体细胞直接重编程为神经元和神经干细胞

doi:10.13560/j.cnki.biotech.bull.1985.2015.07.037

摘要/Abstract

摘要： 体细胞直接重编程是由已分化细胞类型不经过诱导型多能干细胞(Induced pluripotent stem cells，iPSCs)中间阶段，直接转换为另一种细胞类型的重编程过程。体细胞直接重编程避免了iPSC技术存在的重编程效率低下、引入致癌基因等多种缺陷，并为细胞替换治疗和个性化医药研发设想贡献了新的实现途径。现代医学对于诸如神经退行性疾病、神经遗传疾病和外伤导致的神经细胞受损等一些神经系统疾病一直没有有效的治疗手段。而体细胞直接重编程为治疗这些疾病提供了另一种治疗途径，因此体细胞直接重编程为神经细胞相关领域迅速成为研究热点。回顾了体细胞重编程为诱导型神经元(Induced neurons，iNs)和诱导型神经干细胞(Induced neural stem cells，iNSCs)的最新研究进展，并探讨iNs和iNSCs在临床应用上的各自优势、局限性及应用前景。

关键词: 诱导型神经元, 诱导型神经干细胞, 成纤维细胞, 直接重编程, 诱导转分化

Abstract: The direct reprogramming of somatic cells is a process that one differentiated cell type can be directly converted into another kind of differentiated cell type，which bypasses the phase of induced pluripotent stem cells(iPSCs). Compared with the iPSC technology，the direct reprogramming of somatic cells has higher efficiency of reprogramming，and avoids introducing oncogenes.Modern medicine has no effective treatment for nerve cell damage which due to neurodegenerative diseases，neurological genetic diseases and traumatism. Somatic cells directly reprogramming into neural cells may provide another way to treat these diseases. Recently，several studies have shown that the ectopic expression of specific neural and pluripotent stem cell transcription factors can directly convert differentiated cells into induced neurons(iNs)and induced neural stem cells(iNSCs). Here，we will review the most recent progress in the somatic cells directly reprogramming into iNs and iNSCs and also discuss the application of iNs and iNSCs in future.

Key words: induced neurons, induced neural stem cells, fibroblasts, direct reprogramming, induced transdifferentiation

周桢宁. 体细胞直接重编程为神经元和神经干细胞[J]. 生物技术通报, 2015, 31(7): 26-32.

Zhou Zhenning. Direct Reprogramming of Somatic Cells into Neurons and Neural Stem Cells[J]. Biotechnology Bulletin, 2015, 31(7): 26-32.

参考文献

[1]Bain G, Kitchens D, Yao M, et al. Embryonic stem cells express neuronal properties in vitro[J]. Dev Biol, 1995, 168：342-357.
[2]Kawasaki H, Mizuseki K, Nishikawa S, et al. Induction of midbrain dopaminergic neurons from ES cells by stromal cell-derived inducing activity[J]. Neuron, 2000, 28(1)：31-40.
[3]Lee SH, Lumelsky N, Studer L, et al. Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells[J]. Nat Biotechnol, 2000, 18(6)：675-679.
[4]Okabe S, Forsberq-Nilsson K, Spiro AC, et al. Development of neuronal precursor cells and functional postmitotic neurons from embryonic stem cells in vitro[J]. Mech Dev, 1996, 59：89-102.
[5]Cohen CB. Ethical and policy issues surrounding the donation of cryopreserved and fresh embryos for human embryonic stem cell research[J]. Stem Cell Rev, 2009, 5(2)：116-122.
[6]Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors[J]. Cell, 2006, 126(4)：663-676.
[7]Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors[J]. Cell, 2007, 131(5)：861-872.
[8]Park IH, Arora N, Huo H, et al. Disease-specific induced pluripotent stem cells[J]. Cell, 2008, 134(5)：877-886.
[9]Urbach A, Bar-Nur O, Daley GQ, et al. Differential modeling of fragile X syndrome by human embryonic stem cells and induced pluripotent stem cells[J]. Cell Stem Cell, 2010, 6(5)：407-411.
[10]Marchetto MC, Carromeu C, Acab A, et al. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells[J]. Cell, 2010, 143(4)：527-539.
[11]Caiazzo M, Dell'Anno MT, Dvoretskova E, et al. Direct generation of functional dopaminergic neurons from mouse and human fibroblasts[J]. Nature, 2011, 476：224-227.
[12]Dimos JT, Rodolfa KT, Niakan KK, et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons[J]. Science, 2008, 321(5893)：1218-1221.
[13]Vierbuchen T, Ostermeier A, Pang ZP, et al. Direct conversion of fibroblasts to functional neurons by defined factors[J]. Nature, 2010, 463：1035-1041.
[14]Hermann A, Storch A. Induced neural stem cells(iNSCs)in neurodegenerative diseases[J]. J Neural Transm, 2013, 120(Suppl 1)：S19-S25.
[15]Marro S, Pang ZP, Yang N, et al. Direct lineage conversion of terminally differentiated hepatocytes to functional neurons[J]. Cell Stem Cell, 2011, 9：374-382.
[16]Ambasudhan R, Talantova M, Coleman R, et al. Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions[J]. Cell Stem Cell, 2011, 9：113-118.
[17]Pfisterer U, Kirkeby A, Torper O, et al. Direct conversion of human fibroblasts to dopaminergic neurons[J]. Proc Natl Acad Sci USA, 2011, 108：10343-10348.
[18]Pang ZP, Yang N, Vierbuchen T, et al. Induction of human neuronal cells by defined transcription factors[J]. Nature, 2011, 476：220-223.
[19]Yoo AS, Sun AX, Li L, et al. MicroRNA-mediated conversion of human fibroblasts to neurons[J]. Nature, 2011, 476：228-231.
[20]Son EY, Ichida JK, Wainger BJ, et al. Conversion of mouse and human fibroblasts into functional spinal motor neurons[J]. Cell Stem Cell, 2011, 9：205-218.
[21]Maisel M, Habisch HJ, Royer L, et al. Genome-wide expression profiling and functional network analysis upon neuroectodermal conversion of human mesenchymal stem cells suggest HIF-1 and miR-124a as important regulators[J]. Exp Cell Res, 2010, 316(17)：2760-2778.
[22] Xue Y, Ouyang K, Huang J, et al. Direct conversion of fibroblasts to neurons by reprogramming PTB-regulated microRNA circuits[J]. Cell, 2013, 152(1-2)：82-96.
[23]Brambrink T, Foreman R, Welstead GG, et al. Sequential expression of pluripotency markers during direct reprogramming of mouse somatic cells[J]. Cell Stem Cell, 2008, 27(2)151-159.
[24]Hanna J, Saha K, Pando B, et al. Direct cell reprogramming is a stochastic process amenable to acceleration[J]. Nature, 2009, 462(7273)595-601.
[25]Stadtfeld M, Maherali N, Breault D. T, et al. Defining molecular cornerstones during fibroblast to iPS cell reprogramming in mouse[J]. Cell Stem Cell, 2008, 2(3)230-240.
[26]Stadtfeld M, Nagaya M, Utikal J, et al. Induced pluripotent stem cells generated without viral integration[J]. Science, 2008b, 322(5903)945-949.
[27]Kim J, Efe JA, Zhu S, et al. Direct reprogramming of mouse fibroblasts to neural progenitors[J]. Proc Natl Acad Sci USA, 2011, 108(19)7838-7843.
[28]Thier M, W?rsd?rfer P, Lakes YB, et al. Direct conversion of fibroblasts into stably expandable neural stem cells[J]. Cell Stem Cell, 2012, 10(4)473-479.
[29]Han DW, Tapia N, Hermann A, et al. Direct reprogramming of fibroblasts into neural stem cells by defined factors[J]. Cell Stem Cell, 2012, 10(4)465-472.
[30]Lujan E, Chanda S, Ahlenius H, et al. Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells[J]. Proc Natl Acad Sci USA, 2012, 109(7)2527-2532.
[31]Ring KL, Tong LM, Balestra ME, et al. Direct reprogramming of mouse and human fibroblasts into multipotent neural stem cells with a single factor[J]. Cell Stem Cell, 2012, 11(1)100-109.
[32]Stadtfeld M, Nagaya M, Utikal J, et al. Induced pluripotent stem cells generated without viral integration[J]. Science, 2008, 322(5903)：945-949.
[33]Yu J, Hu K, Smuga-Otto K, et al. Human induced pluripotent stem cells free of vector and transgene sequences[J]. Science, 2009, 324(5928)：797-801.
[34]Kaji K, Norrby K, Paca A, et al. Virus-free induction of pluripotency and subsequent excision of reprogramming factors[J]. Nature, 2009, 458(7239)：771-775.
[35]Okita K, Nakagawa M, Hyenjong H, et al. Generation of mouse induced pluripotent stem cells without viral vectors[J]. Science, 2008, 322(5903)：949-953.
[36]Soldner F, Hockemeyer D, Beard C, et al. Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors[J]. Cell, 2009, 136(5)：964-977.
[37]Zhou H, Wu S, Joo JY, et al. Generation of induced pluripotent stem cells using recombinant proteins[J]. Cell Stem Cell, 2009, 4(5)：381-384.
[38]Kim D, Kim CH, Moon JI, et al. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins[J]. Cell Stem Cell, 2009, 4(6)：472-476.
[39]Warren L, Manos PD, Ahfeldt T, et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA[J]. Cell Stem Cell, 2010, 7(5)：618-630.
[40]Chen S, Zhang Q, Wu X, et al. Dedifferentiation of lineage-committed cells by a small molecule[J]. J Am Chem Soc, 2004, 126(2)：410-411.
[41]Huangfu D, Maehr R, Guo W, et al. Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds[J]. Nat Biotechnol, 2008, 26(7)：795-797.
[42]Anokye-Danso F, Trivedi CM, Juhr D, et al. Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency[J]. Cell Stem Cell, 2011, 8(4)：376-388.