培养，模拟异质微环境，才能实现完全修饰。此外，3个亚克隆的成骨能力受到CIN的部分影响，但DSCs的成骨能力仍比亚克隆强。这些结果表明，从异质dsc中分离的异常亚克隆不发生肿瘤，它们之间可以通过串扰修饰CIN，表明异质性在维持牙干细胞的遗传稳定性和分化能力方面发挥了关键作用。
Heterogeneity demonstrates that stem cells are constituted by several sub-clones in various differentiation states. The heterogeneous state is maintained by cross-talk among sub-clones, thereby ensuring stem cell adaption. In this study, we investigated the roles of heterogeneity on genetic stability. Three sub-clones (DF2, DF8 and DF18) were isolated from heterogeneous dental stem cells (DSCs), and were proved to be chromosome instability (CIN) after long term expansion. Cell apoptosis were not detected in sub-clones, which exhibited strong tumorigenesis tendency, coupled with weak expression of p53 and aberrant ultra-structure. However, 3 sub-clones did not overexpress tumor related markers or induce tumorigenesis in vivo. The mixed-culture study suggested that 3-clone-mixed culturing cells (DF1) presented apparent decrease in the ratio of aneuploidy. The screening experiment further proved that 3 sub-clones functioned separately in this modification procedure but only mixed culturing all 3 sub-clones, simulated heterogeneous microenvironment, could achieve complete modification. Additionally, osteogenesis capability of 3 sub-clones was partially influenced by CIN while DSCs still kept stronger osteogenesis than sub-clones. These results suggested aberrant sub-clones isolated from heterogeneous DSCs were not tumorigenesis and could modify CIN by cross-talk among themselves, indicating that the heterogeneity played a key role in maintaining genetic stability and differentiation capability in dental stem cells.