Induced pluripotency and direct reprogramming: a new window for treatment of neurodegenerative diseases

Abstract

Human embryonic stem cells (hESCs) are pluripotent cells that have the ability of unlimited self-renewal and can be differentiated into different cell lineages, including neural stem (NS) cells. Diverse regulatory signaling pathways of neural stem cells differentiation have been discovered, and this will be of great benefit to uncover the mechanisms of neuronal differentiation in vivo and in vitro. However, the limitations of hESCs resource along with the religious and ethical concerns impede the progress of ESCs application. Therefore, the induced pluripotent stem cells (iPSCs) via somatic cell reprogramming have opened up another new territory for regenerative medicine. iPSCs now can be derived from a number of lineages of cells, and are able to differentiate into certain cell types, including neurons. Patient-specific iPSCs are being used in human neurodegenerative disease modeling and drug screening. Furthermore, with the development of somatic direct reprogramming or lineage reprogramming technique, a more effective approach for regenerative medicine could become a complement for iPSCs.

Keywords

human embryonic stem cells (hESCs) / neuronal differentiation / induced pluripotent stem cells (iPSCs) / somatic direct reprogramming / lineage reprogramming / regenerative medicine

References

[1] Aasen, T., Raya, A., Barrero, M.J., Garreta, E., Consiglio, A., Gonzalez, F., Vassena, R., Bilic, J., Pekarik, V., Tiscornia, G., . (2008). Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol 26, 1276-1284 .10.1038/nbt.1503
[2] Altman, J., and Das, G.D. (1965). Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 124, 319-335 .10.1002/cne.901240303
[3] Ambasudhan, R., Talantova, M., Coleman, R., Yuan, X., Zhu, S., Lipton, S.A., and Ding, S. (2011). Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions. Cell Stem Cell 9, 113-118 .10.1016/j.stem.2011.07.002
[4] Ambros, V. (2003). MicroRNA pathways in fl ies and worms: growth, death, fat, stress, and timing. Cell 113, 673-676 .10.1016/S0092-8674(03)00428-8
[5] Ambros, V. (2004). The functions of animal microRNAs. Nature 431, 350-355 .10.1038/nature02871
[6] Aoi, T., Yae, K., Nakagawa, M., Ichisaka, T., Okita, K., Takahashi, K., Chiba, T., and Yamanaka, S. (2008). Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science 321, 699-702 .10.1126/science.1154884
[7] Attisano, L., and Wrana, J.L. (2002). Signal transduction by the TGFbeta superfamily. Science 296, 1646-1647 .10.1126/science.1071809
[8] Avilion, A.A., Nicolis, S.K., Pevny, L.H., Perez, L., Vivian, N., and Lovell-Badge, R. (2003). Multipotent cell lineages in early mouse development depend on SOX2 function. Genes & development 17, 126-140 .10.1101/gad.224503
[9] Botquin, V., Hess, H., Fuhrmann, G., Anastassiadis, C., Gross, M.K., Vriend, G., and Scholer, H.R. (1998). New POU dimer configuration mediates antagonistic control of an osteopontin preimplantation enhancer by Oct-4 and Sox-2. Genes & development 12, 2073-2090 .10.1101/gad.12.13.2073
[10] Boulting, G.L., Kiskinis, E., Croft, G.F., Amoroso, M.W., Oakley, D.H., Wainger, B.J., Williams, D.J., Kahler, D.J., Yamaki, M., Davidow, L., . (2011). A functionally characterized test set of human induced pluripotent stem cells. Nat Biotechnol 29, 279-286 .10.1038/nbt.1783
[11] Boyer, L.A., Lee, T.I., Cole, M.F., Johnstone, S.E., Levine, S.S., Zucker, J.P., Guenther, M.G., Kumar, R.M., Murray, H.L., Jenner, R.G., . (2005). Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122, 947-956 .10.1016/j.cell.2005.08.020
[12] Brennand, K.J., Simone, A., Jou, J., Gelboin-Burkhart, C., Tran, N., Sangar, S., Li, Y., Mu, Y., Chen, G., Yu, D., . (2011). Modelling schizophrenia using human induced pluripotent stem cells. Nature 473, 221-225 .10.1038/nature09915
[13] Caiazzo, M., Dell’Anno, M.T., Dvoretskova, E., Lazarevic, D., Taverna, S., Leo, D., Sotnikova, T.D., Menegon, A., Roncaglia, P., Colciago, G., . (2011). Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 476, 224-227 .10.1038/nature10284
[14] Chambers, S.M., and Studer, L. (2011). Cell fate plug and play: direct reprogramming and induced pluripotency. Cell 145, 827-830 .10.1016/j.cell.2011.05.036
[15] Chen, J., Liu, J., Yang, J., Chen, Y., Ni, S., Song, H., Zeng, L., Ding, K., and Pei, D. (2011). BMPs functionally replace Klf4 and support efficient reprogramming of mouse fibroblasts by Oct4 alone. Cell Res 21, 205-212 .10.1038/cr.2010.172
[16] Cheng, L.C., Pastrana, E., Tavazoie, M., and Doetsch, F. (2009). miR124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nat Neurosci 12, 399-408 .10.1038/nn.2294
[17] Chin, M.H., Mason, M.J., Xie, W., Volinia, S., Singer, M., Peterson, C., Ambartsumyan, G., Aimiuwu, O., Richter, L., Zhang, J., . (2009). Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell 5, 111-123 .10.1016/j.stem.2009.06.008
[18] Choi, J., Costa, M.L., Mermelstein, C.S., Chagas, C., Holtzer, S., and Holtzer, H. (1990). MyoD converts primary dermal fibroblasts, chondroblasts, smooth muscle, and retinal pigmented epithelial cells into striated mononucleated myoblasts and multinucleated myotubes. Proc Natl Acad Sci U S A 87, 7988-7992 .10.1073/pnas.87.20.7988
[19] Cobaleda, C., Jochum, W., and Busslinger, M. (2007). Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors. Nature 449, 473-477 .10.1038/nature06159
[20] Cordero-Llana, O., Scott, S.A., Maslen, S.L., Anderson, J.M., Boyle, J., Chowhdury, R.R., Tyers, P., Barker, R.A., Kelly, C.M., Rosser, A.E., . (2011). Clusterin secreted by astrocytes enhances neuronal differentiation from human neural precursor cells. Cell Death Differ 18, 907-913 .10.1038/cdd.2010.169
[21] Deng, J., Shoemaker, R., Xie, B., Gore, A., LeProust, E.M., AntosiewiczBourget, J., Egli, D., Maherali, N., Park, I.H., Yu, J., . (2009). Targeted bisulfite sequencing reveals changes in DNA methylation associated with nuclear reprogramming. Nat Biotechnol 27, 353-360 .10.1038/nbt.1530
[22] Denham, M., and Dottori, M. (2009). Signals involved in neural differentiation of human embryonic stem cells. Neurosignals 17, 234-241 .10.1159/000231890
[23] Dessaud, E., McMahon, A.P., and Briscoe, J. (2008). Pattern formation in the vertebrate neural tube: a sonic hedgehog morphogenregulated transcriptional network. Development 135, 2489-2503 .10.1242/dev.009324
[24] Dhara, S.K., and Stice, S.L. (2008). Neural differentiation of human embryonic stem cells. J Cell Biochem 105, 633-640 .10.1002/jcb.21891
[25] Dill, H., Linder, B., Fehr, A., and Fischer, U. (2012). Intronic miR-26b controls neuronal differentiation by repressing its host transcript, ctdsp2. Genes Dev 26, 25-30 .10.1101/gad.177774.111
[26] Dimos, J.T., Rodolfa, K.T., Niakan, K.K., Weisenthal, L.M., Mitsumoto, H., Chung, W., Croft, G.F., Saphier, G., Leibel, R., Goland, R., . (2008). Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321, 1218-1221 .10.1126/science.1158799
[27] Ebert, A.D., Yu, J., Rose, F.F., Jr., Mattis, V.B., Lorson, C.L., Thomson, J.A., and Svendsen, C.N. (2009). Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457, 277-280 .10.1038/nature07677
[28] Elkabetz, Y., and Studer, L. (2008). Human ESC-derived neural rosettes and neural stem cell progression. Cold Spring Harb Symp Quant Biol 73, 377-387 .10.1101/sqb.2008.73.052
[29] Evans, M.J., and Kaufman, M.H. (1981). Establishment in culture of pluripotential cells from mouse embryos. Nature 292, 154-156 .10.1038/292154a0
[30] Gaspard, N., and Vanderhaeghen, P. (2010). Mechanisms of neural specification from embryonic stem cells. Curr Opin Neurobiol 20, 37-43 .10.1016/j.conb.2009.12.001
[31] Goll, M.G., and Bestor, T.H. (2005). Eukaryotic cytosine methyltransferases. Annu Rev Biochem 74, 481-514 .10.1146/annurev.biochem.74.010904.153721
[32] Gonzalez, F., Boue, S., and Izpisua Belmonte, J.C. (2011). Methods for making induced pluripotent stem cells: reprogramming a la carte. Nat Rev Genet 12, 231-242 .10.1038/nrg2937
[33] Guttman, M., Donaghey, J., Carey, B.W., Garber, M., Grenier, J.K., Munson, G., Young, G., Lucas, A.B., Ach, R., Bruhn, L., . (2011). lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature 477, 295-300 .10.1038/nature10398
[34] Han, D.W., Tapia, N., Hermann, A., Hemmer, K., Hoing, S., ArauzoBravo, M.J., Zaehres, H., Wu, G., Frank, S., Moritz, S., . (2012). Direct reprogramming of fibroblasts into neural stem cells by defined factors. Cell Stem Cell 10, 465-472 .10.1016/j.stem.2012.02.021
[35] Hanna, J., Markoulaki, S., Schorderet, P., Carey, B.W., Beard, C., Wernig, M., Creyghton, M.P., Steine, E.J., Cassady, J.P., Foreman, R., . (2008). Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency. Cell 133, 250-264 .10.1016/j.cell.2008.03.028
[36] Hanna, J., Wernig, M., Markoulaki, S., Sun, C.W., Meissner, A., Cassady, J.P., Beard, C., Brambrink, T., Wu, L.C., Townes, T.M., . (2007). Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318, 1920-1923 .10.1126/science.1152092
[37] Hanna, J.H., Saha, K., and Jaenisch, R. (2010). Pluripotency and cellular reprogramming: facts, hypotheses, unresolved issues. Cell 143, 508-525 .10.1016/j.cell.2010.10.008
[38] Hart, A.H., Hartley, L., Ibrahim, M., and Robb, L. (2004). Identification, cloning and expression analysis of the pluripotency promoting Nanog genes in mouse and human. Developmental dynamics : an official publication of the American Association of Anatomists 230, 187-198 .10.1002/dvdy.20034
[39] He, L., and Hannon, G.J. (2004). MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 5, 522-531 .10.1038/nrg1379
[40] Israel, M.A., and Goldstein, L.S. (2011). Capturing Alzheimer’s disease genomes with induced pluripotent stem cells: prospects and challenges. Genome Med 3, 49.10.1186/gm265
[41] Israel, M.A., Yuan, S.H., Bardy, C., Reyna, S.M., Mu, Y., Herrera, C., Hefferan, M.P., Van Gorp, S., Nazor, K.L., Boscolo, F.S., . (2012). Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482, 216-220 .
[42] Joo, K.M., Jin, J., Kang, B.G., Lee, S.J., Kim, K.H., Yang, H., Lee, Y.A., Cho, Y.J., Im, Y.S., Lee, D.S., . (2012). Trans-differentiation of neural stem cells: a therapeutic mechanism against the radiation induced brain damage. PLoS One 7, e25936.10.1371/journal.pone.0025936
[43] Juliandi, B., Abematsu, M., and Nakashima, K. (2010). Chromatin remodeling in neural stem cell differentiation. Curr Opin Neurobiol 20, 408-415 .10.1016/j.conb.2010.04.001
[44] Kang, L., Wang, J., Zhang, Y., Kou, Z., and Gao, S. (2009). iPS cells can support full-term development of tetraploid blastocyst-complemented embryos. Cell Stem Cell 5, 135-138 .10.1016/j.stem.2009.07.001
[45] Karumbayaram, S., Novitch, B.G., Patterson, M., Umbach, J.A., Richter, L., Lindgren, A., Conway, A.E., Clark, A.T., Goldman, S.A., Plath, K., . (2009). Directed differentiation of human-induced pluripotent stem cells generates active motor neurons. Stem Cells 27, 806-811 .10.1002/stem.31
[46] Kim, J., Efe, J.A., Zhu, S., Talantova, M., Yuan, X., Wang, S., Lipton, S.A., Zhang, K., and Ding, S. (2011). Direct reprogramming of mouse fibroblasts to neural progenitors. Proc Natl Acad Sci U S A 108, 7838-7843 .10.1073/pnas.1103113108
[47] Kim, J.B., Sebastiano, V., Wu, G., Arauzo-Bravo, M.J., Sasse, P., Gentile, L., Ko, K., Ruau, D., Ehrich, M., van den Boom, D., . (2009). Oct4-induced pluripotency in adult neural stem cells. Cell 136, 411-419 .10.1016/j.cell.2009.01.023
[48] Kim, J.B., Zaehres, H., Wu, G., Gentile, L., Ko, K., Sebastiano, V., Arauzo-Bravo, M.J., Ruau, D., Han, D.W., Zenke, M., . (2008). Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors. Nature 454, 646-650 .10.1038/nature07061
[49] Kim, P.C., Mo, R., and Hui Cc, C. (2001). Murine models of VACTERL syndrome: Role of sonic hedgehog signaling pathway. J Pediatr Surg 36, 381-384 .10.1053/jpsu.2001.20722
[50] Kondo, T., and Raff, M. (2000). Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. Science 289, 1754-1757 .10.1126/science.289.5485.1754
[51] Kuo, M.H., and Allis, C.D. (1998). Roles of histone acetyltransferases and deacetylases in gene regulation. Bioessays 20, 615-626 .10.1002/(SICI)1521-1878(199808)20:8<615::AID-BIES4>3.0.CO;2-H
[52] Lee, J., Platt, K.A., Censullo, P., and Ruizi Altaba, A. (1997). Gli1 is a target of Sonic hedgehog that induces ventral neural tube development. Development 124, 2537-2552 .
[53] Liu, G.H., Barkho, B.Z., Ruiz, S., Diep, D., Qu, J., Yang, S.L., Panopoulos, A.D., Suzuki, K., Kurian, L., Walsh, C., . (2011a). Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome. Nature 472, 221-225 .10.1038/nature09879
[54] Liu, G.H., Suzuki, K., Qu, J., Sancho-Martinez, I., Yi, F., Li, M., Kumar, S., Nivet, E., Kim, J., Soligalla, R.D., . (2011b). Targeted gene correction of laminopathy-associated LMNA mutations in patientspecific iPSCs. Cell Stem Cell 8, 688-694 .10.1016/j.stem.2011.04.019
[55] Loewer, S., Cabili, M.N., Guttman, M., Loh, Y.H., Thomas, K., Park, I.H., Garber, M., Curran, M., Onder, T., Agarwal, S., . (2010). Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells. Nat Genet 42, 1113-1117 .10.1038/ng.710
[56] Loh, Y.H., Agarwal, S., Park, I.H., Urbach, A., Huo, H., Heffner, G.C., Kim, K., Miller, J.D., Ng, K., and Daley, G.Q. (2009). Generation of induced pluripotent stem cells from human blood. Blood 113, 5476-5479 .10.1182/blood-2009-02-204800
[57] Lujan, E., Chanda, S., Ahlenius, H., Sudhof, T.C., and Wernig, M. (2012). Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells. Proc Natl Acad Sci U S A 109, 2527-2532 .10.1073/pnas.1121003109
[58] Ma, D.K., Jang, M.H., Guo, J.U., Kitabatake, Y., Chang, M.L., PowAnpongkul, N., Flavell, R.A., Lu, B., Ming, G.L., and Song, H. (2009). Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science 323, 1074-1077 .10.1126/science.1166859
[59] Marchetto, M.C., Carromeu, C., Acab, A., Yu, D., Yeo, G.W., Mu, Y., Chen, G., Gage, F.H., and Muotri, A.R. (2010a). A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell 143, 527-539 .10.1016/j.cell.2010.10.016
[60] Marchetto, M.C., Winner, B., and Gage, F.H. (2010b). Pluripotent stem cells in neurodegenerative and neurodevelopmental diseases. Hum Mol Genet 19, R71-76 .10.1093/hmg/ddq159
[61] Marti, E., Takada, R., Bumcrot, D.A., Sasaki, H., and McMahon, A.P. (1995). Distribution of Sonic hedgehog peptides in the developing chick and mouse embryo. Development 121, 2537-2547 .
[62] Mullor, J.L., Sanchez, P., and Ruizi Altaba, A. (2002). Pathways and consequences: Hedgehog signaling in human disease. Trends Cell Biol 12, 562-569 .10.1016/S0962-8924(02)02405-4
[63] Muroyama, Y., Kondoh, H., and Takada, S. (2004). Wnt proteins promote neuronal differentiation in neural stem cell culture. Biochem Biophys Res Commun 313, 915-921 .10.1016/j.bbrc.2003.12.023
[64] Nakagawa, M., Koyanagi, M., Tanabe, K., Takahashi, K., Ichisaka, T., Aoi, T., Okita, K., Mochiduki, Y., Takizawa, N., and Yamanaka, S. (2008). Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 26, 101-106 .10.1038/nbt1374
[65] Nichols, J., Zevnik, B., Anastassiadis, K., Niwa, H., Klewe-Nebenius, D., Chambers, I., Scholer, H., and Smith, A. (1998). Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95, 379-391 .10.1016/S0092-8674(00)81769-9
[66] Niwa, H., Miyazaki, J., and Smith, A.G. (2000). Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet 24, 372-376 .10.1038/74199
[67] Nusse, R. (2008). Wnt signaling and stem cell control. Cell Res 18, 523-527 .10.1038/cr.2008.47
[68] Okita, K., Hong, H., Takahashi, K., and Yamanaka, S. (2010). Generation of mouse-induced pluripotent stem cells with plasmid vectors. Nat Protoc 5, 418-428 .10.1038/nprot.2009.231
[69] Okita, K., Ichisaka, T., and Yamanaka, S. (2007). Generation of germline-competent induced pluripotent stem cells. Nature 448, 313-317 .10.1038/nature05934
[70] Okita, K., Nakagawa, M., Hong, H.J., Ichisaka, T., and Yamanaka, S. (2008). Generation of mouse induced pluripotent stem cells without viral vectors. Science 322, 949-953 .10.1126/science.1164270
[71] Orkin, S.H., and Zon, L.I. (2008). Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132, 631-644 .10.1016/j.cell.2008.01.025
[72] Pang, Z.P., Yang, N., Vierbuchen, T., Ostermeier, A., Fuentes, D.R., Yang, T.Q., Citri, A., Sebastiano, V., Marro, S., Sudhof, T.C., . (2011). Induction of human neuronal cells by defined transcription factors. Nature 476, 220-223 .
[73] Park, I.H., Arora, N., Huo, H., Maherali, N., Ahfeldt, T., Shimamura, A., Lensch, M.W., Cowan, C., Hochedlinger, K., and Daley, G.Q. (2008). Disease-specific induced pluripotent stem cells. Cell 134, 877-886 .10.1016/j.cell.2008.07.041
[74] Peljto, M., and Wichterle, H. (2011). Programming embryonic stem cells to neuronal subtypes. Curr Opin Neurobiol 21, 43-51 .10.1016/j.conb.2010.09.012
[75] Pfisterer, U., Kirkeby, A., Torper, O., Wood, J., Nelander, J., Dufour, A., Bjorklund, A., Lindvall, O., Jakobsson, J., and Parmar, M. (2011). Direct conversion of human fibroblasts to dopaminergic neurons. Proc Natl Acad Sci U S A 108, 10343-10348 .10.1073/pnas.1105135108
[76] Qiang, L., Fujita, R., Yamashita, T., Angulo, S., Rhinn, H., Rhee, D., Doege, C., Chau, L., Aubry, L., Vanti, W.B., . (2011). Directed conversion of Alzheimer’s disease patient skin fibroblasts into functional neurons. Cell 146, 359-371 .10.1016/j.cell.2011.07.007
[77] Ring, K.L., Tong, L.M., Balestra, M.E., Javier, R., Andrews-Zwilling, Y., Li, G., Walker, D., Zhang, W.R., Kreitzer, A.C., and Huang, Y. (2012). Direct reprogramming of mouse and human fibroblasts into multipotent neural stem cells with a single factor. Cell Stem Cell 11, 100-109 .10.1016/j.stem.2012.05.018
[78] Saha, K., and Jaenisch, R. (2009). Technical challenges in using human induced pluripotent stem cells to model disease. Cell Stem Cell 5, 584-595 .10.1016/j.stem.2009.11.009
[79] Sheng, C., Zheng, Q., Wu, J., Xu, Z., Wang, L., Li, W., Zhang, H., Zhao, X.Y., Liu, L., Wang, Z., . (2012). Direct reprogramming of Sertoli cells into multipotent neural stem cells by defined factors. Cell Res 22, 208-218 .10.1038/cr.2011.175
[80] Silva, J., Barrandon, O., Nichols, J., Kawaguchi, J., Theunissen, T.W., and Smith, A. (2008). Promotion of reprogramming to ground state pluripotency by signal inhibition. PLoS Biol 6, e253.10.1371/journal.pbio.0060253
[81] Soldner, F., Laganiere, J., Cheng, A.W., Hockemeyer, D., Gao, Q., Alagappan, R., Khurana, V., Golbe, L.I., Myers, R.H., Lindquist, S., . (2011). Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations. Cell 146, 318-331 .10.1016/j.cell.2011.06.019
[82] Son, E.Y., Ichida, J.K., Wainger, B.J., Toma, J.S., Rafuse, V.F., Woolf, C.J., and Eggan, K. (2011). Conversion of mouse and human fibroblasts into functional spinal motor neurons. Cell Stem Cell 9, 205-218 .10.1016/j.stem.2011.07.014
[83] Song, K., Nam, Y.J., Luo, X., Qi, X., Tan, W., Huang, G.N., Acharya, A., Smith, C.L., Tallquist, M.D., Neilson, E.G., . (2012). Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature 485, 599-604 .10.1038/nature11139
[84] Stadtfeld, M., Brennand, K., and Hochedlinger, K. (2008a). Reprogramming of pancreatic beta cells into induced pluripotent stem cells. Curr Biol 18, 890-894 .10.1016/j.cub.2008.05.010
[85] Stadtfeld, M., Nagaya, M., Utikal, J., Weir, G., and Hochedlinger, K. (2008b). Induced pluripotent stem cells generated without viral integration. Science 322, 945-949 .10.1126/science.1162494
[86] Sterner, D.E., and Berger, S.L. (2000). Acetylation of histones and transcription-related factors. Microbiol Mol Biol Rev 64, 435-459 .10.1128/MMBR.64.2.435-459.2000
[87] Surani, M.A., Hayashi, K., and Hajkova, P. (2007). Genetic and epigenetic regulators of pluripotency. Cell 128, 747-762 .10.1016/j.cell.2007.02.010
[88] Tabata, T., and Takei, Y. (2004). Morphogens, their identification and regulation. Development 131, 703-712 .10.1242/dev.01043
[89] Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., and Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861-872 .10.1016/j.cell.2007.11.019
[90] Takahashi, K., and Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676 .10.1016/j.cell.2006.07.024
[91] Tay, Y., Zhang, J., Thomson, A.M., Lim, B., and Rigoutsos, I. (2008). MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature 455, 1124-1128 .10.1038/nature07299
[92] Thier, M., Worsdorfer, P., Lakes, Y.B., Gorris, R., Herms, S., Opitz, T., Seiferling, D., Quandel, T., Hoffmann, P., Nothen, M.M., . (2012). Direct Conversion of Fibroblasts into Stably Expandable Neural Stem Cells. Cell Stem Cell 10, 473-479 .10.1016/j.stem.2012.03.003
[93] Thomson, J.A. (1998). Embryonic Stem Cell Lines Derived from Human Blastocysts. Science 282, 1145-1147 .10.1126/science.282.5391.1145
[94] Varga, A.C., and Wrana, J.L. (2005). The disparate role of BMP in stem cell biology. Oncogene 24, 5713-5721 .10.1038/sj.onc.1208919
[95] Vierbuchen, T., Ostermeier, A., Pang, Z.P., Kokubu, Y., Sudhof, T.C., and Wernig, M. (2010). Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463, 1035-1041 .10.1038/nature08797
[96] Wang, B., Fallon, J.F., and Beachy, P.A. (2000). Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 100, 423-434 .10.1016/S0092-8674(00)80678-9
[97] Warren, L., Manos, P.D., Ahfeldt, T., Loh, Y.H., Li, H., Lau, F., Ebina, W., Mandal, P.K., Smith, Z.D., Meissner, A., . (2010). Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7, 618-630 .10.1016/j.stem.2010.08.012
[98] Wernig, M., Meissner, A., Foreman, R., Brambrink, T., Ku, M., Hochedlinger, K., Bernstein, B.E., and Jaenisch, R. (2007). In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448, 318-324 .10.1038/nature05944
[99] Wernig, M., Zhao, J.P., Pruszak, J., Hedlund, E., Fu, D., Soldner, F., Broccoli, V., Constantine-Paton, M., Isacson, O., and Jaenisch, R. (2008). Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease. Proc Natl Acad Sci U S A 105, 5856-5861 .10.1073/pnas.0801677105
[100] Wichterle, H., Lieberam, I., Porter, J.A., and Jessell, T.M. (2002). Directed differentiation of embryonic stem cells into motor neurons. Cell 110, 385-397 .10.1016/S0092-8674(02)00835-8
[101] Wu, H., Coskun, V., Tao, J., Xie, W., Ge, W., Yoshikawa, K., Li, E., Zhang, Y., and Sun, Y.E. (2010). Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes. Science 329, 444-448 .10.1126/science.1190485
[102] Xie, H., Ye, M., Feng, R., and Graf, T. (2004). Stepwise reprogramming of B cells into macrophages. Cell 117, 663-676 .10.1016/S0092-8674(04)00419-2
[103] Yao, J., Mu, Y., and Gage, F.H. (2012). Neural stem cells: mechanisms and modeling. Protein Cell 3, 251-261 .10.1007/s13238-012-2033-6
[104] Yusa, K., Rashid, S.T., Strick-Marchand, H., Varela, I., Liu, P.Q., Paschon, D.E., Miranda, E., Ordonez, A., Hannan, N.R., Rouhani, F.J., . (2011). Targeted gene correction of alpha1-antitrypsin deficiency in induced pluripotent stem cells. Nature 478, 391-394 .10.1038/nature10424
[105] Zhang, S.C. (2006). Neural subtype specification from embryonic stem cells. Brain Pathol 16, 132-142 .10.1111/j.1750-3639.2006.00008.x
[106] Zhao, X.Y., Li, W., Lv, Z., Liu, L., Tong, M., Hai, T., Hao, J., Guo, C.L., Ma, Q.W., Wang, L., . (2009). iPS cells produce viable mice through tetraploid complementation. Nature 461, 86-90 .10.1038/nature08267
[107] Zhou, H., Wu, S., Joo, J.Y., Zhu, S., Han, D.W., Lin, T., Trauger, S., Bien, G., Yao, S., Zhu, Y., . (2009). Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 4, 381-384 .10.1016/j.stem.2009.04.005
[108] Zhou, Q., Brown, J., Kanarek, A., Rajagopal, J., and Melton, D.A. (2008). In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 455, 627-632 .10.1038/nature07314
[109] Zhu, H., Lensch, M.W., Cahan, P., and Daley, G.Q. (2011). Investigating monogenic and complex diseases with pluripotent stem cells. Nat Rev Genet 12, 266-275 .10.1038/nrg2951