胚胎干细胞重新编程肿瘤细胞的研究
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摘要
胚胎干细胞是来自于囊胚内细胞团的多能性细胞。近年来研究者发现,胚胎干细胞可以通过细胞融合改变成体细胞的表观遗传学特性。在对小鼠的研究中发现,当胚胎干细胞和成体神经细胞、T淋巴细胞或成纤维细胞等融合之后,所得到的杂合细胞(4N)具有和胚胎干细胞类似的特性,如融合细胞可以体外分化和自我更新、将其移植入小鼠皮下可以产生畸胎瘤及进行囊胚注射之后融合细胞可以参入胚胎发育。在表观遗传学方面,表现为分化细胞上某些特异性表达基因的去甲基化、失活的X小体重新活化、多能性基因上组蛋白H3K4重新甲基化,以及H3K27和H3K9的去甲基化等。也有研究结果显示,胚胎干细胞中的某些多能性基因如Nanog,OCT4,SOX2及维持胚胎干细胞特性的某些肿瘤基因如Klf4及C-MYC在重新编程过程中起重要的作用。
我们设想胚胎干细胞也许同样或者在某种程度上具有重新编程肿瘤细胞的能力。在以往的核移植重新编程试验中,虽然卵母细胞可以对某些肿瘤细胞,如畸胎瘤细胞、黑色素瘤细胞和脑肿瘤细胞进行某种程度的重编程,但是所得到的细胞仍具有肿瘤源性,部分原因归咎于卵母细胞核移植的自身特性。已有的研究结果表明,相对于核移植,胚胎干细胞通过细胞融合所得到的杂合细胞可以在更大程度上消除体细胞自身记忆,而且在技术上容易操作。然而,至今为止仍未有人研究胚胎干细胞是否可以通过细胞融合来改变肿瘤细胞的表观遗传学特性。
我们建立了胚胎干细胞和肿瘤细胞融合的方法和条件,并且对融合细胞进行分析。我们选择了两种分化程度不同的肿瘤细胞作为本研究的起始实验材料,即小鼠畸胎瘤细胞P19和小鼠成体肿瘤细胞Hepal-6。两种细胞的区别在于分化的程度以及随着肿瘤细胞的分化程度不同,其肿瘤抑制基因启动子部位DNA超甲基化状态和组蛋白甲基化水平也相应的产生不同程度的差异。通过与胚胎干细胞融合,肿瘤细胞被重新编程,体现在:1)杂合细胞在细胞形态和增殖水平上与胚胎干细胞相似,而与融合母体肿瘤细胞有显著差异。其中ES×P19具有和胚胎干细胞相似的克隆样表型,而ES×Hepa1-6有三种表型。两株杂合细胞的生长速度和胚胎干细胞相类似;2)通过融合,胚胎干细胞可以改变肿瘤细胞和成体细胞的基因表达方式。在成体肿瘤细胞和胸腺细胞中,组织来源的特异性基因表达消失,多能性基因重新表达;在胚胎来源的畸胎瘤细胞中,多能性基因的表达明显上升;3)通过与胚胎干细胞融合,重新编程的成体肿瘤中失活的某些肿瘤抑制基因得以重新表达,而异常活化的一些原癌基因表达下调;4)重新编程后的成体细胞具有和胚胎干细胞相似的体内体外分化潜能。重新编程后的肿瘤细胞可以在体外形成拟胚体,在体外分化中,和胚胎干细胞相似可以分化到三个胚层;5)被重新编程的肿瘤细胞并没有完全的丧失肿瘤源性,表现在组织中成熟细胞所占比例比胚胎干细胞形成的成熟细胞比例低,未成熟组织占到整个组织切片的70%以上。组织切片可见明显的癌巢组织和未成熟的恶性细胞类型。
我们认为,胚胎干细胞不能完全对肿瘤细胞进行重新编程,所得到的杂合细胞是一种具有和胚胎干细胞相类似的可以无限增殖和自我分化的畸胎瘤细胞。这种结果可能归咎于肿瘤细胞的某种特殊表观遗传学调控方式,如抑制性组蛋白H3K9me3和H3K27me2不影响基因表达,但可以使染色质仍处于密集的异染色质状态。在某些诱导条件下这些负性调控机制会募集DNA转甲基化酶使DNA重新甲基化,使肿瘤抑制基因重新被抑制,原癌基因重新表达。我们推测,在胚胎干细胞与肿瘤细胞的杂合细胞中,这些控制染色体结构的表观遗传学调控因子阻碍了胚胎干细胞所启动的重新编程。而这些表观遗传学调控因子在未来可能成为治疗肿瘤的潜在靶点。
本研究的创新点在于:1、首次发现通过与胚胎肝细胞融合,不同分化程度的肿瘤细胞均可以被重新编程,体现在分化程度和基因表达水平的改变;2、首次发现胚胎干细胞不能通过细胞融合完全改变肿瘤细胞的肿瘤源性,其原因可能在于肿瘤细胞内在的某些特性限制了肿瘤细胞被重新编程的程度。
ES cells are pluripotent stem cells, which are derived from inner cell mass of blastocyst. The capacity of ES cell in reprogramming the epigenetic property of several adult cells has been known recently. After mouse ES cells fused with mouse embryonic fibroblasts, mouse adult neuronal cells and mouse adult B-lymphocytes, the fusion hybrid cells (4N) acted as pluripotent stem cells, which carried the similar characters of ES cells. These included the characters of having the capacity of self-renewal and induced differentiation in vitro, to become teratomas after transplantation into adult mouse and to normally become the differentiated after blastcyte injection. Further researches confirmed that the somatic genomes of hybrid cells exhibited hyperacetylation of histones H3 and H4, global di- and tri-methylation of lysine 4 of H3, and hyperacetylation of lysine 4 of H3 within the Oct4 promoter.
Recently several groups tried to reprogram tumor cells into normal embryonic stem cells by nuclear transfer. Nuclear of mouse melanoma, embryonic carcinoma, and medulloblastoma were enucleated and transferred to mouse oocytes to investigate whether aberrant epigenetic status would be altered. While although the reprogrammed NT cell regained pluripotent potential, the malignant tumor properties remained. The results were not unequivocally because of the internal defects of nuclear transfer, such as inadequate reprogramming both in reproductive and therapeutic cloning, though the latter one is more efficient than the former, mice generated from the cumulus cells or ES cells exhibited aberrant gene expression as judged by microarray analysis of liver and placenta RNA. Compared to nuclear transfer, cell fusion with embryonic stem cells seems like to be a more reliable and simple method to perform reprogramming. However, up to now, it has not been known yet that whether ES cells can also reprogram the epigenetic property of malignant tumor cells after cell fusion.
We have investigated how to fuse ES cells with several types of tumor cells and analyzed the fusion cells that are derived from ES cells and tumor cells. Two tumor cell lines with varied differentiation degrees were adopted: mouse teratocarcimona P19 and mouse adult tumor cell Hepal-6, in which the DNA hypermethylation and histone modulation status on the tumor suppressors were distinct according to their differentiation status respectively. By means of fusion with ES cells, both of the tumor cell lines can be reprogrammed in that 1) although ES×P19 owned homogenous clone like phenotype, and the ES×Hepa1-6 owned three ones, the phenotype and the proliferation rate of the survival ES×tumor hybrids under selection were similar with the ES cells, while established great difference with the fusion parent tumor cells. 2) After fused with ES cells, pluripotent gene expression of the ES×tumor were similar with ES cells, and the tissue specific gene expression TTR and ALB in ES×Hepa1-6 were obviously decreased compared to that of Hepa1-6. 3) Tumor associated gene expression were changed after fusion in which tumor supressors expressions were obviously increased in ES-adult cell hybrids. ES-EC cell hybrids also had increased P19 and P16 expression, though the genes originally were expressed in the embryonic carcinomas. Also some oncogenes expressions were decreased via fusion with ES cells. 4) Reprogrammed tumor cells regained differentiation ability as examined by both in vivo and in vitro experiments. 5) Reprogrammed tumor cells did not lose the tumorigenic characters that the percent areas of undifferentiated cells in teratoma were much higher than that of ES cells derived ones and cancer nests were obvious in the ES×tumor hybrids.
In our experiments, the fused cells (4N) derived from ES cells and tumor cells have been found to be different from those derived from ES cells and ES×normal non-tumor cells. Significant differences were found from hybrids derived teratomas. We conclude that ES cells cannot completely reprogram tumor cells to become the hybrid cells (4N) that are similar to ES cells (2N). What we have got were some kind of ES cell like teratoma with infinite self-renew and differentiation ability. The results of partial reprogramming in the hybrid of ES cells×tumor cells suggested a special epigenetic regulation in tumor cells. We hypothesize that, in the fusion hybrids (4N) derived from ES cells and tumor cells, some unique epigenetic control factors from tumor cells such as H3K9me3 and H3K27me2, which compact the chromosome structure into heterochromatin, would block the reprogramming process introduced from ES cells. These potential epigenetic control factors may be the potential key targets to correct tumors in future.
我们设想胚胎干细胞也许同样或者在某种程度上具有重新编程肿瘤细胞的能力。在以往的核移植重新编程试验中,虽然卵母细胞可以对某些肿瘤细胞,如畸胎瘤细胞、黑色素瘤细胞和脑肿瘤细胞进行某种程度的重编程,但是所得到的细胞仍具有肿瘤源性,部分原因归咎于卵母细胞核移植的自身特性。已有的研究结果表明,相对于核移植,胚胎干细胞通过细胞融合所得到的杂合细胞可以在更大程度上消除体细胞自身记忆,而且在技术上容易操作。然而,至今为止仍未有人研究胚胎干细胞是否可以通过细胞融合来改变肿瘤细胞的表观遗传学特性。
我们建立了胚胎干细胞和肿瘤细胞融合的方法和条件,并且对融合细胞进行分析。我们选择了两种分化程度不同的肿瘤细胞作为本研究的起始实验材料,即小鼠畸胎瘤细胞P19和小鼠成体肿瘤细胞Hepal-6。两种细胞的区别在于分化的程度以及随着肿瘤细胞的分化程度不同,其肿瘤抑制基因启动子部位DNA超甲基化状态和组蛋白甲基化水平也相应的产生不同程度的差异。通过与胚胎干细胞融合,肿瘤细胞被重新编程,体现在:1)杂合细胞在细胞形态和增殖水平上与胚胎干细胞相似,而与融合母体肿瘤细胞有显著差异。其中ES×P19具有和胚胎干细胞相似的克隆样表型,而ES×Hepa1-6有三种表型。两株杂合细胞的生长速度和胚胎干细胞相类似;2)通过融合,胚胎干细胞可以改变肿瘤细胞和成体细胞的基因表达方式。在成体肿瘤细胞和胸腺细胞中,组织来源的特异性基因表达消失,多能性基因重新表达;在胚胎来源的畸胎瘤细胞中,多能性基因的表达明显上升;3)通过与胚胎干细胞融合,重新编程的成体肿瘤中失活的某些肿瘤抑制基因得以重新表达,而异常活化的一些原癌基因表达下调;4)重新编程后的成体细胞具有和胚胎干细胞相似的体内体外分化潜能。重新编程后的肿瘤细胞可以在体外形成拟胚体,在体外分化中,和胚胎干细胞相似可以分化到三个胚层;5)被重新编程的肿瘤细胞并没有完全的丧失肿瘤源性,表现在组织中成熟细胞所占比例比胚胎干细胞形成的成熟细胞比例低,未成熟组织占到整个组织切片的70%以上。组织切片可见明显的癌巢组织和未成熟的恶性细胞类型。
我们认为,胚胎干细胞不能完全对肿瘤细胞进行重新编程,所得到的杂合细胞是一种具有和胚胎干细胞相类似的可以无限增殖和自我分化的畸胎瘤细胞。这种结果可能归咎于肿瘤细胞的某种特殊表观遗传学调控方式,如抑制性组蛋白H3K9me3和H3K27me2不影响基因表达,但可以使染色质仍处于密集的异染色质状态。在某些诱导条件下这些负性调控机制会募集DNA转甲基化酶使DNA重新甲基化,使肿瘤抑制基因重新被抑制,原癌基因重新表达。我们推测,在胚胎干细胞与肿瘤细胞的杂合细胞中,这些控制染色体结构的表观遗传学调控因子阻碍了胚胎干细胞所启动的重新编程。而这些表观遗传学调控因子在未来可能成为治疗肿瘤的潜在靶点。
本研究的创新点在于:1、首次发现通过与胚胎肝细胞融合,不同分化程度的肿瘤细胞均可以被重新编程,体现在分化程度和基因表达水平的改变;2、首次发现胚胎干细胞不能通过细胞融合完全改变肿瘤细胞的肿瘤源性,其原因可能在于肿瘤细胞内在的某些特性限制了肿瘤细胞被重新编程的程度。
ES cells are pluripotent stem cells, which are derived from inner cell mass of blastocyst. The capacity of ES cell in reprogramming the epigenetic property of several adult cells has been known recently. After mouse ES cells fused with mouse embryonic fibroblasts, mouse adult neuronal cells and mouse adult B-lymphocytes, the fusion hybrid cells (4N) acted as pluripotent stem cells, which carried the similar characters of ES cells. These included the characters of having the capacity of self-renewal and induced differentiation in vitro, to become teratomas after transplantation into adult mouse and to normally become the differentiated after blastcyte injection. Further researches confirmed that the somatic genomes of hybrid cells exhibited hyperacetylation of histones H3 and H4, global di- and tri-methylation of lysine 4 of H3, and hyperacetylation of lysine 4 of H3 within the Oct4 promoter.
Recently several groups tried to reprogram tumor cells into normal embryonic stem cells by nuclear transfer. Nuclear of mouse melanoma, embryonic carcinoma, and medulloblastoma were enucleated and transferred to mouse oocytes to investigate whether aberrant epigenetic status would be altered. While although the reprogrammed NT cell regained pluripotent potential, the malignant tumor properties remained. The results were not unequivocally because of the internal defects of nuclear transfer, such as inadequate reprogramming both in reproductive and therapeutic cloning, though the latter one is more efficient than the former, mice generated from the cumulus cells or ES cells exhibited aberrant gene expression as judged by microarray analysis of liver and placenta RNA. Compared to nuclear transfer, cell fusion with embryonic stem cells seems like to be a more reliable and simple method to perform reprogramming. However, up to now, it has not been known yet that whether ES cells can also reprogram the epigenetic property of malignant tumor cells after cell fusion.
We have investigated how to fuse ES cells with several types of tumor cells and analyzed the fusion cells that are derived from ES cells and tumor cells. Two tumor cell lines with varied differentiation degrees were adopted: mouse teratocarcimona P19 and mouse adult tumor cell Hepal-6, in which the DNA hypermethylation and histone modulation status on the tumor suppressors were distinct according to their differentiation status respectively. By means of fusion with ES cells, both of the tumor cell lines can be reprogrammed in that 1) although ES×P19 owned homogenous clone like phenotype, and the ES×Hepa1-6 owned three ones, the phenotype and the proliferation rate of the survival ES×tumor hybrids under selection were similar with the ES cells, while established great difference with the fusion parent tumor cells. 2) After fused with ES cells, pluripotent gene expression of the ES×tumor were similar with ES cells, and the tissue specific gene expression TTR and ALB in ES×Hepa1-6 were obviously decreased compared to that of Hepa1-6. 3) Tumor associated gene expression were changed after fusion in which tumor supressors expressions were obviously increased in ES-adult cell hybrids. ES-EC cell hybrids also had increased P19 and P16 expression, though the genes originally were expressed in the embryonic carcinomas. Also some oncogenes expressions were decreased via fusion with ES cells. 4) Reprogrammed tumor cells regained differentiation ability as examined by both in vivo and in vitro experiments. 5) Reprogrammed tumor cells did not lose the tumorigenic characters that the percent areas of undifferentiated cells in teratoma were much higher than that of ES cells derived ones and cancer nests were obvious in the ES×tumor hybrids.
In our experiments, the fused cells (4N) derived from ES cells and tumor cells have been found to be different from those derived from ES cells and ES×normal non-tumor cells. Significant differences were found from hybrids derived teratomas. We conclude that ES cells cannot completely reprogram tumor cells to become the hybrid cells (4N) that are similar to ES cells (2N). What we have got were some kind of ES cell like teratoma with infinite self-renew and differentiation ability. The results of partial reprogramming in the hybrid of ES cells×tumor cells suggested a special epigenetic regulation in tumor cells. We hypothesize that, in the fusion hybrids (4N) derived from ES cells and tumor cells, some unique epigenetic control factors from tumor cells such as H3K9me3 and H3K27me2, which compact the chromosome structure into heterochromatin, would block the reprogramming process introduced from ES cells. These potential epigenetic control factors may be the potential key targets to correct tumors in future.
引文
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53. Blau, H.M., et al., Plasticity of the differentiated state. Science, 1985. 230(4727): 758-66.
54. Miller, S.C., et al., Muscle cell components dictate hepatocyte gene expression and the distribution of the Golgi apparatus in heterokaryons. Genes Dev, 1988. 2(3): 330-40.
55. Klinger, H.P., Suppression of tumorigenicity. Cytogenet Cell Genet, 1982. 32(1-4): 68-84.
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62. Onishi, A., et al., Pig cloning by microinjection of fetal fibroblast nuclei. Science, 2000.289(5482): 1188-90.
63. Kato, Y, et al., Eight calves cloned from somatic cells of a single adult. Science, 1998. 282(5396): 2095-8.
64. Wakayama, T., et al., Cloning of mice to six generations. Nature, 2000. 407(6802): 318-9.
65. Polejaeva, I.A., et al., Cloned pigs produced by nuclear transfer from adult somatic cells. Nature, 2000. 407(6800): 86-90.
66. Hochedlinger, K. and R. Jaenisch, Nuclear transplantation, embryonic stem cells, and the potential for cell therapy. N Engl J Med, 2003.349(3): 275-86.
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72. Yu, J., et al., Induced pluripotent stem cell lines derived from human somatic cells. Science, 2007.318(5858): 1917-20.
73. Takahashi, K., et al., Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 2007.131(5): 861-72.
74. Hochedlinger, K. and R. Jaenisch, Nuclear reprogramming and pluripotency. Nature, 2006. 441(7097): 1061-7.
75. Cowan, C.A., et al., Nuclear reprogramming of somatic cells after fusion with human embryonic stem cells. Science, 2005.309(5739): 1369-73.
76. Do, J.T. and H.R. Scholer, Comparison of neurosphere cells with cumulus cells after fusion with embryonic stem cells: reprogramming potential. Reprod Fertil Dev, 2005.17(1-2): 143-9.
77. Tada, M., et al., Nuclear reprogramming of somatic cells by in vitro hybridization with ES cells. Curr Biol, 2001.11(19): 1553-8.
78. Do, J.T. and H.R. Scholer, Nuclei of embryonic stem cells reprogram somatic cells. Stem Cells, 2004. 22(6): 941-9.
79. Matveeva, N.M., et al., In vitro and in vivo study of pluripotency in intraspecific hybrid cells obtained by fusion of murine embryonic stem cells with splenocytes. Mol Reprod Dev, 1998. 50(2): 128-38.
80. Tada, M., et al., Embryonic germ cells induce epigenetic reprogramming of somatic nucleus in hybrid cells. Embo J, 1997.16(21): 6510-20.
81. Tae Do, J., et al., Erasure of cellular memory by fusion with pluripotent cells. Stem Cells, 2007. 25(4): 1013-20.
82. Matsumura, H., et al., Targeted chromosome elimination from ES-somatic hybrid cells. Nat Methods, 2007. 4(1): 23-5.
83. Silva, J., et al., Nanog promotes transfer of pluripotency after cell fusion. Nature, 2006. 441(7096): 997-1001.
84. Miller, R.A. and F.H. Ruddle, Pluripotent teratocarcinoma-thymus somatic cell hybrids. Cell, 1976. 9(1): 45-55.
85. Miller, R.A. and F.H. Ruddle, Properties of teratocarcinoma-thymus somatic cell hybrids. Somatic Cell Genet, 1977. 3(3): 247-61.
86. Miller, R.A. and F.H. Ruddle, Teratocarcinoma X friend erythroleukemia cell hybrids resemble their pluripotent embryonal carcinoma parent. Dev Biol, 1977. 56(1): 157-73.
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