Mechanism and methods to induce pluripotency

Abstract

Pluripotent stem cells are able to self-renew indefinitely and differentiate into all types of cells in the body. They can thus be an inexhaustible source for future cell transplantation therapy to treat degenerative diseases which currently have no cure. However, non-autologous cells will cause immune rejection. Induced pluripotent stem cell (iPSC) technology can convert somatic cells to the pluripotent state, and therefore offers a solution to this problem. Since the first generation of iPSCs, there has been an explosion of relevant research, from which we have learned much about the genetic networks and epigenetic landscape of pluripotency, as well as how to manipulate genes, epigenetics, and microRNAs to obtain iPSCs. In this review, we focus on the mechanism of cellular reprogramming and current methods to induce pluripotency. We also highlight new problems emerging from iPSCs. Better understanding of the fundamental mechanisms underlying pluripotenty and refining the methodology of iPSC generation will have a significant impact on future development of regenerative medicine.

Keywords

reprogramming / induced pluripotent stem cells / pluripotency

References

[1] Anokye-Danso, F., Trivedi, C.M., Juhr, D., Gupta, M., Cui, Z., Tian, Y., Zhang, Y., Yang, W., Gruber, P.J., Epstein, J.A., (2011). Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell 8, 376–388. 21474102.
[2] Banito, A., Rashid, S.T., Acosta, J.C., Li, S., Pereira, C.F., Geti, I., Pinho, S., Silva, J.C., Azuara, V., Walsh, M., (2009). Senescence impairs successful reprogramming to pluripotent stem cells. Genes Dev 23, 2134–2139. 19696146.
[3] Bar-Nur, O., Russ, H.A., Efrat, S., and Benvenisty, N. (2011). Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet Beta cells. Cell Stem Cell 9, 17–23. 21726830.
[4] Bernstein, B.E., Mikkelsen, T.S., Xie, X., Kamal, M., Huebert, D.J., Cuff, J., Fry, B., Meissner, A., Wernig, M., Plath, K., (2006). A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326. 16630819.
[5] Card, D.A., Hebbar, P.B., Li, L., Trotter, K.W., Komatsu, Y., Mishina, Y., and Archer, T.K. (2008). Oct4/Sox2-regulated miR-302 targets cyclin D1 in human embryonic stem cells. Mol Cell Biol 28, 6426–6438. 18710938.
[6] Chambers, I., Colby, D., Robertson, M., Nichols, J., Lee, S., Tweedie, S., and Smith, A. (2003). Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113, 643–655. 12787505.
[7] Chambers, I., Silva, J., Colby, D., Nichols, J., Nijmeijer, B., Robertson, M., Vrana, J., Jones, K., Grotewold, L., and Smith, A. (2007). Nanog safeguards pluripotency and mediates germline development. Nature 450, 1230–1234. 18097409.
[8] Chen, Z.Y., He, C.Y., Ehrhardt, A., and Kay, M.A. (2003). Minicircle DNA vectors devoid of bacterial DNA result in persistent and high-level transgene expression in vivo. Mol Ther 8, 495–500. 12946323.
[9] Chen, Z.Y., He, C.Y., and Kay, M.A. (2005). Improved production and purification of minicircle DNA vector free of plasmid bacterial sequences and capable of persistent transgene expression in vivo. Hum Gene Ther 16, 126–131. 15703495.
[10] Cowan, C.A., Atienza, J., Melton, D.A., and Eggan, K. (2005). Nuclear reprogramming of somatic cells after fusion with human embryonic stem cells. Science 309, 1369–1373. 16123299.
[11] Egli, D., Rosains, J., Birkhoff, G., and Eggan, K. (2007). Developmental reprogramming after chromosome transfer into mitotic mouse zygotes. Nature 447, 679–685. 17554301.
[12] Eminli, S., Foudi, A., Stadtfeld, M., Maherali, N., Ahfeldt, T., Mostoslavsky, G., Hock, H., and Hochedlinger, K. (2009). Differentiation stage determines potential of hematopoietic cells for reprogramming into induced pluripotent stem cells. Nat Genet 41, 968–976. 19668214.
[13] Esteban, M.A., Wang, T., Qin, B., Yang, J., Qin, D., Cai, J., Li, W., Weng, Z., Chen, J., Ni, S., (2010). Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. Cell Stem Cell 6, 71–79. 20036631.
[14] Gore, A., Li, Z., Fung, H.L., Young, J.E., Agarwal, S., Antosiewicz-Bourget, J., Canto, I., Giorgetti, A., Israel, M.A., Kiskinis, E., (2011). Somatic coding mutations in human induced pluripotent stem cells. Nature 471, 63–67. 21368825.
[15] Guo, G., Yang, J., Nichols, J., Hall, J.S., Eyres, I., Mansfield, W., and Smith, A. (2009). Klf4 reverts developmentally programmed restriction of ground state pluripotency. Development 136, 1063–1069. 19224983.
[16] Hanna, J., Cheng, A.W., Saha, K., Kim, J., Lengner, C.J., Soldner, F., Cassady, J.P., Muffat, J., Carey, B.W., and Jaenisch, R. (2010a). Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs. Proc Natl Acad Sci U S A , 107, 9222–9227 .
[17] Hanna, J., Saha, K., Pando, B., van Zon, J., Lengner, C.J., Creyghton, M.P., van Oudenaarden, A., and Jaenisch, R. (2009). Direct cell reprogramming is a stochastic process amenable to acceleration. Nature 462, 595–601. 19898493.
[18] Hanna, J.H., Saha, K., and Jaenisch, R. (2010b). Pluripotency and cellular reprogramming: facts, hypotheses, unresolved issues. Cell 143, 508–525. 21074044.
[19] Heng, J.C., Feng, B., Han, J., Jiang, J., Kraus, P., Ng, J.H., Orlov, Y.L., Huss, M., Yang, L., Lufkin, T., (2010). The nuclear receptor Nr5a2 can replace Oct4 in the reprogramming of murine somatic cells to pluripotent cells. Cell Stem Cell 6, 167–174. 20096661.
[20] Heo, I., Joo, C., Cho, J., Ha, M., Han, J., and Kim, V.N. (2008). Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA. Mol Cell 32, 276–284. 18951094.
[21] Hong, H., Takahashi, K., Ichisaka, T., Aoi, T., Kanagawa, O., Nakagawa, M., Okita, K., and Yamanaka, S. (2009). Suppression of induced pluripotent stem cell generation by the p53-p21 pathway. Nature 460, 1132–1135. 19668191.
[22] Huangfu, D., Maehr, R., Guo, W., Eijkelenboom, A., Snitow, M., Chen, A.E., and Melton, D.A. (2008a). Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat Biotechnol 26, 795–797. 18568017.
[23] Huangfu, D., Osafune, K., Maehr, R., Guo, W., Eijkelenboom, A., Chen, S., Muhlestein, W., and Melton, D.A. (2008b). Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol 26, 1269–1275. 18849973.
[24] Hussein, S.M., Batada, N.N., Vuoristo, S., Ching, R.W., Autio, R., N?rv?, E., Ng, S., Sourour, M., H?m?l?inen, R., Olsson, C., (2011). Copy number variation and selection during reprogramming to pluripotency. Nature 471, 58–62. 21368824.
[25] Ichida, J.K., Blanchard, J., Lam, K., Son, E.Y., Chung, J.E., Egli, D., Loh, K.M., Carter, A.C., Di Giorgio, F.P., Koszka, K., (2009). A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog. Cell Stem Cell 5, 491–503. 19818703.
[26] Jia, F., Wilson, K.D., Sun, N., Gupta, D.M., Huang, M., Li, Z., Panetta, N.J., Chen, Z.Y., Robbins, R.C., Kay, M.A., (2010). A nonviral minicircle vector for deriving human iPS cells. Nat Methods 7, 197–199. 20139967.
[27] Judson, R.L., Babiarz, J.E., Venere, M., and Blelloch, R. (2009). Embryonic stem cell-specific microRNAs promote induced pluripotency. Nat Biotechnol 27, 459–461. 19363475.
[28] Kaji, K., Norrby, K., Paca, A., Mileikovsky, M., Mohseni, P., and Woltjen, K. (2009). Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 458, 771–775. 19252477.
[29] Kane, N.M., Nowrouzi, A., Mukherjee, S., Blundell, M.P., Greig, J.A., Lee, W.K., Houslay, M.D., Milligan, G., Mountford, J.C., von Kalle, C., (2010). Lentivirus-mediated reprogramming of somatic cells in the absence of transgenic transcription factors. Mol Ther 18, 2139–2145. 20978477.
[30] Kawamura, T., Suzuki, J., Wang, Y.V., Menendez, S., Morera, L.B., Raya, A., Wahl, G.M., and Belmonte, J.C. (2009). Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature 460, 1140–1144. 19668186.
[31] Kim, D., Kim, C.H., Moon, J.I., Chung, Y.G., Chang, M.Y., Han, B.S., Ko, S., Yang, E., Cha, K.Y., Lanza, R., (2009a). Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 4, 472–476. 19481515.
[32] Kim, J., Chu, J., Shen, X., Wang, J., and Orkin, S.H. (2008). An extended transcriptional network for pluripotency of embryonic stem cells. Cell 132, 1049–1061. 18358816.
[33] Kim, J.B., Greber, B., Araúzo-Bravo, M.J., Meyer, J., Park, K.I., Zaehres, H., and Sch?ler, H.R. (2009b). Direct reprogramming of human neural stem cells by OCT4. Nature 461, 649-653 19718018.
[34] Laurenti, E., Wilson, A., and Trumpp, A. (2009). Myc’s other life: stem cells and beyond. Curr Opin Cell Biol 21, 844–854. 19836223.
[35] Li, H., Collado, M., Villasante, A., Strati, K., Ortega, S., Ca?amero, M., Blasco, M.A., and Serrano, M. (2009). The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature 460, 1136–1139. 19668188.
[36] Li, R., Liang, J., Ni, S., Zhou, T., Qing, X., Li, H., He, W., Chen, J., Li, F., Zhuang, Q., (2010). A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell 7, 51–63. 20621050.
[37] Lin, C.H., Jackson, A.L., Guo, J., Linsley, P.S., and Eisenman, R.N. (2009). Myc-regulated microRNAs attenuate embryonic stem cell differentiation. EMBO J 28, 3157–3170. 19745813.
[38] Lin, S.L., Chang, D.C., Chang-Lin, S., Lin, C.H., Wu, D.T., Chen, D.T., and Ying, S.Y. (2008). Mir-302 reprograms human skin cancer cells into a pluripotent ES-cell-like state. RNA 14, 2115–2124 .
[39] Lister, R., Pelizzola, M., Kida, Y.S., Hawkins, R.D., Nery, J.R., Hon, G., Antosiewicz-Bourget, J., O’Malley, R., Castanon, R., Klugman, S., (2011). Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471, 68–73. 21289626.
[40] Maekawa, M., Yamaguchi, K., Nakamura, T., Shibukawa, R., Kodanaka, I., Ichisaka, T., Kawamura, Y., Mochizuki, H., Goshima, N., and Yamanaka, S. (2011). Direct reprogramming of somatic cells is promoted by maternal transcription factor Glis1. Nature 474, 225–229. 21654807.
[41] Maherali, N., and Hochedlinger, K. (2009). Tgfbeta signal inhibition cooperates in the induction of iPSCs and replaces Sox2 and cMyc. Curr Biol 19, 1718–1723. 19765992.
[42] Mali, P., Ye, Z., Hommond, H.H., Yu, X., Lin, J., Chen, G., Zou, J., and Cheng, L. (2008). Improved Efficiency and Pace of Generating Induced Pluripotent Stem Cells from Human Adult and Fetal Fibroblasts. Stem Cells 26,1998–2005
[43] Marión, R.M., Strati, K., Li, H., Murga, M., Blanco, R., Ortega, S., Fernandez-Capetillo, O., Serrano, M., and Blasco, M.A. (2009). A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature 460, 1149–1153. 19668189.
[44] Masui, S., Nakatake, Y., Toyooka, Y., Shimosato, D., Yagi, R., Takahashi, K., Okochi, H., Okuda, A., Matoba, R., Sharov, A.A., (2007). Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells. Nat Cell Biol 9, 625–635. 17515932.
[45] Mikkelsen, T.S., Hanna, J., Zhang, X., Ku, M., Wernig, M., Schorderet, P., Bernstein, B.E., Jaenisch, R., Lander, E.S., and Meissner, A. (2008). Dissecting direct reprogramming through integrative genomic analysis. Nature 454, 49–55. 18509334.
[46] Miyoshi, N., Ishii, H., Nagano, H., Haraguchi, N., Dewi, D.L., Kano, Y., Nishikawa, S., Tanemura, M., Mimori, K., Tanaka, F., (2011). Reprogramming of mouse and human cells to pluripotency using mature microRNAs. Cell Stem Cell 8, 633–638. 21620789.
[47] 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. 18059259.
[48] Nichols, J., Zevnik, B., Anastassiadis, K., Niwa, H., Klewe-Nebenius, D., Chambers, I., Sch?ler, 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. 9814708.
[49] Niwa, H., Ogawa, K., Shimosato, D., and Adachi, K. (2009). A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells. Nature 460, 118–122. 19571885.
[50] Pardo, M., Lang, B., Yu, L., Prosser, H., Bradley, A., Babu, M.M., and Choudhary, J. (2010). An expanded Oct4 interaction network: implications for stem cell biology, development, and disease. Cell Stem Cell 6, 382–395. 20362542.
[51] Plews, J.R., Li, J., Jones, M., Moore, H.D., Mason, C., Andrews, P.W., and Na, J. (2010). Activation of pluripotency genes in human fibroblast cells by a novel mRNA based approach. PLoS One 5, e1439721209933.
[52] Roush, S., and Slack, F.J. (2008). The let-7 family of microRNAs. Trends Cell Biol 18, 505–516. 18774294.
[53] Shi, Y., Do, J.T., Desponts, C., Hahm, H.S., Sch?ler, H.R., and Ding, S. (2008). A combined chemical and genetic approach for the generation of induced pluripotent stem cells. Cell Stem Cell 2, 525–528. 18522845.
[54] 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 6e253.18942890.
[55] Suh, M.R., Lee, Y., Kim, J.Y., Kim, S.K., Moon, S.H., Lee, J.Y., Cha, K.Y., Chung, H.M., Yoon, H.S., Moon, S.Y., (2004). Human embryonic stem cells express a unique set of microRNAs. Dev Biol 270, 488–498. 15183728.
[56] Szymczak, A.L., Workman, C.J., Wang, Y., Vignali, K.M., Dilioglou, S., Vanin, E.F., and Vignali, D.A. (2004). Correction of multi-gene deficiency in vivo using a single ‘self-cleaving’ 2A peptide-based retroviral vector. Nat Biotechnol 22, 589–594. 15064769.
[57] 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. 18035408.
[58] 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. 16904174.
[59] Taranger, C.K., Noer, A., S?rensen, A.L., H?kelien, A.M., Boquest, A.C., and Collas, P. (2005). Induction of dedifferentiation, genomewide transcriptional programming, and epigenetic reprogramming by extracts of carcinoma and embryonic stem cells. Mol Biol Cell 16, 5719–5735. 16195347.
[60] Urbach, A., Bar-Nur, O., Daley, G.Q., and Benvenisty, N. (2010). Differential modeling of fragile X syndrome by human embryonic stem cells and induced pluripotent stem cells. Cell Stem Cell 6, 407–411. 20452313.
[61] Utikal, J., Maherali, N., Kulalert, W., and Hochedlinger, K. (2009a). Sox2 is dispensable for the reprogramming of melanocytes and melanoma cells into induced pluripotent stem cells. J Cell Sci 122, 3502–3510. 19723802.
[62] Utikal, J., Polo, J.M., Stadtfeld, M., Maherali, N., Kulalert, W., Walsh, R.M., Khalil, A., Rheinwald, J.G., and Hochedlinger, K. (2009b). Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature 460, 1145–1148. 19668190.
[63] Viswanathan, S.R., Daley, G.Q., and Gregory, R.I. (2008). Selective blockade of microRNA processing by Lin28. Science 320, 97–100. 18292307.
[64] Wang, J., Rao, S., Chu, J., Shen, X., Levasseur, D.N., Theunissen, T.W., and Orkin, S.H. (2006). A protein interaction network for pluripotency of embryonic stem cells. Nature 444, 364–368. 17093407.
[65] 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. 20888316.
[66] Wilmut, I., Schnieke, A.E., McWhir, J., Kind, A.J., and Campbell, K.H. (1997). Viable offspring derived from fetal and adult mammalian cells. Nature 385, 810–813. 9039911.
[67] Woltjen, K., Michael, I.P., Mohseni, P., Desai, R., Mileikovsky, M., H?m?l?inen, R., Cowling, R., Wang, W., Liu, P., Gertsenstein, M., (2009). piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 458, 766–770. 19252478.
[68] Yu, J., Hu, K., Smuga-Otto, K., Tian, S., Stewart, R., Slukvin, I.I., and Thomson, J.A. (2009). Human induced pluripotent stem cells free of vector and transgene sequences. Science 324, 797–801. 19325077.
[69] Yu, J., Vodyanik, M.A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J.L., Tian, S., Nie, J., Jonsdottir, G.A., Ruotti, V., Stewart, R., (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science , 318, 1917–1920 .
[70] Yusa, K., Rad, R., Takeda, J., and Bradley, A. (2009). Generation of transgene-free induced pluripotent mouse stem cells by the piggyBac transposon. Nat Methods 6, 363–369 .
[71] Zhao, T., Zhang, Z.N., Rong, Z., and Xu, Y. (2011). Immunogenicity of induced pluripotent stem cells. Nature 474, 212–215. 21572395.
[72] Zhao, Y., Yin, X., Qin, H., Zhu, F., Liu, H., Yang, W., Zhang, Q., Xiang, C., Hou, P., Song, Z., (2008a). Two supporting factors greatly improve the efficiency of human iPSC generation. Cell Stem Cell 3, 475–479. 18983962.
[73] Zhao, Y., Yin, X., Qin, H., Zhu, F., Liu, H., Yang, W., Zhang, Q., Xiang, C., Hou, P., Song, Z., (2008b). Two supporting factors greatly improve the efficiency of human iPSC generation. Cell Stem Cell 3, 475–479. 18983962.
[74] 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. 19398399.
[75] Zhu, S., Li, W., Zhou, H., Wei, W., Ambasudhan, R., Lin, T., Kim, J., Zhang, K., and Ding, S. (2010). Reprogramming of human primary somatic cells by OCT4 and chemical compounds. Cell Stem Cell 7, 651–655. 21112560.