克服多能干细胞移植免疫排斥反应的实验研究
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摘要
多能干细胞(Pluripotent Stem Cells)主要包括胚胎干细胞和诱导多潜能干细胞(induced pluripotent stem cell, iPS),均具有自我复制及多潜能分化的能力。理论上,它们能够为细胞移植治疗提供无限的供体细胞来源,因此是理想的“种子细胞”。然而,免疫排斥反应是细胞移植治疗面临的共同问题,当然是多能干细胞移植治疗首先需要考虑的问题。本课题根据两种多能干细胞的不同特点,为解决免疫排斥进行了以下两个方面尝试:
一、通过在人胚胎干细胞上稳定表达人白细胞抗原G(Human Leucocyte Antigen G,HLA-G),获得具有免疫耐受能力的通用的种子细胞。HLA-G是母胎免疫及器官移植免疫耐受的重要分子。本研究建立了稳定表达HLA-G1的hES细胞系。该细胞系核型正常,仍具有自我复制和多潜能性(表达干细胞特异性的转录因子Oct4和Sox2,接种SCID小鼠后能够形成畸胎瘤,其中有三胚层的分化细胞)。由HLA-G1+hESCs分化为神经前体细胞(Neural Progenitor cells,NPCs)的过程中,HLA-G1持续表达,通过细胞毒实验及混合淋巴细胞反应证实HLA-G1对由hESCs分化获得的NPCs具有明显的免疫保护作用。
二、提高建立iPS细胞(induced pluripotent stem cells,iPS细胞)的效率,同时探讨iPS细胞形成的机制。iPS细胞是个体特异性多能干细胞,可完全避免个体的免疫排斥反应。本研究采用人胚胎神经干细胞作为重编程对象,与传统的四分子转染体系不同,我们用Oct4进行单分子转染。转染1周后出现iPS细胞克隆,2周统计iPS细胞的形成效率为0.015±0.001,比成纤维细胞效率高10倍。对获得的iPS细胞与hES细胞进行比较鉴定后发现,二者在表达谱、重要标志物以及DNA甲基化方式和多潜能分化能力等方面都非常相似。由此,本研究仅采用了一个分子就获得了人iPS细胞,同时神经干细胞重编程获得iPS细胞的效率远高于成纤维细胞。
Pluripotent stem cell, incuding human embryonic stem cells (ES cells) and induced pluripotent stem cells (iPS cells), can be maintained as a pluripotent, self-renewing population. Theriotically, pluripotent stem cells may provide unlimited source for cell transplantation-based treatment, which makes them become the ideal seed cells. One major challenge of cell therapy is the rejection by the transplant recipient. Pluripotent stem cells are certainly no exception. This study was designed to develop methods either to improve immune tolerance or to make completely immune compatible cells for cell therapy.
1. Generation of immune tolerant hES cell line by stable HLA-G expression. HLA-G is one of the key molecules involving in pregnancy and engraftment tolerance. We established human ES cell line with stable HLA-G expression. These ES cells have been shown to present a stable diploid karyotype and maintained self-renewal and pluripotency. They are Oct4 and Sox2 positive cells and formed teratoma in SCID mice. While differentiating HLA-G1+hESCs into neural progenitor cells (NPCs), HLA-G1 was stably expressed in the differentiated cells. Cytotoxicity assay and mixed lymphocyte reaction (MLR) suggested HLA-G protected hESC-derived NPCs from attacking in vitro.
2. Improve the effeciency of iPS cells, make immune compatible transplant cells and explore mechanism underlying iPS cell induction. In this study, human neural progenitor cells were used for genetic reprogramming by applying single molecule - Oct4, instead of the four Yamanaka factors Oct3/4, Sox2, Klf4, and c-Myc. Our results showed that Oct4 alone was sufficient to reprogram human NPCs into iPS cells. The reprogramming efficiency was 0.015±0.001, about 10-fold higher than that of human skin fibroblast cells using 4 factors system. Comparing these human NPC-derived iPS cells (NiPS) with hES cells, they had similar gene expression profiling, DNA methylation pattern,expressed all pluripotent markers and maintained pluripotency. Hence, we generated iPS cells from human NPC by using Oct4 alone, moreover, the efficiency of inducing NiPS by oct4 is much higher that that of fibroblast.
一、通过在人胚胎干细胞上稳定表达人白细胞抗原G(Human Leucocyte Antigen G,HLA-G),获得具有免疫耐受能力的通用的种子细胞。HLA-G是母胎免疫及器官移植免疫耐受的重要分子。本研究建立了稳定表达HLA-G1的hES细胞系。该细胞系核型正常,仍具有自我复制和多潜能性(表达干细胞特异性的转录因子Oct4和Sox2,接种SCID小鼠后能够形成畸胎瘤,其中有三胚层的分化细胞)。由HLA-G1+hESCs分化为神经前体细胞(Neural Progenitor cells,NPCs)的过程中,HLA-G1持续表达,通过细胞毒实验及混合淋巴细胞反应证实HLA-G1对由hESCs分化获得的NPCs具有明显的免疫保护作用。
二、提高建立iPS细胞(induced pluripotent stem cells,iPS细胞)的效率,同时探讨iPS细胞形成的机制。iPS细胞是个体特异性多能干细胞,可完全避免个体的免疫排斥反应。本研究采用人胚胎神经干细胞作为重编程对象,与传统的四分子转染体系不同,我们用Oct4进行单分子转染。转染1周后出现iPS细胞克隆,2周统计iPS细胞的形成效率为0.015±0.001,比成纤维细胞效率高10倍。对获得的iPS细胞与hES细胞进行比较鉴定后发现,二者在表达谱、重要标志物以及DNA甲基化方式和多潜能分化能力等方面都非常相似。由此,本研究仅采用了一个分子就获得了人iPS细胞,同时神经干细胞重编程获得iPS细胞的效率远高于成纤维细胞。
Pluripotent stem cell, incuding human embryonic stem cells (ES cells) and induced pluripotent stem cells (iPS cells), can be maintained as a pluripotent, self-renewing population. Theriotically, pluripotent stem cells may provide unlimited source for cell transplantation-based treatment, which makes them become the ideal seed cells. One major challenge of cell therapy is the rejection by the transplant recipient. Pluripotent stem cells are certainly no exception. This study was designed to develop methods either to improve immune tolerance or to make completely immune compatible cells for cell therapy.
1. Generation of immune tolerant hES cell line by stable HLA-G expression. HLA-G is one of the key molecules involving in pregnancy and engraftment tolerance. We established human ES cell line with stable HLA-G expression. These ES cells have been shown to present a stable diploid karyotype and maintained self-renewal and pluripotency. They are Oct4 and Sox2 positive cells and formed teratoma in SCID mice. While differentiating HLA-G1+hESCs into neural progenitor cells (NPCs), HLA-G1 was stably expressed in the differentiated cells. Cytotoxicity assay and mixed lymphocyte reaction (MLR) suggested HLA-G protected hESC-derived NPCs from attacking in vitro.
2. Improve the effeciency of iPS cells, make immune compatible transplant cells and explore mechanism underlying iPS cell induction. In this study, human neural progenitor cells were used for genetic reprogramming by applying single molecule - Oct4, instead of the four Yamanaka factors Oct3/4, Sox2, Klf4, and c-Myc. Our results showed that Oct4 alone was sufficient to reprogram human NPCs into iPS cells. The reprogramming efficiency was 0.015±0.001, about 10-fold higher than that of human skin fibroblast cells using 4 factors system. Comparing these human NPC-derived iPS cells (NiPS) with hES cells, they had similar gene expression profiling, DNA methylation pattern,expressed all pluripotent markers and maintained pluripotency. Hence, we generated iPS cells from human NPC by using Oct4 alone, moreover, the efficiency of inducing NiPS by oct4 is much higher that that of fibroblast.
引文
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2. Takahashi, K. and S. Yamanaka, Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 2006. 126(4): p. 663-76.
3. Yu, J., et al., Induced pluripotent stem cell lines derived from human somatic cells. Science, 2007. 318(5858): p. 1917-20.
4. Daley, G.Q. and D.T. Scadden, Prospects for stem cell-based therapy. Cell, 2008. 132(4): p. 544-8.
5. Drukker, M., et al., Characterization of the expression of MHC proteins in human embryonic stem cells. Proc Natl Acad Sci U S A, 2002. 99(15): p. 9864-9.
6. Chidgey, A.P., et al., Tolerance strategies for stem-cell-based therapies. Nature, 2008. 453(7193): p. 330-7.
7. Hviid, T.V., HLA-G in human reproduction: aspects of genetics, function and pregnancy complications. Hum Reprod Update, 2006. 12(3): p. 209-32.
8. von Rango, U., Fetal tolerance in human pregnancy--a crucial balance between acceptance and limitation of trophoblast invasion. Immunol Lett, 2008. 115(1): p. 21-32.
9. Hunt, J.S., et al., HLA-G and immune tolerance in pregnancy. FASEB J, 2005. 19(7): p. 681-93.
10. van Wijk, I.J., et al., HLA-G expression in trophoblast cells circulating in maternal peripheral blood during early pregnancy. Am J Obstet Gynecol, 2001. 184(5): p. 991-7.
11. Fuzzi, B., et al., HLA-G expression in early embryos is a fundamental prerequisite for the obtainment of pregnancy. Eur J Immunol, 2002. 32(2): p. 311-5.
12. Warner, C.M., et al., Soluble HLA-G (sHLA-G) a predictor of IVF outcome? J Assist Reprod Genet, 2004. 21(9): p. 315-6.
13. Aldrich, C.L., et al., HLA-G genotypes and pregnancy outcome in couples with unexplained recurrent miscarriage. Mol Hum Reprod, 2001. 7(12): p. 1167-72.
14. Hara, N., et al., Altered expression of human leukocyte antigen G (HLA-G) on extravillous trophoblasts in preeclampsia: immunohistological demonstration with anti-HLA-G specific antibody "87G" and anti-cytokeratin antibody "CAM5.2". Am J Reprod Immunol, 1996. 36(6): p. 349-58.
15. Yie, S.M., et al., HLA-G protein concentrations in maternal serum and placental tissue are decreased in preeclampsia. Am J Obstet Gynecol, 2004. 191(2): p. 525-9.
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