转基因脑肿瘤模型鼠脑肿瘤干细胞和神经干细胞的比较研究
|
摘要
目的：通过Tet-on调控系统同时诱导表达c-myc、SV40Tag基因,建立更加稳定的具有干细胞特性的可调控的脑肿瘤小鼠模型,对脑肿瘤干细胞和神经干细胞进行比较研究,旨在为脑肿瘤发病机制的深入研究提供有意义的实验资料。从该模型小鼠诱导前后的室管膜下区及肿瘤组织中,分别分离鉴定正常神经干细胞(neural stem cells)、诱导后神经干细胞(NSC's)和肿瘤干细胞(brain tumor stem cells, BTSCs)。通过三者的比较研究了解三者的异同点,确定存在差异的分子机制,为脑肿瘤干细胞起源于神经干细胞的假说提供更多依据。
方法：将pTRE2-c-myc转基因小鼠与Tet-on、pTRE2-SV40Tag转基因小鼠进行交配,将子代中同时表达pTRE2-c-myc、Tet-on和]pTRE2-SV40Tag的转基因小鼠,进行强力霉素(四环素类)诱导,观察脑肿瘤的发生。通过磁共振成像、大体标本、组织切片、免疫组化对模型鼠脑肿瘤的特征进行研究。从未经强力霉素诱导的Tet-on转基因成年小鼠以及诱导发生脑肿瘤的转基因成体小鼠室管膜下区取材,制成单细胞悬液,培养于无血清干细胞培养基(DMEM/F12,添加bFGF、EGF和B27)以及含血清分化培养基(DMEM+10%FCS)。从出现临床症状的转基因小鼠松果体区肉眼可见的肿瘤组织中取材,制成单细胞悬液,培养于含生长因子的无血清培养基和含血清培养基。用相差显微镜观察正常神经干细胞球体,诱导后神经干细胞球体和肿瘤干细胞球体及其分化细胞形态,细胞增殖情况,电镜观察其超微结构,用流式细胞仪检测三组细胞中Hoechst33342阴性的SP (side population)细胞,细胞周期和染色体倍体。通过免疫荧光,检测球体及其分化细胞中的nestn、NSE、GFAP、MAP2表达情况。通过免疫荧光,比较脑肿瘤干细胞和诱导前后神经干细胞p53, c-myc通路的表达差异。
结果：(1)73只同时表达pTRE2-c-myc、Tet-on和pTRE2-SV40Tag的转基因小鼠,经过强力霉素诱导后,30只小鼠发生脑肿瘤,发生率为41.1%。除1例脑干肿瘤外,均位于松果体区,诱导后到发生脑肿瘤的时间最长184d,最短为64d,平均为95d。肿瘤在T1加权像表现为等信号或稍高信号,在T2加权像表现为等信号或稍低信号,增强后可表现为均一强化或不均一强化。病理诊断为未分化成神经管细胞瘤,肿瘤具有高侵袭性。免疫组化显示,肿瘤高表达c-myc、SV40Tag和干/祖细胞标志物nestin。
(2)未诱导成体转基因小鼠和诱导发生脑肿瘤的成体小鼠室管膜下区细胞,在无血清培养条件下,均呈悬浮的球状生长。未诱导神经干细胞(NSCs)球体,在含血清培养条件下,贴壁并分化为胶质细胞、神经元。诱导后的神经干细胞(NSC's)球体,则表现为增殖活性增加和分化抑制。电镜可见核质比高、细胞器不发达,具干细胞特征的细胞。诱导后神经干细胞与诱导前相比,细胞分化以及降解有关的细胞器(如溶酶体等)、自噬小体显著减少。流式细胞仪检测诱导前后的神经干细胞球中的SP细胞,分别为10.43%、16.89%,所有细胞均为二倍体,大部分细胞位于G0/G1期。免疫荧光显示,未诱导神经干细胞球体大部分细胞表达nestin,分化细胞分别表达GFAP和MAP2。诱导后的神经干细胞球体中,大部分细胞表达nestin,少部分表达分化标志物GFAP、NSE,而部分分化细胞仍然共表达干细胞标志物nestin和分化标志物GFAP和MAP2,甚至同时表达两种分化标志物GFAP和MAP2。
(3)肿瘤细胞在无血清培养条件下,呈悬浮的球状生长,在含血清培养条件下贴壁并分化为瘤性胶质细胞、神经元。电镜下见到核质比高、细胞器不发达、与细胞分化降解有关的细胞器罕见。流式细胞仪检测肿瘤细胞球中的SP细胞为17.27%,异倍体细胞为26.77%,大部分细胞处于S期。免疫荧光染色发现,细胞球中大部分细胞表达干细胞标志物nestin,少数细胞表达分化标志物GFAP和NSE。贴壁细胞大部分仍然共表达干细胞标志物nestin和分化标志物GFAP和MAP2,甚至同时表达两种分化标志物GFAP和MAP2。脑肿瘤干细胞和诱导后,神经干细胞高表达c-myc, MDM2(p53抑制基因)
结论：(1)成功建立更加稳定的、可调控的、具有干细胞特性的脑肿瘤小鼠模型,为进一步研究脑肿瘤干细胞的特性奠定基础。
(2)成功从诱导前后的Tet-on转基因成体小鼠室管膜下区中,分离到神经干细胞,且发现诱导后的神经干细胞表现为增殖活性增加和分化抑制,表明神经干细胞已经出现早期恶性转化表现。
(3) Tet-on转基因小鼠脑肿瘤组织中,存在具有自我更新和多向分化潜能的脑肿瘤干细胞,且发现脑肿瘤干细胞与诱导后的神经干细胞一样,表现为增殖活性增加和分化抑制。C-myc通路活化和p53通路破坏,在脑肿瘤干细胞维系与神经干细胞恶性转化中起关键作用。
(4)在同一动物模型个体中,同时分离到脑肿瘤干细胞和神经干细胞,使该模型成为肿瘤干细胞研究的有力工具。
Objective:To establish stable regulated brain tumor mouse model with sternness coexpressing c-myc and SV40Tag induced by Tet-on system and lay the ground work for future research on the special property of the brain tumor stem cells (BTSCs). To isolate and identify normal adult neural stem cells (NSCs), induced adult neural stem cells (NSC's) and mouse brain tumor stem cells from subventricular zone (SVZ) tissue of non-induced genetically engineered mouse models, SVZ tissue and tumor tissue of induced genetically engineered brain cancer mouse models respectively. To learn the similarities and differences among normal adult neural stem cells, induced adult neural stem cells and mouse brain tumor stem cells, and define the differential molecular mechanisms. To provide evidences for the hypothesis that brain tumor stem cells originate from neural stem cells.
Methods:Transgenic mouse coexpressing pTRE2-c-myc, Tet-on and pTRE2-SV40Tag were generated by crossing the pTRE2-c-myc transgenic mouse with transgenic mouse coexpressing both Tet-on and pTRE2-SV40Tag, and induced by doxycycline (DOX) to generate brain tumor mouse model. Magnetic resonance image, macroscopy and histopathology of the tumor specimen and immunohistochemistry were used to investigate the characteristics of the model. Cells from SVZ tissue of non-induced genetically engineered mouse models and SVZ tissue of induced genetically engineered brain cancer mouse models were cultured in DMEM/F12 mediume containing FGF2, epidermal growth factor and B27 minus retinyl acetate. Differentiated cells of the two group cell spheres were cultured in DMEM/F12 containing 10% FCS. Brain tumor tissues were obtained from genetically engineered mouse which symptoms appear. Cells from tumor tissue were cultured in DMEM/F12 mediume containing fibroblast grwoth factor-2 (bFGF), epidermal growth factor (EGF) and B27 minus retinyl acetate. Differentiated cells of mouse brain tumor spheres were cultured in DMEM/F12 containing 10% FCS. The morphous and proliferation of normal adult neural stem cells, induced adult neural stem cells and mouse brain tumor stem cells were obeserved under phase contrast microscope. The ultrastructures of the three group cells spheres were obeserved under transmission electron microscope (TEM). To determine whether the three group cells spheres contain stem cells, Hoechst 33342 was used to sort for the side population (SP) phenotype. Cell cycle and chromosome ploidy of the three group cells spheres were performed on Flow cytometry. Multiple immunofluorescence was used to assays the cell markers of the three group cells spheres and differentiated cells. Immunofluorescence was used to define the differential expression in c-myc and p53 pathway among normal adult neural stem cells, induced adult neural stem cells and mouse brain tumor stem cells.
Results:(1) Thirty of Seventy-three transgenic mouse coexpressing pTRE2-c-myc, Tet-on and pTRE2-SV40Tag generate brain tumor induced by DOX. The incidence of brain tumor was 41.1%. Beside of one brain stem tumor, all of the other tumors were located on the pineal region. On magnetic resonance imaging (MRI), these lesions appear isointense to hyperintense on TI-weighted images and and isointense to hypointense on T2 weighted images. These lesions were enhanced and rather homogeneous to moderately heterogeneous with contrast images. The brain tumors were diagnosed as undifferentiated medulloblastoma. The brain tumors were highly invasive. And immunohistochemistry indicated that the tumors overexpressed c-myc, SV40Tag and stem/progenitor cells mark nestin.
(2) Cells from SVZ of uninduced and induced genetically engineered adult mouse formed cell spheres when cultured in DMEM/F12 mediume containing FGF2, epidermal growth factor and B27 minus retinyl acetate. Uninduced adult neural stem cells spheres differentiated into neuronal and glial cells when cultured in DMEM/F12 containing 10% FCS. Induced adult neural stem cell spheres exhibited enhanced proliferating capacity and impaired differentiation. The ultrastructures of uninduced and induced adult neural stem cell spheres indicated stem cells characteristics of undevelopped organelles, high nuclear-cytoplasmic ratio. Compared with uninduced adult neural stem cell spheres, cellular organs associated with differentiation and degradation, for example lysosome, autophagosome, were significant reduced in induced adult neural stem cell spheres. The average first sort percentage of SP cells was 10.43% and 16.89% in uninduced and induced adult neural stem cell spheres respectively. All uninduced and induced adult neural stem cell spheres were diploid. A majority of cells in uninduced adult neural stem cell spheres were at S phase. A majority of cells in uninduced adult neural stem cell spheres were nestin positive. The differentiated cells of uninduced adult neural stem cell spheres were GFAP and MAP2 positive respectively. A majority of cells in induced adult neural stem cell spheres were nestin positive, and small fraction were GFAP and NSE positive. But partially differentiated cells still coexpressed stem cells marker nestin and differentiation markers GFAP and MAP2, and even coexpressed differentiation markers GFAP and MAP2.
(3) Cells from genetically engineered mouse brain cancer tissue formed stem-like sphere when cultured in DMEM/F12 mediume containing FGF2, epidermal growth factor and B27 minus retinyl acetate, and differentiated into neuronal and glial like cells when cultured in DMEM/F12 containing 10% FCS. The ultrastructures of brain tumor sphere indicated stem cells characteristics of undevelopped organelles, high nuclear-cytoplasmic ratio. Cellular organs associated with differentiation and degradation were seldom seen. The average first sort percentage of SP cells was 17.27%. Heteroploid in mouse brain cancer spheres was 26.77%. A majority of cells were at S phase. A majority of cells in mouse brain cancer spheres were nestin positive and small fraction of cells were NSE and GFAP positive. Most differentiated cells coexpress nestin with MAP2 or GFAP, and even coexpressed differentiation markers GFAP and MAP2. Brain tumor stem cells and induced neural stem cells overexpressed c-myc and MDM2 (negative regulator of p53).
Conclusion:(1) Stable regulated brain tumor mouse model coexpressing c-myc and SV40Tag induced by Tet-on system was established. The ground work was laied for future research on the special property of the brain tumor stem cells (BTSCs).
(2) Adult neural stem cells were isolated from SVZ of uninduced and induced Tet-on genetically engineered mouse models. Induced neural stem cells exhibited enhanced proliferating capacity and impaired differentiation. Our data indicated adult neural stem cells acquired early malignant transformation.
(3) Tet-on genetically engineered mouse brain cancer contains brain tumor stem cells which have the capacity to self-renew and muti-differential potentiality. Brain tumor stem cells exhibited enhanced proliferating capacity and impaired differentiation as same as induced neural stem cells. Activation of c-myc and inactivation of p53 pathway play critical roles in substance of brain tumor stem cells and malignant transformation of neural stem cells.
(4) Adult neural stem cells and brain tumor stem cells were isolated from one Tet-on genetically engineered brain cancer mouse models. Tet-on genetically engineered brain cancer mouse models become powerful tool for brain tumor stem cells research.
方法：将pTRE2-c-myc转基因小鼠与Tet-on、pTRE2-SV40Tag转基因小鼠进行交配,将子代中同时表达pTRE2-c-myc、Tet-on和]pTRE2-SV40Tag的转基因小鼠,进行强力霉素(四环素类)诱导,观察脑肿瘤的发生。通过磁共振成像、大体标本、组织切片、免疫组化对模型鼠脑肿瘤的特征进行研究。从未经强力霉素诱导的Tet-on转基因成年小鼠以及诱导发生脑肿瘤的转基因成体小鼠室管膜下区取材,制成单细胞悬液,培养于无血清干细胞培养基(DMEM/F12,添加bFGF、EGF和B27)以及含血清分化培养基(DMEM+10%FCS)。从出现临床症状的转基因小鼠松果体区肉眼可见的肿瘤组织中取材,制成单细胞悬液,培养于含生长因子的无血清培养基和含血清培养基。用相差显微镜观察正常神经干细胞球体,诱导后神经干细胞球体和肿瘤干细胞球体及其分化细胞形态,细胞增殖情况,电镜观察其超微结构,用流式细胞仪检测三组细胞中Hoechst33342阴性的SP (side population)细胞,细胞周期和染色体倍体。通过免疫荧光,检测球体及其分化细胞中的nestn、NSE、GFAP、MAP2表达情况。通过免疫荧光,比较脑肿瘤干细胞和诱导前后神经干细胞p53, c-myc通路的表达差异。
结果：(1)73只同时表达pTRE2-c-myc、Tet-on和pTRE2-SV40Tag的转基因小鼠,经过强力霉素诱导后,30只小鼠发生脑肿瘤,发生率为41.1%。除1例脑干肿瘤外,均位于松果体区,诱导后到发生脑肿瘤的时间最长184d,最短为64d,平均为95d。肿瘤在T1加权像表现为等信号或稍高信号,在T2加权像表现为等信号或稍低信号,增强后可表现为均一强化或不均一强化。病理诊断为未分化成神经管细胞瘤,肿瘤具有高侵袭性。免疫组化显示,肿瘤高表达c-myc、SV40Tag和干/祖细胞标志物nestin。
(2)未诱导成体转基因小鼠和诱导发生脑肿瘤的成体小鼠室管膜下区细胞,在无血清培养条件下,均呈悬浮的球状生长。未诱导神经干细胞(NSCs)球体,在含血清培养条件下,贴壁并分化为胶质细胞、神经元。诱导后的神经干细胞(NSC's)球体,则表现为增殖活性增加和分化抑制。电镜可见核质比高、细胞器不发达,具干细胞特征的细胞。诱导后神经干细胞与诱导前相比,细胞分化以及降解有关的细胞器(如溶酶体等)、自噬小体显著减少。流式细胞仪检测诱导前后的神经干细胞球中的SP细胞,分别为10.43%、16.89%,所有细胞均为二倍体,大部分细胞位于G0/G1期。免疫荧光显示,未诱导神经干细胞球体大部分细胞表达nestin,分化细胞分别表达GFAP和MAP2。诱导后的神经干细胞球体中,大部分细胞表达nestin,少部分表达分化标志物GFAP、NSE,而部分分化细胞仍然共表达干细胞标志物nestin和分化标志物GFAP和MAP2,甚至同时表达两种分化标志物GFAP和MAP2。
(3)肿瘤细胞在无血清培养条件下,呈悬浮的球状生长,在含血清培养条件下贴壁并分化为瘤性胶质细胞、神经元。电镜下见到核质比高、细胞器不发达、与细胞分化降解有关的细胞器罕见。流式细胞仪检测肿瘤细胞球中的SP细胞为17.27%,异倍体细胞为26.77%,大部分细胞处于S期。免疫荧光染色发现,细胞球中大部分细胞表达干细胞标志物nestin,少数细胞表达分化标志物GFAP和NSE。贴壁细胞大部分仍然共表达干细胞标志物nestin和分化标志物GFAP和MAP2,甚至同时表达两种分化标志物GFAP和MAP2。脑肿瘤干细胞和诱导后,神经干细胞高表达c-myc, MDM2(p53抑制基因)
结论：(1)成功建立更加稳定的、可调控的、具有干细胞特性的脑肿瘤小鼠模型,为进一步研究脑肿瘤干细胞的特性奠定基础。
(2)成功从诱导前后的Tet-on转基因成体小鼠室管膜下区中,分离到神经干细胞,且发现诱导后的神经干细胞表现为增殖活性增加和分化抑制,表明神经干细胞已经出现早期恶性转化表现。
(3) Tet-on转基因小鼠脑肿瘤组织中,存在具有自我更新和多向分化潜能的脑肿瘤干细胞,且发现脑肿瘤干细胞与诱导后的神经干细胞一样,表现为增殖活性增加和分化抑制。C-myc通路活化和p53通路破坏,在脑肿瘤干细胞维系与神经干细胞恶性转化中起关键作用。
(4)在同一动物模型个体中,同时分离到脑肿瘤干细胞和神经干细胞,使该模型成为肿瘤干细胞研究的有力工具。
Objective:To establish stable regulated brain tumor mouse model with sternness coexpressing c-myc and SV40Tag induced by Tet-on system and lay the ground work for future research on the special property of the brain tumor stem cells (BTSCs). To isolate and identify normal adult neural stem cells (NSCs), induced adult neural stem cells (NSC's) and mouse brain tumor stem cells from subventricular zone (SVZ) tissue of non-induced genetically engineered mouse models, SVZ tissue and tumor tissue of induced genetically engineered brain cancer mouse models respectively. To learn the similarities and differences among normal adult neural stem cells, induced adult neural stem cells and mouse brain tumor stem cells, and define the differential molecular mechanisms. To provide evidences for the hypothesis that brain tumor stem cells originate from neural stem cells.
Methods:Transgenic mouse coexpressing pTRE2-c-myc, Tet-on and pTRE2-SV40Tag were generated by crossing the pTRE2-c-myc transgenic mouse with transgenic mouse coexpressing both Tet-on and pTRE2-SV40Tag, and induced by doxycycline (DOX) to generate brain tumor mouse model. Magnetic resonance image, macroscopy and histopathology of the tumor specimen and immunohistochemistry were used to investigate the characteristics of the model. Cells from SVZ tissue of non-induced genetically engineered mouse models and SVZ tissue of induced genetically engineered brain cancer mouse models were cultured in DMEM/F12 mediume containing FGF2, epidermal growth factor and B27 minus retinyl acetate. Differentiated cells of the two group cell spheres were cultured in DMEM/F12 containing 10% FCS. Brain tumor tissues were obtained from genetically engineered mouse which symptoms appear. Cells from tumor tissue were cultured in DMEM/F12 mediume containing fibroblast grwoth factor-2 (bFGF), epidermal growth factor (EGF) and B27 minus retinyl acetate. Differentiated cells of mouse brain tumor spheres were cultured in DMEM/F12 containing 10% FCS. The morphous and proliferation of normal adult neural stem cells, induced adult neural stem cells and mouse brain tumor stem cells were obeserved under phase contrast microscope. The ultrastructures of the three group cells spheres were obeserved under transmission electron microscope (TEM). To determine whether the three group cells spheres contain stem cells, Hoechst 33342 was used to sort for the side population (SP) phenotype. Cell cycle and chromosome ploidy of the three group cells spheres were performed on Flow cytometry. Multiple immunofluorescence was used to assays the cell markers of the three group cells spheres and differentiated cells. Immunofluorescence was used to define the differential expression in c-myc and p53 pathway among normal adult neural stem cells, induced adult neural stem cells and mouse brain tumor stem cells.
Results:(1) Thirty of Seventy-three transgenic mouse coexpressing pTRE2-c-myc, Tet-on and pTRE2-SV40Tag generate brain tumor induced by DOX. The incidence of brain tumor was 41.1%. Beside of one brain stem tumor, all of the other tumors were located on the pineal region. On magnetic resonance imaging (MRI), these lesions appear isointense to hyperintense on TI-weighted images and and isointense to hypointense on T2 weighted images. These lesions were enhanced and rather homogeneous to moderately heterogeneous with contrast images. The brain tumors were diagnosed as undifferentiated medulloblastoma. The brain tumors were highly invasive. And immunohistochemistry indicated that the tumors overexpressed c-myc, SV40Tag and stem/progenitor cells mark nestin.
(2) Cells from SVZ of uninduced and induced genetically engineered adult mouse formed cell spheres when cultured in DMEM/F12 mediume containing FGF2, epidermal growth factor and B27 minus retinyl acetate. Uninduced adult neural stem cells spheres differentiated into neuronal and glial cells when cultured in DMEM/F12 containing 10% FCS. Induced adult neural stem cell spheres exhibited enhanced proliferating capacity and impaired differentiation. The ultrastructures of uninduced and induced adult neural stem cell spheres indicated stem cells characteristics of undevelopped organelles, high nuclear-cytoplasmic ratio. Compared with uninduced adult neural stem cell spheres, cellular organs associated with differentiation and degradation, for example lysosome, autophagosome, were significant reduced in induced adult neural stem cell spheres. The average first sort percentage of SP cells was 10.43% and 16.89% in uninduced and induced adult neural stem cell spheres respectively. All uninduced and induced adult neural stem cell spheres were diploid. A majority of cells in uninduced adult neural stem cell spheres were at S phase. A majority of cells in uninduced adult neural stem cell spheres were nestin positive. The differentiated cells of uninduced adult neural stem cell spheres were GFAP and MAP2 positive respectively. A majority of cells in induced adult neural stem cell spheres were nestin positive, and small fraction were GFAP and NSE positive. But partially differentiated cells still coexpressed stem cells marker nestin and differentiation markers GFAP and MAP2, and even coexpressed differentiation markers GFAP and MAP2.
(3) Cells from genetically engineered mouse brain cancer tissue formed stem-like sphere when cultured in DMEM/F12 mediume containing FGF2, epidermal growth factor and B27 minus retinyl acetate, and differentiated into neuronal and glial like cells when cultured in DMEM/F12 containing 10% FCS. The ultrastructures of brain tumor sphere indicated stem cells characteristics of undevelopped organelles, high nuclear-cytoplasmic ratio. Cellular organs associated with differentiation and degradation were seldom seen. The average first sort percentage of SP cells was 17.27%. Heteroploid in mouse brain cancer spheres was 26.77%. A majority of cells were at S phase. A majority of cells in mouse brain cancer spheres were nestin positive and small fraction of cells were NSE and GFAP positive. Most differentiated cells coexpress nestin with MAP2 or GFAP, and even coexpressed differentiation markers GFAP and MAP2. Brain tumor stem cells and induced neural stem cells overexpressed c-myc and MDM2 (negative regulator of p53).
Conclusion:(1) Stable regulated brain tumor mouse model coexpressing c-myc and SV40Tag induced by Tet-on system was established. The ground work was laied for future research on the special property of the brain tumor stem cells (BTSCs).
(2) Adult neural stem cells were isolated from SVZ of uninduced and induced Tet-on genetically engineered mouse models. Induced neural stem cells exhibited enhanced proliferating capacity and impaired differentiation. Our data indicated adult neural stem cells acquired early malignant transformation.
(3) Tet-on genetically engineered mouse brain cancer contains brain tumor stem cells which have the capacity to self-renew and muti-differential potentiality. Brain tumor stem cells exhibited enhanced proliferating capacity and impaired differentiation as same as induced neural stem cells. Activation of c-myc and inactivation of p53 pathway play critical roles in substance of brain tumor stem cells and malignant transformation of neural stem cells.
(4) Adult neural stem cells and brain tumor stem cells were isolated from one Tet-on genetically engineered brain cancer mouse models. Tet-on genetically engineered brain cancer mouse models become powerful tool for brain tumor stem cells research.
引文
[1]黄文清.神经肿瘤病理学.军事医学科学出版社(第二版),2000：49.
[2]Prados MD and Wilson CB. Neoplasms of the central nervous system. In Cancer Medicine. Holland JF, Bast R, Morton DL, Frei E, Kufe DW, Weichselbaum RR, eds. 1993,1080-1119.
[3]Rainov NO, Ren H. Gene therapy for human malignant brain tumors. Cancer J,2003, 9:180-188.
[4]Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature,1994,367:645-648.
[5]Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res,2003,63:5821-5828.
[6]Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci USA,2003,100:3983-3988.
[7]Reya T, Morrison SJ, Clarke MF, et al. Stem cells, cancer, and cancer stem cells. Nature,2001,414:105-111.
[8]Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature,2006,444:756-760.
[9]Tan BT, Park CY, Ailles LE, et al. The cancer stem cell hypothesis:a work in progress. Lab. Invest,2006,86:1203-1207.
[10]Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell,2007,131:861-72.
[11]Holland EC, Hively WP, DePinho RA, et al. A constitutively active epidermal growth factor receptor cooperates with disruption of Gl cell-cycle arrest pathways to induce glioma-like lesions in mice. Genes Dev,1998,12:3675-3685.
[12]Ding H, Roncari L, Shannon P, et al. Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas. Cancer Res,2001,61:3826-3836.
[13]Weiss WA, Burns MJ, Hackett C, et al. Genetic determinants of malignancy in a mouse model for oligodendroglioma. Cancer Res,2003,63:1589-1595.
[14]Bachoo RM, Maher EA, Ligon KL, et al. Epidermal growth factor receptor and Ink4a/Arf convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell,2002, 1:197-227.
[15]Maher EA, Furnari FB, Bachoo RM, et al. Malignant glioma:genetics and biology of a grave matter. Genes Dev,2001,15:1311-1333.
[16]Laywell ED, Rakic P, Kukekov VG, et al. Identification of a multipotent astrocytic stem cell in the immature and adult mouse brain. Proc. Natl. Acad. Sci. USA,2000, 97:13883-13888.
[17]Reynolds BA, and Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science,1992,255:1707-1710.
[18]Reya T, Morrison SJ, Clarke MF, et al. Stem cells, cancer, and cancer stem cells. Nature,2001,414:105-111.
[19]Gaiano N, Nye JS, and Fishell G. Radial glial identity is promoted by Notchl signaling in the murine forebrain. Neuron,2000,26:395-404.
[20]Anderson DJ, Gage FH, and Weissman IL. Can stem cells cross lineage boundaries? Nat. Med,2001,7:393-395.
[21]Purow BW, Haque RM, Noel MW, et al. Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation. Cancer Res,2005,65:2353-2363.
[22]Jackson EL, Garcia-Verdugo JM, Gil-Perotin S, et al. PDGFR alpha-positive B cells are neural stem cells in the adult SVZ that form glioma-like growths in response to increased PDGF signaling. Neuron,2006,51:187-199.
[23]Kesari S, Ramakrishna N, Sauvageot C, et al. Targeted molecular therapy of malignant gliomas. Curr. Oncol. Rep,2006,8:58-70.
[24]Zhu Y, Guignard F, Zhao D, et al. Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell,2005,8:119-130.
[25]Lim DA, Cha S, Mayo MC, et al. Relationship of glioblastoma multiforme to neural stem cell regions predicts invasive and multifocal tumor phenotype. Neuro-oncol, 2007,9:424-429.
[26]Sanai N, Alvarez-Buylla A, and Berger MS. Neural stem cells and the origin of gliomas. N. Engl. J. Med,2005,353:811-822.
[27]Vescovi AL, Galli R, and Reynolds BA. Brain tumour stem cells. Nat. Rev. Cancer, 2006,6:425-436.
[1]Legler JM, Ries LA, Smith MA, et al. Brain and other central nervous system cancers: recent trends in incidence and mortality. J Natl Cancer Inst,1999,91:1382-1390.
[2]Zalatnai, Tumour microenvironment. Aspects of stromal-parenchymal interaction. In Baronzio Gianfranco, Fiorentini Giammaria, Cogle Christopher R (Eds.), Tumour microenvironment. Aspects of stromal-parenchymal interaction; Cancer Microenviron-ment and Therapeutic Implications, Springer,2009:19-38.
[3]Becher OJ, Holland EC. Genetically engineered models have advantages over xenografts for preclinical studies. Cancer Res,2006,66:3355-3359
[4]Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res,2003,63:5821-5828.
[5]Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature,2006,444:756-60.
[6]Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer, 2005,5:275-84.
[7]Fung K-M, Chikaraishi DM, Theuring F, et al. Molecular phenotype of Simian virus 40 large T antigen-induced primitive neuroectodermal tumors in four different lines of transgenic mice. Lab Invest,1994,70:114-24.
[8]Korf H-W, GOtz W, Herken R, et al. S-antigen and rod-opsin immunoreactions in midline brain neoplasms of transgenic mice:Similarities to pineal cell tumors and certain medulloblastomas in man. J Neuropathol Exp Neurol,1990,49:424-37.
[9]GOtz W, Theuring F, Schachenmayr W, et al. Midline brain tumors in MSV-SV 40 transgenic mice originate from the pineal organ. Acta Neuropathol,1992,83:308-14.
[10]Beier D, Hau P, Proescholdt M, et al. CD133+ and CD133- Glioblastoma-Derived Cancer Stem Cells Show Differential Growth Characteristics and Molecular Profiles. Cancer Res,2007,67:4010-4015.
[11]Bao S, Wu Q, Sathornsumetee S,, et al. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res.2006, 66:7843-7848.
[12]Feng Li, Benjamin Tiede, Joan Massague, et al. Beyond tumorigenesis:cancer stem cells in metastasis, Cell Research,2007,17:3-14.
[13]Galli R, Binda E, Orfanelli U, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res,2004,64: 7011-7021.
[14]李茗初,邓永文,伍军,等.髓母细胞瘤中脑肿瘤干细胞的分离培养及鉴定.癌症,2006,25(2)：241-246.
[15]Beier D, Wischhusen J, Dietmaier W, et al. CD 133 expression and cancer stem cells predict prognosis in high-grade oligodendroglial tumors. Brain Pathol,2008,18: 370-377.
[16]Eberhart CG. In search of the medulloblast:neural stem cells and embryonal brain tumors. Neurosurg Clin N Am,2007,18:59-69.
[17]Buhren J, Christoph AH, Buslei R, et al. Expression of the neurotrophin receptor p75NTR in medulloblastomas is correlated with distinct histological and clinical features:evidence for a medulloblastoma subtype derived from the external granule cell layer. J Neuropathol Exp Neurol,2000,59:229-240.
[18]Salsano E, Pollo B, Eoli M, et al. Expression of MATH1, a marker of cerebellar granule cell progenitors, identifies different medulloblastoma subtypes. Neurosci. Lett,2004,370:180-185.
[19]Yokota N, Aruga J, Takai S, et al. Predominant expression of human zic in cerebellar granule cell lineage and medulloblastoma. Cancer Res,1996,56:377-383.
[20]Pomeroy SL, Sutton ME, Goumnerova LC, et al. Neurotrophins in cerebellar granule cell development and medulloblastoma. J. Neurooncol,1997,35:347-352.
[21]Hemmati HD, Nakano I, Lazareff JA, et al. Cancerous stem cells can arise from pediatric brain tumors. Proc. Natl. Acad. Sci. USA,2003,100:15178-15183.
[22]Gilbertson RJ, and Ellison DW. The origins of medulloblastoma subtypes. Annu. Rev. Pathol,2008,3:341-365.
[23]Yang ZJ, Ellis T, Markant SL, et al. Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer Cell,2008, 14:135-45.
[24]Gossen M, Bujard H. Tight control of gene expression in mammalian cells by tetracycline responsive promotors. Proc Natl Acad Sci USA,1992,89:5547-5551.
[25]Gossen M, Freundlieb S, Bender G et al. Transcriptional activation by tetracyclines in mammalian cells. Science,1995,268:1766-1769.
[26]Christofori G, Hanahan D. Molecular dissection of multi-stage tumorigenesis in transgenic mice. Semin Cancer Biol,1994,5:3-12
[27]Blondal JA, Benchimol S. The role of p53 in tumor progression. Semin Cancer Biol 1999,5:177-86.
[28]Symonds H, Krall L, Remington L, et al. p53-dependent apoptosis suppresses tumor growth and progression in vivo. Cell,1994,78:703-11.
[29]Vita M, Henriksson M. The Myc oncoprotein as a therapeutic target for human cancer. Semin Cancer Biol,2006,16:318-330.
[30]Murphy MJ, Wilson A, Trumpp A. More than just proliferation:Myc function in stem cells. Trends Cell Biol,2005,15:128-137.
[31]Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell,2006,126: 663-676.
[32]Nakagawa M, Koyanagi M, Tanabe K, et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol,2008, 26:101-106.
[33]Wilson A, Murphy MJ, Oskarsson T, et al. c-myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev,2004, 18:2747-2763.
[34]Herms JW, von Loewenich FD, Behnke J, et al. c-myc oncogene family expression in glioblastoma and survival. Surg Neurol,1999,51:536-542.
[35]Jensen NA, Pedersen KM, Lihme F, et al. Astroglial c-myc overexpression predisposes mice to primary malignant gliomas. J Biol Chem 2003,278:8300-8308.
[36]Wang J, Wang H, Li Z, et al. C-myc is required for maintenance of glioma cancer stem cells. PLoS One,2008,3:3769.
[1]Reynolds BA, and Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian nervous system. Science,1992,255:1707-1710.
[2]Lois C and Alvarez-Buylla A. Proliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia. Proc Natl Acad Sci., 1993,90:2074-2077.
[3]Morshead CM, Reynolds BA, Craig CG, et al. Neural stem cells in the adult mammalian forebrain:a relatively quiescent subpopulation of subependymal cells. Neuron,1994,13:1071-1082.
[4]Weiss S, Dunne C, Hewson J, et al. Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J Neurosci.,1996,16: 7599-7609.
[5]Palmer TD, Takahashi J, and Gage FH. The adult rat hippocampus contains primordial neural stem cells. Mol Cell Neurosci,1997,8:389-404.
[6]Johansson CB, Momma S, Clarke DL, et al. Identification of a neural stem cell in the adult mammalian central nervous system. Cell,1999,96:25-34.
[7]Lee A, Kessler JD, Read TA, et al. Isolation of neural stem cells from the postnatal cerebellum. Nat Neurosci,2005,8:723-729.
[8]Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature,1994,367:645-648.
[9]Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res,2003,63:5821-5828.
[10]Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci USA,2003,100:3983-3988.
[11]陈骅,黄强,董军,等.肿瘤起源细胞学说与争论.癌症,2006,25：779-784.
[12]吴红,张成香,郑逸梅,等Tet-on系统诱导表达c-myc转基因小鼠的建立.中国兽医学报,2007,27：207-210.
[13]孙敬方.时空表达可控的转基因动物模型调控体系的研究,中国实验动物学报,2005,13：72-75.
[14]Goodell MA, Brose K, Paradis G, et al. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 1996; 183: 1797-1806
[15]Margaret A, Goodell, Stem Cell Identification and Sorting Using the Hoechst 33342 Side Population (SP), Current Protocols in Cytometry.2002:9.18.1-9.18.11
[16]Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, et al, Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness, Proc. Natl Acad. Sci USA,2006,103:11154-11159.
[17]Stevens MC, Cameron AH, Muir KR, et al, Descriptive epidemiology of primary central nervous system tumours in children:a population-based study. Clin Oncol (R Coll Radiol) 1991,3:323-329.
[18]Central Brain Tumor Registry of the United States,2009, http://www.cbtrus.org/ reports/reports.html.
[19]Bailey P, Cushing H. A classification of the tumors of the glioma group on a histogenetic basis with a correlated study of prognosis. Philadelphia:J.B. Lippincott, 1926.
[20]Kleihues P, Louis DN, Scheithauer BW, et al. The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol,2002,61:215-225.
[21]Leon SP, Folkerth RD, Black PM. Microvessel density is a prognostic indicator for patients with astroglial brain tumors. Cancer,1996,77:362-372.
[22]Lacroix M, Abi-Said D, Fourney DR, et al. A multivariate analysis of 416 patients with glioblastoma multiforme:prognosis, extent of resection, and survival. J Neurosurg,2001,95:190-198.
[23]Hammoud MA, Sawaya R, Shi W, et al. Prognostic significance of preoperative MRI scans in glioblastoma multiforme. J Neurooncol 1996,27:65-73.
[24]Morrison SJ, Shah NM and Anderson DJ. Regulatory mechanisms in stem cell biology. Cell,1997,88:287-298
[25]Galderisi U, Jori FP and Giordano A. Cell cycle regulation and neural differentiation. Oncogene,2003,22:5208-5219
[26]Valk-Lingbeek ME, Bruggeman SW and van Lohuizen M. Stem cells and cancer; the polycomb connection. Cell,2004,118:409-418
[27]Dai C, Celestino J C, Okada Y, et al. PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes Dev,2001,15:1913-1925.
[28]Bachoo RM, Maher EA, Ligon KL, et al. Epidermal growth factor receptor and Ink4a/Arf:convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell,2002, 1:269-277.
[29]Uhrbom L, Dai C, Celestino JC, et al. Holland EC. Ink4a-Arf loss cooperates with KRas activation in astrocytes and neural progenitors to generate glioblastomas of various morphologies depending on activated Akt. Cancer Res.2002,62:5551-5558.
[30]Heikens J, Michiels EM, Behrendt H, et al. Long-term neuro-endocrine sequelae after treatment for childhood medulloblastoma. Eur J Cancer.1998,34:1592-1597.
[31]Mulhern, R.K., Palmer, S.L., Merchant, T.E, et al. Neurocognitive consequences of risk-adapted therapy for childhood medulloblastoma. J Clin Oncol,2005,23: 5511-5519.
[32]Packer, R.J., Cogen, P., Vezina, G, et al. Medulloblastoma:clinical and biologic aspects. Neuro-oncol,1999,1:232-250.
[33]Eberhart CG. In search of the medulloblast:neural stem cells and embryonal brain tumors. Neurosurg Clin N Am,2007,18:59-69.
[34]Read TA, Hegedus B, Wechsler-Reya R, et al. The neurobiology of neurooncology. Ann Neurol,2006,60:3-11.
[35]Buhren J, Christoph AH, Buslei R, et al. Expression of the neurotrophin receptor p75NTR in medulloblastomas is correlated with distinct histological and clinical features:evidence for a medulloblastoma subtype derived from the external granule cell layer. J Neuropathol Exp Neurol,2000,59:229-240.
[36]Pomeroy SL, Sutton ME, Goumnerova LC, et al. Neurotrophins in cerebellar granule cell development and medulloblastoma. J Neurooncol,1997,35:347-352.
[37]Salsano E, Pollo B, Eoli M, et al. Expression of MATH1, a marker of cerebellar granule cell progenitors, identifies different medulloblastoma sub-types. Neurosci. Lett,2004,370:180-185.
[38]Yokota N, Aruga J, Takai S, et al. Predominant expression of human zic in cerebellar granule cell lineage and medulloblastoma. Cancer Res,1996,56:377-383.
[39]Hemmati HD, Nakano I, Lazareff JA, et al. Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA,2003,100:15178-15183.
[40]Yang ZJ, Ellis T, Markant SL, et al. Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer Cell,2008,14:135-45.
[41]Alcantara Llaguno S, Chen J, Kwon CH, et al. Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. Cancer Cell,2009,15:45-56.
[42]Zheng H, Ying H, Yan H, et al. Pten and p53 converge on c-Myc to control differentiation, self-renewal, and transformation of normal and neoplastic stem cells in glioblastoma. Cold Spring Harb Symp Quant Biol,2008,73:427-437.
[1]Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature,1994,367:645-648.
[2]Bonnet D, Dick J E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Med,1997,3:730-737.
[3]Sutherland HJ, Blair A, Zapf RW. Characterization of a hierarchy in human myeloid leukemia progenitor cells. Blood,1996,87:4754-4761.
[4]Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res,2003,63:5821-5828.
[5]Al-Hajj M, Clarke MF. Self-renewal and solid tumor stem cells. Oncogene,2004, 23:7274-7282.
[6]Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA,2003,100:3983-3988.
[7]王金鹏,黄强,张全斌,等.人脑胶质瘤干细胞SHG44s的克隆及初步鉴定.中国肿瘤临床,2005,3：604-607.
[8]黄强,朱玉德,董军,等.人脑胶质瘤组织中分离与培养肿瘤干细胞.中华肿瘤杂志,2006,28：15-17.
[9]Bjerkvig R, Tysnes BB, Aboody KS, et al, The origin of the cancer stem cell:current controversies and new insights, Nat Rev Cancer,2005,5:899-904.
[10]吴红,张成香,郑逸梅,等Tet-on系统诱导表达c-myc转基因小鼠的建立.中国兽医学报,2007,27：207-210.
[11]孙敬方.时空表达可控的转基因动物模型调控体系的研究.中国实验动物学报,2005,13：72-75.
[12]Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, et al, Ovarian cancer side population defines cells with stem cell-like characteristics and mullerian inhibiting substance responsiveness. Proc Natl Acad Sci USA,2006,6:11154-11159.
[13]Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature,2004,432:396-401.
[14]Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature,2006,444:687-688.
[15]储亮,黄强,董军,等.肿瘤千细胞的耐药性及其治疗策略.中国新药与临床杂志,2006,25：868-872.
[16]Alvarez-Buylla A, Lim DA. For the long run:maintaining germinal niches in the adult brain. Neuron,2004,41:683-686.
[17]Gage FH. Mammalian neural stem cells. Science,2000,287:1433-1438.
[18]Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell,2008,132:645-660.
[19]Eriksson PS, Perfilieva E, Bjork-Eriksson T, et al. Neurogenesis in the adult human hippocampus. Nat Med,1998,4:1313-1317.
[20]Sanai N, Tramontin AD, Quinones-Hinojosa A, et al. Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature,2004, 427:740-744.
[21]Wang J, Wang H, Li Z, et al. c-myc is required for maintenance of glioma cancer stem cells. PLoS One,2008,3:3769.
[22]Strasser A, Harris AW, Bath ML, et al. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature,1990,348:331-333.
[23]Jacobs JJ, Scheijen B, Voncken JW, et al. Bmi-1 collaborates with c-myc in tumorigenesis by inhibiting c-myc-induced apoptosis via INK4a/ARF. Genes Dev, 1999,13:2678-2690.
[24]Eischen CM, Weber JD, Roussel MF, et al. Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dev,1999,13:2658-2669.
[25]Arvanitis C, Felsher DW. Conditional transgenic models define how MYC initiates and maintains tumorigenesis. Semin Cancer Biol,2006,16:313-317.
[26]Shachaf CM, Kopelman AM, Arvanitis C, et al. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature, 2004,431:1112-1117.
[27]Dahlstrand J, Collins VP, Lendahl U. Expression of the class VI intermediate filament nestin in human central nervous system tumors. Cancer Res,1992,52:5334-5341.
[28]Toda M, Iizuka Y, Yu W, et al. Expression of the neural RNA-binding protein Musashil in human gliomas. Glia,2001,34:1-7.
[29]Ignatova TN, Kukekov VG, Laywell ED, et al. Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia,2002, 39:193-206.
[30]Bouvier C, Bartoli C, Aguirre-Cruz L, et al. Shared oligodendrocyte lineage gene expression in gliomas and oligodendrocyte progenitor cells. J Neurosurg,2003,99:344-350.
[31]Holland EC. A mouse model for glioma:biology, pathology, and therapeutic opportunities. Toxicol Pathol,2001,28:171-177.
[32]von Deimling A, Eibl RH, Ohgaki H, et al. p53 mutations are associated with 17p allelic loss in grade II and grade III astrocytoma. Cancer Res,1992,52:2987-2990.
[33]Watanabe K, Tachibana O, Sata K, et al. Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol,1996,6:217-223.
[34]Hayashi Y, Yamashita J, Watanabe T. Molecular genetic analysis of deep-seated glioblastomas. Cancer Genet Cytogenet,2004,153:64-68.
[35]van Lookeren Campagne M, Gill R. Tumor-suppressor p53 is expressed in proliferating and newly formed neurons of the embryonic and postnatal rat brain: comparison with expression of the cell cycle regulators p21Wafl/Cipl, p27Kip1, p57Kip2, pl6Ink4a, cyclin G1, and the protooncogene bax. J Comp Neurol,1998, 397:181-198.
[36]Gil-Perotin S, Marin-Husstege M, Li J, et al, Loss of p53 induces changes in the behavior of subventricular zone cells:implication for the genesis of glial tumors. J Neurosci,2006,26:1107-16.
[1]Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonic stem cell lines derived from human blastocysts. Science,1998,282:1145-1147.
[2]Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell,2007,131:861-872.
[3]Jaenisch R. Human cloning—the science and ethics of nuclear transplantation. N Engl J Med,2004,351:2787-2791.
[4]Byrne JA, Pedersen DA, Clepper LL, et al. Producing primate embryonic stem cells by somatic cell nuclear transfer. Nature,2007,450:497-502.
[5]Rideout WM III, Hochedlinger K, Kyba M, et al. Correction of a genetic defect by nuclear transplantation and combined cell and gene therapy. Cell,2002,109:17-27.
[6]Cowan CA, Atienza J, Melton DA, et al. Nuclear reprogramming of somatic cells after fusion with human embryonic stem cells. Science,2005,309:1369-1373.
[7]Kanatsu-Shinohara M, Inoue K, Lee J, et al. Generation of pluripotent stem cells from neonatal mouse testis. Cell,2004,119:1001-1012.
[8]Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell,2006,126:663-676.
[9]Tokuzawa Y, Kaiho E, Maruyama M, et al. Fbx15 is a novel target of Oct3/4 but is dispensable for embryonic stem cell selfrenewal and mouse development. Mol Cell Biol,2003,23:2699-2708.
[10]Maherali N, Sridharan R, Xie W, et al. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell, 2007,1:55-70.
[11]Meissner A, Wernig M, Jaenisch R. Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells. Nat Biotechnol,2007,25:1177-1181.
[12]Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature,2007,448:313-317.
[13]Wernig M, Meissner A, Foreman R, et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature,2007,448:318-324.
[14]Park IH, Zhao R, West JA, et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature,2008,451:141-146.
[15]Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science,2007,318:1917-1920.
[16]Dimos JT, Rodolfa KT, Niakan KK, et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science,2008, 321:1218-1221.
[17]Park IH, Arora N, Huo H, et al. Disease-specific induced pluripotent stem cells. Cell, 2008,134:877-886.
[18]Ebert AD, Yu J, Rose FF Jr, et al. Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature,2009,457:277-280.
[19]Jaenisch R, Bird A. Epigenetic regulation of gene expression:how the genome integrates intrinsic and environmental signals. Nat Genet,2003,33:245-254.
[20]Hemberger M, Dean W, Reik W. Epigenetic dynamics of stem cells and cell lineage commitment:digging Waddington's canal. Nat Rev Mol Cell Biol,2009, 10:526-537.
[21]Egli D, Birkhoff G, Eggan K. Mediators of reprogramming:transcription factors and transitions through mitosis. Nat Rev Mol Cell Biol,2008,9:505-516.
[22]Nichols J, Zevnik B, Anastassiadis K, et al. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell,1998, 95:379-391.
[23]Avilion AA, Nicolis SK, Pevny LH, et al. Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev,2003,17:126-140.
[24]Chambers I, Silva J, Colby D, et al. Nanog safeguards pluripotency and mediates germline development. Nature,2007,450:1230-1234.
[25]Mitsui K, Tokuzawa Y, Itoh H, et al. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell,2003, 113:631-642.
[26]Sridharan R, Tchieu J, Mason MJ, et al. Role of the murine reprogramming factors in the induction of pluripotency. Cell,2009,136:364-377.
[27]Stadtfeld M, Nagaya M, Utikal J, et al. Hochedlinger K. Induced pluripotent stem cells generated without viral integration. Science,2008,322:945-949.
[28]Okita K, Nakagawa M, Hyenjong H, et al. Generation of mouse induced pluripotent stem cells without viral vectors. Science,2008,322:949-953.
[29]Zhou H, Wu S, Joo JY, et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell,2009,4:381-384.
[30]Kim D, Kim CH, Moon JI, et al. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell,2009,4:472-476.
[31]Yu J, Hu K, Smuga-Otto K, et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science,2009,324:797-801.
[32]Hanna J, Markoulaki S, Schorderet P, et al. Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency. Cell,2008,133:250-264.
[33]Mikkelsen TS, Hanna J, Zhang X, et al. Dissecting direct reprogramming through integrative genomic analysis. Nature,2008,454:49-55.
[34]Soldner F, Hockemeyer D, Beard C, et al. Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell,2009, 136:964-977.
[35]Amabile G, Meissner A. Induced pluripotent stem cells:current progress and potential for regenerative medicine. Trends Mol Med,2009,15:59-68.
[36]Marion RM, Strati K, Li H, et al. Telomeres acquire embryonic stem cell characteristics in induced pluripotent stem cells. Cell Stem Cell,2009,4:141-154.
[37]Chin MH, Mason MJ, Xie W, et al. Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell,2009, 5:111-123.
[38]Chen AE, Egli D, Niakan K, et al. Optimal timing of inner cell mass isolation increases the efficiency of human embryonic stem cell derivation and allows generation of sibling cell lines. Cell Stem Cell,2009,4:103-106.
[39]Brambrink T, Hochedlinger K, Bell G, et al. ES cells derived from cloned and fertilized blastocysts are transcriptionally and functionally indistinguishable. Proc Natl Acad Sci U S A,2006,103:933-938.
[40]Boland MJ, Hazen JL, Nazor KL, et al. Adult mice generated from induced pluripotent stem cells. Nature,2009,461:91-94.
[41]Kang L, Wang J, Zhang Y, et al. iPS cells can support full-term development of tetraploid blastocyst-complemented embryos. Cell Stem Cell,2009,5:135-138.
[42]Zhao XY, Li W, Lv Z, et al. iPS cells produce viable mice through tetraploid complementation. Nature,2009,461:86-90.
[43]Aoi T, Yae K, Nakagawa M, et al. Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science,2008,321:699-702.
[44]Stadtfeld M, Brennand K, Hochedlinger K. Reprogramming of pancreatic beta cells into induced pluripotent stem cells. Curr Biol,2008,18:890-894.
[45]Eminli S, Utikal J, Arnold K, et al. Reprogramming of neural progenitor cells into induced pluripotent stem cells in the absence of exogenous Sox2 expression. Stem Cell,2008,26:2467-2474.
[46]Aasen T, Raya A, Barrero MJ, et al. Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol,2008, 26:1276-1284.
[47]Loh YH, Agarwal S, Park IH, et al. Generation of induced pluripotent stem cells from human blood. Blood,2009,113:5476-5479.
[48]Sun N, Panetta NJ, Gupta DM, et al. Feeder-free derivation of induced pluripotent stem cells from adult human adipose stem cells. Proc Natl Acad Sci U S A, 2009,106:15720-15725
[49]Raya A, Rodriguez-Piza I, Guenechea G, et al. Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature,2009, 460:53-59.
[50]Eminli S, Foudi A, Stadtfeld M, et al. Differentiation stage determines potential of hematopoietic cells for reprogramming into induced pluripotent stem cells. Nat Genet,2009,41:968-976.
[51]Huangfu D, Maehr R, Guo W, et al. Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat Biotechnol,2008, 26:795-797.
[52]Huangfu D, Osafune K, Maehr R, et al. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol,2008, 26:1269-1275.
[53]Shi Y, Do JT, Desponts C, et al. A combined chemical and genetic approach for the generation of induced pluripotent stem cells. Cell Stem Cell,2008,2:525-528.
[54]Shi Y, Desponts C, Do JT, et al. Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds. Cell Stem Cell,2008,3:568-574.
[55]Ichida JK, Blanchard J, Lam K,, et al. A small-molecule inhibitor of Tgfbeta signaling replaces Sox2 in reprogramming by inducing Nanog. Cell Stem Cell.2009, 5:491-503
[56]Hacein-Bey-Abina S, Garrigue A, Wang GP, et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest.2008, 118:3132-3142.
[57]Nakagawa M, Koyanagi M, Tanabe K, et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol,2008, 26:101-106.
[58]Kaji K, Norrby K, Paca A, et al. Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature,2009,458:771-775.
[59]Woltjen K, Michael IP, Mohseni P, et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature,2009,458:766-770.
[60]Gonzalez F, Barragan Monasterio M, Tiscornia G, et al. Generation of mouse-induced pluripotent stem cells by transient expression of a single nonviral polycistronic vector. Proc Natl Acad Sci USA,2009,106:8918-8922.
[61]Murry CE, Keller G. Differentiation of embryonic stem cells to clinically relevant populations:lessons from embryonic development. Cell,2008,132:661-680.
[62]Lamba DA, Gust J, Reh TA. Transplantation of human embryonic stem cell-derived photoreceptors restores some visual function in Crx-deficient mice. Cell Stem Cell, 2009,4:73-79.
[63]Yang D, Zhang ZJ, Oldenburg M, et al. Human embryonic stem cell-derived dopaminergic neurons reverse functional deficit in parkinsonian rats. Stem Cells, 2008,26:55-63.
[64]Kim JH, Auerbach JM, Rodriguez-Gomez JA, et al. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease. Nature, 2002,418:50-56.
[65]Keirstead HS, Nistor G, Bernal G, et al. Human embryonic stem cellderived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci,2005,25:4694-4705.
[66]Sharp J, Keirstead HS. Stem cell-based cell replacement strategies for the central nervous system. Neurosci Lett,2009,456:107-111.
[67]He J, Liu J, Zhang Z, et al. Expression of fasciculation and elongation protein zeta-1 (FEZ1) in cultured rat neonatal astrocytes. Mol Cell Biochem.2009, 325(1-2):159-67.
[68]Yan M, Xia C, Niu S, et al. The role of TNF-alpha and its receptors in the production of beta-1,4-galactosyltransferase I mRNA by rat primary type-2 astrocytes. Cell Mol Neurobiol.2008,28(2):223-36.
[69]Yan M, Xia C, Cheng C, et al. The role of TNF-alpha and its receptors in the production of Src-suppressed C kinase substrate by rat primary type-2 astrocytes. Brain Res.2007,1184:28-37.
[70]Yan M, Xia C, Niu S, et al. The role of TNF-alpha and its receptors in the production of beta-1,4 galactosyltransferase I and V mRNAs by rat primary astrocytes. J Mol Neurosci.2007,33(2):155-62.
[71]Zwaka TP, Thomson JA. Homologous recombination in human embryonic stem cells. Nat Biotechnol,2003,21:319-321.
[72]Zou J, Maeder ML, Mali P, et al. Gene targeting of a disease-related gene in human induced pluripotent stem and embryonic stem cells. Cell Stem Cell,2009,5:97-110.
[73]Dunckley T, Huentelman MJ, Craig DW, et al. Whole-genome analysis of sporadic amyotrophic lateral sclerosis. N Engl J Med,2007,357:775-788.
[74]Johnson FO, Atchison WD. The role of environmental mercury, lead and pesticide exposure in development of amyotrophic lateral sclerosis. Neurotoxicology,2009, 30:761-765.
[75]Migliore L, Coppede F. Genetics, environmental factors and the emerging role of epigenetics in neurodegenerative diseases. Mutat Res,2009,667:82-97.
[76]Lee G, Papapetrou EP, Kim H, et al. Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature,2009,461:402-406.
[77]Rubin LL. Stem cells and drug discovery:the beginning of a new era? Cell,2008, 132:549-552.
[78]Friedrich Ben-Nun I, Benvenisty N. Human embryonic stem cells as a cellular model for human disorders. Mol Cell Endocrinol,2006,252:154-159.
[79]Di Giorgio FP, Carrasco MA, Siao MC, et al. Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat Neurosci,2007, 10:608-614.
[80]Nagai M, Re DB, Nagata T, et al. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci,2007,10:615-622.
[81]Yamashita H, Nakamura T, Takahashi T, et al. Embryonic stem cell-derived neuron models of Parkinson's disease exhibit delayed neuronal death. J Neurochem,2006, 98:45-56.
[82]Maehr R, Chen S, Snitow M, et al. Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci U S A,2009,106:15768-15773.
[2]Prados MD and Wilson CB. Neoplasms of the central nervous system. In Cancer Medicine. Holland JF, Bast R, Morton DL, Frei E, Kufe DW, Weichselbaum RR, eds. 1993,1080-1119.
[3]Rainov NO, Ren H. Gene therapy for human malignant brain tumors. Cancer J,2003, 9:180-188.
[4]Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature,1994,367:645-648.
[5]Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res,2003,63:5821-5828.
[6]Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci USA,2003,100:3983-3988.
[7]Reya T, Morrison SJ, Clarke MF, et al. Stem cells, cancer, and cancer stem cells. Nature,2001,414:105-111.
[8]Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature,2006,444:756-760.
[9]Tan BT, Park CY, Ailles LE, et al. The cancer stem cell hypothesis:a work in progress. Lab. Invest,2006,86:1203-1207.
[10]Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell,2007,131:861-72.
[11]Holland EC, Hively WP, DePinho RA, et al. A constitutively active epidermal growth factor receptor cooperates with disruption of Gl cell-cycle arrest pathways to induce glioma-like lesions in mice. Genes Dev,1998,12:3675-3685.
[12]Ding H, Roncari L, Shannon P, et al. Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas. Cancer Res,2001,61:3826-3836.
[13]Weiss WA, Burns MJ, Hackett C, et al. Genetic determinants of malignancy in a mouse model for oligodendroglioma. Cancer Res,2003,63:1589-1595.
[14]Bachoo RM, Maher EA, Ligon KL, et al. Epidermal growth factor receptor and Ink4a/Arf convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell,2002, 1:197-227.
[15]Maher EA, Furnari FB, Bachoo RM, et al. Malignant glioma:genetics and biology of a grave matter. Genes Dev,2001,15:1311-1333.
[16]Laywell ED, Rakic P, Kukekov VG, et al. Identification of a multipotent astrocytic stem cell in the immature and adult mouse brain. Proc. Natl. Acad. Sci. USA,2000, 97:13883-13888.
[17]Reynolds BA, and Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science,1992,255:1707-1710.
[18]Reya T, Morrison SJ, Clarke MF, et al. Stem cells, cancer, and cancer stem cells. Nature,2001,414:105-111.
[19]Gaiano N, Nye JS, and Fishell G. Radial glial identity is promoted by Notchl signaling in the murine forebrain. Neuron,2000,26:395-404.
[20]Anderson DJ, Gage FH, and Weissman IL. Can stem cells cross lineage boundaries? Nat. Med,2001,7:393-395.
[21]Purow BW, Haque RM, Noel MW, et al. Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation. Cancer Res,2005,65:2353-2363.
[22]Jackson EL, Garcia-Verdugo JM, Gil-Perotin S, et al. PDGFR alpha-positive B cells are neural stem cells in the adult SVZ that form glioma-like growths in response to increased PDGF signaling. Neuron,2006,51:187-199.
[23]Kesari S, Ramakrishna N, Sauvageot C, et al. Targeted molecular therapy of malignant gliomas. Curr. Oncol. Rep,2006,8:58-70.
[24]Zhu Y, Guignard F, Zhao D, et al. Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell,2005,8:119-130.
[25]Lim DA, Cha S, Mayo MC, et al. Relationship of glioblastoma multiforme to neural stem cell regions predicts invasive and multifocal tumor phenotype. Neuro-oncol, 2007,9:424-429.
[26]Sanai N, Alvarez-Buylla A, and Berger MS. Neural stem cells and the origin of gliomas. N. Engl. J. Med,2005,353:811-822.
[27]Vescovi AL, Galli R, and Reynolds BA. Brain tumour stem cells. Nat. Rev. Cancer, 2006,6:425-436.
[1]Legler JM, Ries LA, Smith MA, et al. Brain and other central nervous system cancers: recent trends in incidence and mortality. J Natl Cancer Inst,1999,91:1382-1390.
[2]Zalatnai, Tumour microenvironment. Aspects of stromal-parenchymal interaction. In Baronzio Gianfranco, Fiorentini Giammaria, Cogle Christopher R (Eds.), Tumour microenvironment. Aspects of stromal-parenchymal interaction; Cancer Microenviron-ment and Therapeutic Implications, Springer,2009:19-38.
[3]Becher OJ, Holland EC. Genetically engineered models have advantages over xenografts for preclinical studies. Cancer Res,2006,66:3355-3359
[4]Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res,2003,63:5821-5828.
[5]Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature,2006,444:756-60.
[6]Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer, 2005,5:275-84.
[7]Fung K-M, Chikaraishi DM, Theuring F, et al. Molecular phenotype of Simian virus 40 large T antigen-induced primitive neuroectodermal tumors in four different lines of transgenic mice. Lab Invest,1994,70:114-24.
[8]Korf H-W, GOtz W, Herken R, et al. S-antigen and rod-opsin immunoreactions in midline brain neoplasms of transgenic mice:Similarities to pineal cell tumors and certain medulloblastomas in man. J Neuropathol Exp Neurol,1990,49:424-37.
[9]GOtz W, Theuring F, Schachenmayr W, et al. Midline brain tumors in MSV-SV 40 transgenic mice originate from the pineal organ. Acta Neuropathol,1992,83:308-14.
[10]Beier D, Hau P, Proescholdt M, et al. CD133+ and CD133- Glioblastoma-Derived Cancer Stem Cells Show Differential Growth Characteristics and Molecular Profiles. Cancer Res,2007,67:4010-4015.
[11]Bao S, Wu Q, Sathornsumetee S,, et al. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res.2006, 66:7843-7848.
[12]Feng Li, Benjamin Tiede, Joan Massague, et al. Beyond tumorigenesis:cancer stem cells in metastasis, Cell Research,2007,17:3-14.
[13]Galli R, Binda E, Orfanelli U, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res,2004,64: 7011-7021.
[14]李茗初,邓永文,伍军,等.髓母细胞瘤中脑肿瘤干细胞的分离培养及鉴定.癌症,2006,25(2)：241-246.
[15]Beier D, Wischhusen J, Dietmaier W, et al. CD 133 expression and cancer stem cells predict prognosis in high-grade oligodendroglial tumors. Brain Pathol,2008,18: 370-377.
[16]Eberhart CG. In search of the medulloblast:neural stem cells and embryonal brain tumors. Neurosurg Clin N Am,2007,18:59-69.
[17]Buhren J, Christoph AH, Buslei R, et al. Expression of the neurotrophin receptor p75NTR in medulloblastomas is correlated with distinct histological and clinical features:evidence for a medulloblastoma subtype derived from the external granule cell layer. J Neuropathol Exp Neurol,2000,59:229-240.
[18]Salsano E, Pollo B, Eoli M, et al. Expression of MATH1, a marker of cerebellar granule cell progenitors, identifies different medulloblastoma subtypes. Neurosci. Lett,2004,370:180-185.
[19]Yokota N, Aruga J, Takai S, et al. Predominant expression of human zic in cerebellar granule cell lineage and medulloblastoma. Cancer Res,1996,56:377-383.
[20]Pomeroy SL, Sutton ME, Goumnerova LC, et al. Neurotrophins in cerebellar granule cell development and medulloblastoma. J. Neurooncol,1997,35:347-352.
[21]Hemmati HD, Nakano I, Lazareff JA, et al. Cancerous stem cells can arise from pediatric brain tumors. Proc. Natl. Acad. Sci. USA,2003,100:15178-15183.
[22]Gilbertson RJ, and Ellison DW. The origins of medulloblastoma subtypes. Annu. Rev. Pathol,2008,3:341-365.
[23]Yang ZJ, Ellis T, Markant SL, et al. Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer Cell,2008, 14:135-45.
[24]Gossen M, Bujard H. Tight control of gene expression in mammalian cells by tetracycline responsive promotors. Proc Natl Acad Sci USA,1992,89:5547-5551.
[25]Gossen M, Freundlieb S, Bender G et al. Transcriptional activation by tetracyclines in mammalian cells. Science,1995,268:1766-1769.
[26]Christofori G, Hanahan D. Molecular dissection of multi-stage tumorigenesis in transgenic mice. Semin Cancer Biol,1994,5:3-12
[27]Blondal JA, Benchimol S. The role of p53 in tumor progression. Semin Cancer Biol 1999,5:177-86.
[28]Symonds H, Krall L, Remington L, et al. p53-dependent apoptosis suppresses tumor growth and progression in vivo. Cell,1994,78:703-11.
[29]Vita M, Henriksson M. The Myc oncoprotein as a therapeutic target for human cancer. Semin Cancer Biol,2006,16:318-330.
[30]Murphy MJ, Wilson A, Trumpp A. More than just proliferation:Myc function in stem cells. Trends Cell Biol,2005,15:128-137.
[31]Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell,2006,126: 663-676.
[32]Nakagawa M, Koyanagi M, Tanabe K, et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol,2008, 26:101-106.
[33]Wilson A, Murphy MJ, Oskarsson T, et al. c-myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev,2004, 18:2747-2763.
[34]Herms JW, von Loewenich FD, Behnke J, et al. c-myc oncogene family expression in glioblastoma and survival. Surg Neurol,1999,51:536-542.
[35]Jensen NA, Pedersen KM, Lihme F, et al. Astroglial c-myc overexpression predisposes mice to primary malignant gliomas. J Biol Chem 2003,278:8300-8308.
[36]Wang J, Wang H, Li Z, et al. C-myc is required for maintenance of glioma cancer stem cells. PLoS One,2008,3:3769.
[1]Reynolds BA, and Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian nervous system. Science,1992,255:1707-1710.
[2]Lois C and Alvarez-Buylla A. Proliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia. Proc Natl Acad Sci., 1993,90:2074-2077.
[3]Morshead CM, Reynolds BA, Craig CG, et al. Neural stem cells in the adult mammalian forebrain:a relatively quiescent subpopulation of subependymal cells. Neuron,1994,13:1071-1082.
[4]Weiss S, Dunne C, Hewson J, et al. Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J Neurosci.,1996,16: 7599-7609.
[5]Palmer TD, Takahashi J, and Gage FH. The adult rat hippocampus contains primordial neural stem cells. Mol Cell Neurosci,1997,8:389-404.
[6]Johansson CB, Momma S, Clarke DL, et al. Identification of a neural stem cell in the adult mammalian central nervous system. Cell,1999,96:25-34.
[7]Lee A, Kessler JD, Read TA, et al. Isolation of neural stem cells from the postnatal cerebellum. Nat Neurosci,2005,8:723-729.
[8]Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature,1994,367:645-648.
[9]Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res,2003,63:5821-5828.
[10]Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci USA,2003,100:3983-3988.
[11]陈骅,黄强,董军,等.肿瘤起源细胞学说与争论.癌症,2006,25：779-784.
[12]吴红,张成香,郑逸梅,等Tet-on系统诱导表达c-myc转基因小鼠的建立.中国兽医学报,2007,27：207-210.
[13]孙敬方.时空表达可控的转基因动物模型调控体系的研究,中国实验动物学报,2005,13：72-75.
[14]Goodell MA, Brose K, Paradis G, et al. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 1996; 183: 1797-1806
[15]Margaret A, Goodell, Stem Cell Identification and Sorting Using the Hoechst 33342 Side Population (SP), Current Protocols in Cytometry.2002:9.18.1-9.18.11
[16]Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, et al, Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness, Proc. Natl Acad. Sci USA,2006,103:11154-11159.
[17]Stevens MC, Cameron AH, Muir KR, et al, Descriptive epidemiology of primary central nervous system tumours in children:a population-based study. Clin Oncol (R Coll Radiol) 1991,3:323-329.
[18]Central Brain Tumor Registry of the United States,2009, http://www.cbtrus.org/ reports/reports.html.
[19]Bailey P, Cushing H. A classification of the tumors of the glioma group on a histogenetic basis with a correlated study of prognosis. Philadelphia:J.B. Lippincott, 1926.
[20]Kleihues P, Louis DN, Scheithauer BW, et al. The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol,2002,61:215-225.
[21]Leon SP, Folkerth RD, Black PM. Microvessel density is a prognostic indicator for patients with astroglial brain tumors. Cancer,1996,77:362-372.
[22]Lacroix M, Abi-Said D, Fourney DR, et al. A multivariate analysis of 416 patients with glioblastoma multiforme:prognosis, extent of resection, and survival. J Neurosurg,2001,95:190-198.
[23]Hammoud MA, Sawaya R, Shi W, et al. Prognostic significance of preoperative MRI scans in glioblastoma multiforme. J Neurooncol 1996,27:65-73.
[24]Morrison SJ, Shah NM and Anderson DJ. Regulatory mechanisms in stem cell biology. Cell,1997,88:287-298
[25]Galderisi U, Jori FP and Giordano A. Cell cycle regulation and neural differentiation. Oncogene,2003,22:5208-5219
[26]Valk-Lingbeek ME, Bruggeman SW and van Lohuizen M. Stem cells and cancer; the polycomb connection. Cell,2004,118:409-418
[27]Dai C, Celestino J C, Okada Y, et al. PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes Dev,2001,15:1913-1925.
[28]Bachoo RM, Maher EA, Ligon KL, et al. Epidermal growth factor receptor and Ink4a/Arf:convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell,2002, 1:269-277.
[29]Uhrbom L, Dai C, Celestino JC, et al. Holland EC. Ink4a-Arf loss cooperates with KRas activation in astrocytes and neural progenitors to generate glioblastomas of various morphologies depending on activated Akt. Cancer Res.2002,62:5551-5558.
[30]Heikens J, Michiels EM, Behrendt H, et al. Long-term neuro-endocrine sequelae after treatment for childhood medulloblastoma. Eur J Cancer.1998,34:1592-1597.
[31]Mulhern, R.K., Palmer, S.L., Merchant, T.E, et al. Neurocognitive consequences of risk-adapted therapy for childhood medulloblastoma. J Clin Oncol,2005,23: 5511-5519.
[32]Packer, R.J., Cogen, P., Vezina, G, et al. Medulloblastoma:clinical and biologic aspects. Neuro-oncol,1999,1:232-250.
[33]Eberhart CG. In search of the medulloblast:neural stem cells and embryonal brain tumors. Neurosurg Clin N Am,2007,18:59-69.
[34]Read TA, Hegedus B, Wechsler-Reya R, et al. The neurobiology of neurooncology. Ann Neurol,2006,60:3-11.
[35]Buhren J, Christoph AH, Buslei R, et al. Expression of the neurotrophin receptor p75NTR in medulloblastomas is correlated with distinct histological and clinical features:evidence for a medulloblastoma subtype derived from the external granule cell layer. J Neuropathol Exp Neurol,2000,59:229-240.
[36]Pomeroy SL, Sutton ME, Goumnerova LC, et al. Neurotrophins in cerebellar granule cell development and medulloblastoma. J Neurooncol,1997,35:347-352.
[37]Salsano E, Pollo B, Eoli M, et al. Expression of MATH1, a marker of cerebellar granule cell progenitors, identifies different medulloblastoma sub-types. Neurosci. Lett,2004,370:180-185.
[38]Yokota N, Aruga J, Takai S, et al. Predominant expression of human zic in cerebellar granule cell lineage and medulloblastoma. Cancer Res,1996,56:377-383.
[39]Hemmati HD, Nakano I, Lazareff JA, et al. Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA,2003,100:15178-15183.
[40]Yang ZJ, Ellis T, Markant SL, et al. Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer Cell,2008,14:135-45.
[41]Alcantara Llaguno S, Chen J, Kwon CH, et al. Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. Cancer Cell,2009,15:45-56.
[42]Zheng H, Ying H, Yan H, et al. Pten and p53 converge on c-Myc to control differentiation, self-renewal, and transformation of normal and neoplastic stem cells in glioblastoma. Cold Spring Harb Symp Quant Biol,2008,73:427-437.
[1]Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature,1994,367:645-648.
[2]Bonnet D, Dick J E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Med,1997,3:730-737.
[3]Sutherland HJ, Blair A, Zapf RW. Characterization of a hierarchy in human myeloid leukemia progenitor cells. Blood,1996,87:4754-4761.
[4]Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res,2003,63:5821-5828.
[5]Al-Hajj M, Clarke MF. Self-renewal and solid tumor stem cells. Oncogene,2004, 23:7274-7282.
[6]Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA,2003,100:3983-3988.
[7]王金鹏,黄强,张全斌,等.人脑胶质瘤干细胞SHG44s的克隆及初步鉴定.中国肿瘤临床,2005,3：604-607.
[8]黄强,朱玉德,董军,等.人脑胶质瘤组织中分离与培养肿瘤干细胞.中华肿瘤杂志,2006,28：15-17.
[9]Bjerkvig R, Tysnes BB, Aboody KS, et al, The origin of the cancer stem cell:current controversies and new insights, Nat Rev Cancer,2005,5:899-904.
[10]吴红,张成香,郑逸梅,等Tet-on系统诱导表达c-myc转基因小鼠的建立.中国兽医学报,2007,27：207-210.
[11]孙敬方.时空表达可控的转基因动物模型调控体系的研究.中国实验动物学报,2005,13：72-75.
[12]Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, et al, Ovarian cancer side population defines cells with stem cell-like characteristics and mullerian inhibiting substance responsiveness. Proc Natl Acad Sci USA,2006,6:11154-11159.
[13]Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature,2004,432:396-401.
[14]Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature,2006,444:687-688.
[15]储亮,黄强,董军,等.肿瘤千细胞的耐药性及其治疗策略.中国新药与临床杂志,2006,25：868-872.
[16]Alvarez-Buylla A, Lim DA. For the long run:maintaining germinal niches in the adult brain. Neuron,2004,41:683-686.
[17]Gage FH. Mammalian neural stem cells. Science,2000,287:1433-1438.
[18]Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell,2008,132:645-660.
[19]Eriksson PS, Perfilieva E, Bjork-Eriksson T, et al. Neurogenesis in the adult human hippocampus. Nat Med,1998,4:1313-1317.
[20]Sanai N, Tramontin AD, Quinones-Hinojosa A, et al. Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature,2004, 427:740-744.
[21]Wang J, Wang H, Li Z, et al. c-myc is required for maintenance of glioma cancer stem cells. PLoS One,2008,3:3769.
[22]Strasser A, Harris AW, Bath ML, et al. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature,1990,348:331-333.
[23]Jacobs JJ, Scheijen B, Voncken JW, et al. Bmi-1 collaborates with c-myc in tumorigenesis by inhibiting c-myc-induced apoptosis via INK4a/ARF. Genes Dev, 1999,13:2678-2690.
[24]Eischen CM, Weber JD, Roussel MF, et al. Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dev,1999,13:2658-2669.
[25]Arvanitis C, Felsher DW. Conditional transgenic models define how MYC initiates and maintains tumorigenesis. Semin Cancer Biol,2006,16:313-317.
[26]Shachaf CM, Kopelman AM, Arvanitis C, et al. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature, 2004,431:1112-1117.
[27]Dahlstrand J, Collins VP, Lendahl U. Expression of the class VI intermediate filament nestin in human central nervous system tumors. Cancer Res,1992,52:5334-5341.
[28]Toda M, Iizuka Y, Yu W, et al. Expression of the neural RNA-binding protein Musashil in human gliomas. Glia,2001,34:1-7.
[29]Ignatova TN, Kukekov VG, Laywell ED, et al. Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia,2002, 39:193-206.
[30]Bouvier C, Bartoli C, Aguirre-Cruz L, et al. Shared oligodendrocyte lineage gene expression in gliomas and oligodendrocyte progenitor cells. J Neurosurg,2003,99:344-350.
[31]Holland EC. A mouse model for glioma:biology, pathology, and therapeutic opportunities. Toxicol Pathol,2001,28:171-177.
[32]von Deimling A, Eibl RH, Ohgaki H, et al. p53 mutations are associated with 17p allelic loss in grade II and grade III astrocytoma. Cancer Res,1992,52:2987-2990.
[33]Watanabe K, Tachibana O, Sata K, et al. Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol,1996,6:217-223.
[34]Hayashi Y, Yamashita J, Watanabe T. Molecular genetic analysis of deep-seated glioblastomas. Cancer Genet Cytogenet,2004,153:64-68.
[35]van Lookeren Campagne M, Gill R. Tumor-suppressor p53 is expressed in proliferating and newly formed neurons of the embryonic and postnatal rat brain: comparison with expression of the cell cycle regulators p21Wafl/Cipl, p27Kip1, p57Kip2, pl6Ink4a, cyclin G1, and the protooncogene bax. J Comp Neurol,1998, 397:181-198.
[36]Gil-Perotin S, Marin-Husstege M, Li J, et al, Loss of p53 induces changes in the behavior of subventricular zone cells:implication for the genesis of glial tumors. J Neurosci,2006,26:1107-16.
[1]Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonic stem cell lines derived from human blastocysts. Science,1998,282:1145-1147.
[2]Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell,2007,131:861-872.
[3]Jaenisch R. Human cloning—the science and ethics of nuclear transplantation. N Engl J Med,2004,351:2787-2791.
[4]Byrne JA, Pedersen DA, Clepper LL, et al. Producing primate embryonic stem cells by somatic cell nuclear transfer. Nature,2007,450:497-502.
[5]Rideout WM III, Hochedlinger K, Kyba M, et al. Correction of a genetic defect by nuclear transplantation and combined cell and gene therapy. Cell,2002,109:17-27.
[6]Cowan CA, Atienza J, Melton DA, et al. Nuclear reprogramming of somatic cells after fusion with human embryonic stem cells. Science,2005,309:1369-1373.
[7]Kanatsu-Shinohara M, Inoue K, Lee J, et al. Generation of pluripotent stem cells from neonatal mouse testis. Cell,2004,119:1001-1012.
[8]Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell,2006,126:663-676.
[9]Tokuzawa Y, Kaiho E, Maruyama M, et al. Fbx15 is a novel target of Oct3/4 but is dispensable for embryonic stem cell selfrenewal and mouse development. Mol Cell Biol,2003,23:2699-2708.
[10]Maherali N, Sridharan R, Xie W, et al. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell, 2007,1:55-70.
[11]Meissner A, Wernig M, Jaenisch R. Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells. Nat Biotechnol,2007,25:1177-1181.
[12]Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature,2007,448:313-317.
[13]Wernig M, Meissner A, Foreman R, et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature,2007,448:318-324.
[14]Park IH, Zhao R, West JA, et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature,2008,451:141-146.
[15]Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science,2007,318:1917-1920.
[16]Dimos JT, Rodolfa KT, Niakan KK, et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science,2008, 321:1218-1221.
[17]Park IH, Arora N, Huo H, et al. Disease-specific induced pluripotent stem cells. Cell, 2008,134:877-886.
[18]Ebert AD, Yu J, Rose FF Jr, et al. Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature,2009,457:277-280.
[19]Jaenisch R, Bird A. Epigenetic regulation of gene expression:how the genome integrates intrinsic and environmental signals. Nat Genet,2003,33:245-254.
[20]Hemberger M, Dean W, Reik W. Epigenetic dynamics of stem cells and cell lineage commitment:digging Waddington's canal. Nat Rev Mol Cell Biol,2009, 10:526-537.
[21]Egli D, Birkhoff G, Eggan K. Mediators of reprogramming:transcription factors and transitions through mitosis. Nat Rev Mol Cell Biol,2008,9:505-516.
[22]Nichols J, Zevnik B, Anastassiadis K, et al. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell,1998, 95:379-391.
[23]Avilion AA, Nicolis SK, Pevny LH, et al. Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev,2003,17:126-140.
[24]Chambers I, Silva J, Colby D, et al. Nanog safeguards pluripotency and mediates germline development. Nature,2007,450:1230-1234.
[25]Mitsui K, Tokuzawa Y, Itoh H, et al. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell,2003, 113:631-642.
[26]Sridharan R, Tchieu J, Mason MJ, et al. Role of the murine reprogramming factors in the induction of pluripotency. Cell,2009,136:364-377.
[27]Stadtfeld M, Nagaya M, Utikal J, et al. Hochedlinger K. Induced pluripotent stem cells generated without viral integration. Science,2008,322:945-949.
[28]Okita K, Nakagawa M, Hyenjong H, et al. Generation of mouse induced pluripotent stem cells without viral vectors. Science,2008,322:949-953.
[29]Zhou H, Wu S, Joo JY, et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell,2009,4:381-384.
[30]Kim D, Kim CH, Moon JI, et al. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell,2009,4:472-476.
[31]Yu J, Hu K, Smuga-Otto K, et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science,2009,324:797-801.
[32]Hanna J, Markoulaki S, Schorderet P, et al. Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency. Cell,2008,133:250-264.
[33]Mikkelsen TS, Hanna J, Zhang X, et al. Dissecting direct reprogramming through integrative genomic analysis. Nature,2008,454:49-55.
[34]Soldner F, Hockemeyer D, Beard C, et al. Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell,2009, 136:964-977.
[35]Amabile G, Meissner A. Induced pluripotent stem cells:current progress and potential for regenerative medicine. Trends Mol Med,2009,15:59-68.
[36]Marion RM, Strati K, Li H, et al. Telomeres acquire embryonic stem cell characteristics in induced pluripotent stem cells. Cell Stem Cell,2009,4:141-154.
[37]Chin MH, Mason MJ, Xie W, et al. Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell,2009, 5:111-123.
[38]Chen AE, Egli D, Niakan K, et al. Optimal timing of inner cell mass isolation increases the efficiency of human embryonic stem cell derivation and allows generation of sibling cell lines. Cell Stem Cell,2009,4:103-106.
[39]Brambrink T, Hochedlinger K, Bell G, et al. ES cells derived from cloned and fertilized blastocysts are transcriptionally and functionally indistinguishable. Proc Natl Acad Sci U S A,2006,103:933-938.
[40]Boland MJ, Hazen JL, Nazor KL, et al. Adult mice generated from induced pluripotent stem cells. Nature,2009,461:91-94.
[41]Kang L, Wang J, Zhang Y, et al. iPS cells can support full-term development of tetraploid blastocyst-complemented embryos. Cell Stem Cell,2009,5:135-138.
[42]Zhao XY, Li W, Lv Z, et al. iPS cells produce viable mice through tetraploid complementation. Nature,2009,461:86-90.
[43]Aoi T, Yae K, Nakagawa M, et al. Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science,2008,321:699-702.
[44]Stadtfeld M, Brennand K, Hochedlinger K. Reprogramming of pancreatic beta cells into induced pluripotent stem cells. Curr Biol,2008,18:890-894.
[45]Eminli S, Utikal J, Arnold K, et al. Reprogramming of neural progenitor cells into induced pluripotent stem cells in the absence of exogenous Sox2 expression. Stem Cell,2008,26:2467-2474.
[46]Aasen T, Raya A, Barrero MJ, et al. Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol,2008, 26:1276-1284.
[47]Loh YH, Agarwal S, Park IH, et al. Generation of induced pluripotent stem cells from human blood. Blood,2009,113:5476-5479.
[48]Sun N, Panetta NJ, Gupta DM, et al. Feeder-free derivation of induced pluripotent stem cells from adult human adipose stem cells. Proc Natl Acad Sci U S A, 2009,106:15720-15725
[49]Raya A, Rodriguez-Piza I, Guenechea G, et al. Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature,2009, 460:53-59.
[50]Eminli S, Foudi A, Stadtfeld M, et al. Differentiation stage determines potential of hematopoietic cells for reprogramming into induced pluripotent stem cells. Nat Genet,2009,41:968-976.
[51]Huangfu D, Maehr R, Guo W, et al. Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat Biotechnol,2008, 26:795-797.
[52]Huangfu D, Osafune K, Maehr R, et al. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol,2008, 26:1269-1275.
[53]Shi Y, Do JT, Desponts C, et al. A combined chemical and genetic approach for the generation of induced pluripotent stem cells. Cell Stem Cell,2008,2:525-528.
[54]Shi Y, Desponts C, Do JT, et al. Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds. Cell Stem Cell,2008,3:568-574.
[55]Ichida JK, Blanchard J, Lam K,, et al. A small-molecule inhibitor of Tgfbeta signaling replaces Sox2 in reprogramming by inducing Nanog. Cell Stem Cell.2009, 5:491-503
[56]Hacein-Bey-Abina S, Garrigue A, Wang GP, et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest.2008, 118:3132-3142.
[57]Nakagawa M, Koyanagi M, Tanabe K, et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol,2008, 26:101-106.
[58]Kaji K, Norrby K, Paca A, et al. Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature,2009,458:771-775.
[59]Woltjen K, Michael IP, Mohseni P, et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature,2009,458:766-770.
[60]Gonzalez F, Barragan Monasterio M, Tiscornia G, et al. Generation of mouse-induced pluripotent stem cells by transient expression of a single nonviral polycistronic vector. Proc Natl Acad Sci USA,2009,106:8918-8922.
[61]Murry CE, Keller G. Differentiation of embryonic stem cells to clinically relevant populations:lessons from embryonic development. Cell,2008,132:661-680.
[62]Lamba DA, Gust J, Reh TA. Transplantation of human embryonic stem cell-derived photoreceptors restores some visual function in Crx-deficient mice. Cell Stem Cell, 2009,4:73-79.
[63]Yang D, Zhang ZJ, Oldenburg M, et al. Human embryonic stem cell-derived dopaminergic neurons reverse functional deficit in parkinsonian rats. Stem Cells, 2008,26:55-63.
[64]Kim JH, Auerbach JM, Rodriguez-Gomez JA, et al. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease. Nature, 2002,418:50-56.
[65]Keirstead HS, Nistor G, Bernal G, et al. Human embryonic stem cellderived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci,2005,25:4694-4705.
[66]Sharp J, Keirstead HS. Stem cell-based cell replacement strategies for the central nervous system. Neurosci Lett,2009,456:107-111.
[67]He J, Liu J, Zhang Z, et al. Expression of fasciculation and elongation protein zeta-1 (FEZ1) in cultured rat neonatal astrocytes. Mol Cell Biochem.2009, 325(1-2):159-67.
[68]Yan M, Xia C, Niu S, et al. The role of TNF-alpha and its receptors in the production of beta-1,4-galactosyltransferase I mRNA by rat primary type-2 astrocytes. Cell Mol Neurobiol.2008,28(2):223-36.
[69]Yan M, Xia C, Cheng C, et al. The role of TNF-alpha and its receptors in the production of Src-suppressed C kinase substrate by rat primary type-2 astrocytes. Brain Res.2007,1184:28-37.
[70]Yan M, Xia C, Niu S, et al. The role of TNF-alpha and its receptors in the production of beta-1,4 galactosyltransferase I and V mRNAs by rat primary astrocytes. J Mol Neurosci.2007,33(2):155-62.
[71]Zwaka TP, Thomson JA. Homologous recombination in human embryonic stem cells. Nat Biotechnol,2003,21:319-321.
[72]Zou J, Maeder ML, Mali P, et al. Gene targeting of a disease-related gene in human induced pluripotent stem and embryonic stem cells. Cell Stem Cell,2009,5:97-110.
[73]Dunckley T, Huentelman MJ, Craig DW, et al. Whole-genome analysis of sporadic amyotrophic lateral sclerosis. N Engl J Med,2007,357:775-788.
[74]Johnson FO, Atchison WD. The role of environmental mercury, lead and pesticide exposure in development of amyotrophic lateral sclerosis. Neurotoxicology,2009, 30:761-765.
[75]Migliore L, Coppede F. Genetics, environmental factors and the emerging role of epigenetics in neurodegenerative diseases. Mutat Res,2009,667:82-97.
[76]Lee G, Papapetrou EP, Kim H, et al. Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature,2009,461:402-406.
[77]Rubin LL. Stem cells and drug discovery:the beginning of a new era? Cell,2008, 132:549-552.
[78]Friedrich Ben-Nun I, Benvenisty N. Human embryonic stem cells as a cellular model for human disorders. Mol Cell Endocrinol,2006,252:154-159.
[79]Di Giorgio FP, Carrasco MA, Siao MC, et al. Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat Neurosci,2007, 10:608-614.
[80]Nagai M, Re DB, Nagata T, et al. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci,2007,10:615-622.
[81]Yamashita H, Nakamura T, Takahashi T, et al. Embryonic stem cell-derived neuron models of Parkinson's disease exhibit delayed neuronal death. J Neurochem,2006, 98:45-56.
[82]Maehr R, Chen S, Snitow M, et al. Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci U S A,2009,106:15768-15773.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |