Chemical-only reprogramming to pluripotency

Abstract

Direct reprogramming technology has emerged as an outstanding technique for the generation of induced pluripotent stem cells (iPSCs) and various specialized cells directly from somatic cells of different species. Reprogramming techniques conventionally use viral vectors encoding transcription factors to induce fate conversion. However, the introduction of transgenes limits the therapeutic applications of the reprogrammed cells. To overcome safety-related concerns, small molecules offer some advantages over the existing methods for the control of gene expression and induction of cell fate conversion. Technical advances in optimizing concentrations, durations, structures, and combinations of small molecules make chemical reprogramming a safe and feasible method. This review provides a concise overview of cutting-edge findings regarding chemical-only reprogramming as one of the integration-free approaches to iPSC generation.

Key words： cellular reprogramming; small molecule; chemical reprogramming; induced pluripotency; regenerative medicine

Acknowledgments

I would like to greatly appreciate Professor Hongkui Deng form Peking University for his kind help and professor Miguel A. Esteban from the Guangzhou Institutes of Biomedicine and Health for reading the manuscript and helpful comments.

This work was supported by Yazd Cardiovascular Research Center.

The author declares that there are no competing interests.

This manuscript is a review article and does not contain any studies with human or animal subjects.

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, Morrisey E E (2011). Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell, 8(4): 376–388

2 Babos K, Ichida J K (2015). Small molecules take a big step by converting fibroblasts into neurons. Cell Stem Cell, 17(2): 127–129

3 Ban H, Nishishita N, Fusaki N, Tabata T, Saeki K, Shikamura M, Takada N, Inoue M, Hasegawa M, Kawamata S, Nishikawa S (2011). Efficient generation of transgene-free human induced pluripotent stem cells (iPSCs) by temperature-sensitive Sendai virus vectors. Proc Natl Acad Sci USA, 108(34): 14234–14239

4 Cahan P, Li H, Morris S A, Lummertz da Rocha E, Daley G Q, Collins J J (2014). Cell net: Network biology applied to stem cell engineering. Cell, 158(4): 903–915

5 Chen J K, Liu H, Liu J, Qi J, Wei B, Yang J Q, Liang H Q, Chen Y, Chen J, Wu Y R, Guo L, Zhu J Y, Zhao X J, Peng T R, Zhang Y X, Chen S, Li X J, Li D W, Wang T, Pei D Q (2013). H3K9 methylation is a barrier during somatic cell reprogramming into iPSCs. Nat Genet, 45(1): 34–U62

6 Cheng L, Gao L, Guan W, Mao J, Hu W, Qiu B, Zhao J, Yu Y, Pei G (2015). Direct conversion of astrocytes into neuronal cells by drug cocktail. Cell Res, 25(11): 1269–1272

7 Cheng L, Hu W, Qiu B, Zhao J, Yu Y, Guan W, Wang M, Yang W, Pei G (2014). Generation of neural progenitor cells by chemical cocktails and hypoxia. Cell Res, 24(6): 665–679

8 Chou B K, Gu H, Gao Y, Dowey S N, Wang Y, Shi J, Li Y, Ye Z, Cheng T, Cheng L (2015). A facile method to establish human induced pluripotent stem cells from adult blood cells under feeder-free and xeno-free culture conditions: a clinically compliant approach. Stem Cells Transl Med, 4(4): 320–332

9 Chou B K, Mali P, Huang X, Ye Z, Dowey S N, Resar L M, Zou C, Zhang Y A, Tong J, Cheng L (2011). Efficient human iPS cell derivation by a non-integrating plasmid from blood cells with unique epigenetic and gene expression signatures. Cell Res, 21(3): 518–529

10 Cyranoski D 2014. Japanese woman is first recipient of next-generation stem cells. Nature Publishing Group.

11 Davies S G, Kennewell P D, Russell A J, Seden P T, Westwood R, Wynne G M (2015). Stemistry: The control of stem cells in situ using chemistry. J Med Chem, 58(7): 2863–2894

12 Durruthy-Durruthy J, Briggs S F, Awe J, Ramathal C Y, Karumbayaram S, Lee P C, Heidmann J D, Clark A, Karakikes I, Loh K M, Wu J C, Hoffman A R, Byrne J, Reijo Pera R A, Sebastiano V (2014). Rapid and Efficient Conversion of Integration-Free Human Induced Pluripotent Stem Cells to GMP-Grade Culture Conditions. PLoS ONE, 9(4): e94231

13 Ebrahimi B (2015a). Reprogramming barriers and enhancers: strategies to enhance the efficiency and kinetics of induced pluripotency. Cell Regen (Lond), 4(1): 1–12

14 Ebrahimi B (2015b). Reprogramming of adult stem/progenitor cells into iPSCs without reprogramming factors. Journal of Medical Hypotheses and Ideas, 9(2): 99–103

15 Ebrahimi B (2016). Biological computational approaches: new hopes to improve (re)programming robustness, regenerative medicine and cancer therapeutics. Differentiation, doi: 10.1016/j.diff.2016.03.001

16 Eriksson P S, Perfilieva E, Bjork-Eriksson T, Alborn A M, Nordborg C, Peterson D A, Gage F H (1998). Neurogenesis in the adult human hippocampus. Nat Med, 4(11): 1313–1317

17 Esteban M A, Wang T, Qin B, Yang J, Qin D, Cai J, Li W, Weng Z, Chen J, Ni S, Chen K, Li Y, Liu X, Xu J, Zhang S, Li F, He W, Labuda K, Song Y, Peterbauer A, Wolbank S, Redl H, Zhong M, Cai D, Zeng L, Pei D (2010). Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. Cell Stem Cell, 6(1): 71–79

18 Foster K W, Liu Z, Nail C D, Li X, Fitzgerald T J, Bailey S K, Frost A R, Louro I D, Townes T M, Paterson A J, Kudlow J E, Lobo-Ruppert S M, Ruppert J M (2005). Induction of KLF4 in basal keratinocytes blocks the proliferation-differentiation switch and initiates squamous epithelial dysplasia. Oncogene, 24(9): 1491–1500

19 Fu Y, Huang C, Xu X, Gu H, Ye Y, Jiang C, Qiu Z, Xie X (2015). Direct reprogramming of mouse fibroblasts into cardiomyocytes with chemical cocktails. Cell Res, 25(9): 1013–1024

20 Fusaki N, Ban H, Nishiyama A, Saeki K, Hasegawa M (2009). Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proc Jpn Acad, Ser B, Phys Biol Sci, 85(8): 348–362

21 Goh P A, Caxaria S, Casper C, Rosales C, Warner T T, Coffey P J, Nathwani A C (2013). A systematic evaluation of integration free reprogramming methods for deriving clinically relevant patient specific induced pluripotent stem (iPS) cells. PLoS ONE, 8(11): e81622

22 González F, Boué S, Belmonte J C I (2011). Methods for making induced pluripotent stem cells: reprogramming à la carte. Nat Rev Genet, 12(4): 231–242

23 He S, Guo Y, Zhang Y, Li Y, Feng C, Li X, Lin L, Guo L, Wang H, Liu C, Zheng Y, Luo C, Liu Q, Wang F, Sun H, Liang L, Li L, Su H, Chen J, Pei D, Zheng H (2015). Reprogramming somatic cells to cells with neuronal characteristics by defined medium both in vitro and in vivo. Cell Regen (Lond), 4(1): 1–9

24 Higuchi A, Ling Q D, Kumar S S, Munusamy M A, Alarfaj A A, Chang Y, Kao S H, Lin K C, Wang H C, Umezawa A (2015). Generation of pluripotent stem cells without the use of genetic material. Lab Invest, 95(1): 26–42

25 Hochedlinger K, Yamada Y, Beard C, Jaenisch R (2005). Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues. Cell, 121(3): 465–477

26 Hou P, Li Y, Zhang X, Liu C, Guan J, Li H, Zhao T, Ye J, Yang W, Liu K, Ge J, Xu J, Zhang Q, Zhao Y, Deng H (2013). Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science, 341(6146): 651–654

27 Hu W, Qiu B, Guan W, Wang Q, Wang M, Li W, Gao L, Shen L, Huang Y, Xie G, Zhao H, Jin Y, Tang B, Yu Y, Zhao J, Pei G (2015). Direct conversion of normal and alzheimer’s disease human fibroblasts into neuronal cells by small molecules. Cell Stem Cell, 17(2): 204–212

28 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, Huangfu D, Akutsu H, Liu D R, Rubin L L, Eggan K (2009). A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog. Cell Stem Cell, 5(5): 491–503

29 Jung D W, Kim W H, Williams D R (2014). Reprogram or reboot: small molecule approaches for the production of induced pluripotent stem cells and direct cell reprogramming. ACS Chem Biol, 9(1): 80–95

30 Kaji K, Norrby K, Paca A, Mileikovsky M, Mohseni P, Woltjen K (2009). Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature, 458(7239): 771–775

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, Kim K S (2009). Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell, 4(6): 472–476

32 Koyanagi-Aoi M, Ohnuki M, Takahashi K, Okita K, Noma H, Sawamura Y, Teramoto I, Narita M, Sato Y, Ichisaka T, Amano N, Watanabe A, Morizane A, Yamada Y, Sato T, Takahashi J, Yamanaka S (2013). Differentiation-defective phenotypes revealed by large-scale analyses of human pluripotent stem cells. Proc Natl Acad Sci USA, 110(51): 20569–20574

33 Lee A S, Tang C, Rao M S, Weissman I L, Wu J C (2013). Tumorigenicity as a clinical hurdle for pluripotent stem cell therapies. Nat Med, 19(8): 998–1004

34 Lee J, Sayed N, Hunter A, Au K F, Wong W H, Mocarski E S, Pera R R, Yakubov E, Cooke J P (2012). Activation of Innate Immunity Is Required for Efficient Nuclear Reprogramming. Cell, 151(3): 547–558

35 Li W, Jiang K, Ding S (2012a). Concise review: A chemical approach to control cell fate and function. Stem Cells, 30(1): 61–68

36 Li W, Jiang K, Wei W, Shi Y, Ding S (2013a). Chemical approaches to studying stem cell biology. Cell Res, 23(1): 81–91

37 Li W, Li K, Wei W, Ding S (2013b). Chemical approaches to stem cell biology and therapeutics. Cell Stem Cell, 13(3): 270–283

38 Li W, Tian E, Chen Z X, Sun G, Ye P, Yang S, Lu D, Xie J, Ho T V, Tsark W M, Wang C, Horne D A, Riggs A D, Yip M L, Shi Y (2012b). Identification of Oct4-activating compounds that enhance reprogramming efficiency. Proc Natl Acad Sci USA, 109(51): 20853–20858

39 Li X, Zuo X, Jing J, Ma Y, Wang J, Liu D, Zhu J, Du X, Xiong L, Du Y, Xu J, Xiao X, Wang J, Chai Z, Zhao Y, Deng H (2015). Small-molecule-driven direct reprogramming of mouse fibroblasts into functional n<?Pub Caret?>eurons. Cell Stem Cell, 17(2): 195–203

40 Li Y, Zhang Q, Yin X, Yang W, Du Y, Hou P, Ge J, Liu C, Zhang W, Zhang X, Wu Y, Li H, Liu K, Wu C, Song Z, Zhao Y, Shi Y, Deng H (2011). Generation of iPSCs from mouse fibroblasts with a single gene, Oct4, and small molecules. Cell Res, 21(1): 196–204

41 Lin T, Ambasudhan R, Yuan X, Li W, Hilcove S, Abujarour R, Lin X, Hahm H S, Hao E, Hayek A, Ding S (2009). A chemical platform for improved induction of human iPSCs. Nat Methods, 6(11): 805–808

42 Lin T, Wu S (2015). Reprogramming with Small Molecules instead of Exogenous Transcription Factors. Stem Cells Int, 2015: 794632

43 Long Y, Wang M, Gu H, Xie X (2015). Bromodeoxyuridine promotes full-chemical induction of mouse pluripotent stem cells. Cell Res, 25(10): 1171–1174

44 Lu X, Zhao T (2013). Clinical Therapy Using iPSCs: Hopes and Challenges. Genomics Proteomics Bioinformatics, 11(5): 294–298

45 Ma H, Morey R, O'Neil R C, He Y, Daughtry B, Schultz M D, Hariharan M, Nery J R, Castanon R, Sabatini K, Thiagarajan R D, Tachibana M, Kang E, Tippner-Hedges R, Ahmed R, Gutierrez N M, Van Dyken C, Polat A, Sugawara A, Sparman M, Gokhale S, Amato P, Wolf P, Ecker D Jr, Laurent L C, Mitalipov S (2014). Abnormalities in human pluripotent cells due to reprogramming mechanisms. Nature, 511: 177–183

46 Masuda S, Wu J, Hishida T, Pandian G N, Sugiyama H, Izpisua Belmonte J C (2013). Chemically induced pluripotent stem cells (CiPSCs): a transgene-free approach. J Mol Cell Biol, 5(5): 354–355

47 Morris S A, Cahan P, Li H, Zhao A M, San Roman A K, Shivdasani R A, Collins J J, Daley G Q (2014). Dissecting Engineered Cell Types and Enhancing Cell Fate Conversion via CellNet. Cell, 158(4): 889–902

48 Ohnishi K, Semi K, Yamamoto T, Shimizu M, Tanaka A, Mitsunaga K, Okita K, Osafune K, Arioka Y, Maeda T, Soejima H, Moriwaki H, Yamanaka S, Woltjen K, Yamada Y (2014). Premature Termination of Reprogramming In Vivo Leads to Cancer Development through Altered Epigenetic Regulation. Cell, 156(4): 663–677

49 Okano H, Nakamura M, Yoshida K, Okada Y, Tsuji O, Nori S, Ikeda E, Yamanaka S, Miura K (2013). Steps toward safe cell therapy using induced pluripotent stem cells. Circ Res, 112(3): 523–533

50 Okita K, Ichisaka T, Yamanaka S (2007). Generation of germline-competent induced pluripotent stem cells. Nature, 448(7151): 313–317

51 Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S (2008). Generation of mouse induced pluripotent stem cells without viral vectors. Science, 322(5903): 949–953

52 Okita K, Yamakawa T, Matsumura Y, Sato Y, Amano N, Watanabe A, Goshima N, Yamanaka S (2013). An efficient nonviral method to generate integration-free human-induced pluripotent stem cells from cord blood and peripheral blood cells. Stem Cells, 31(3): 458–466

53 Okita K, Yamanaka S (2011). Induced pluripotent stem cells: opportunities and challenges. Philos Trans R Soc Lond B Biol Sci, 366(1575): 2198–2207

54 Onder T T, Kara N, Cherry A, Sinha A U, Zhu N, Bernt K M, Cahan P, Marcarci B O, Unternaehrer J, Gupta P B, Lander E S, Armstrong S A, Daley G Q (2012). Chromatin-modifying enzymes as modulators of reprogramming. Nature, 483(7391): 598–602

55 Pandian G N, Nakano Y, Sato S, Morinaga H, Bando T, Nagase H, Sugiyama H (2012). A synthetic small molecule for rapid induction of multiple pluripotency genes in mouse embryonic fibroblasts. Sci Rep, 2: 544

56 Pennarossa G, Maffei S, Campagnol M, Tarantini L, Gandolfi F, Brevini T A (2013). Brief demethylation step allows the conversion of adult human skin fibroblasts into insulin-secreting cells. Proc Natl Acad Sci USA, 110(22): 8948–8953

57 Piao Y, Hung S S, Lim S Y, Wong R C, Ko M S (2014). Efficient generation of integration-free human induced pluripotent stem cells from keratinocytes by simple transfection of episomal vectors. Stem Cells Transl Med, 3(7): 787–791

58 Sayed N, Wong W T, Ospino F, Meng S, Lee J, Jha A, Dexheimer P, Aronow B J, Cooke J P (2015). Transdifferentiation of human fibroblasts to endothelial cells: role of innate immunity. Circulation, 131(3): 300–309

59 Schlaeger T M, Daheron L, Brickler T R, Entwisle S, Chan K, Cianci A, DeVine A, Ettenger A, Fitzgerald K, Godfrey M, Gupta D, McPherson J, Malwadkar P, Gupta M, Bell B, Doi A, Jung N, Li X, Lynes M S, Brookes E, Cherry A B C, Demirbas D, Tsankov A M, Zon L I, Rubin L L, Feinberg A P, Meissner A, Cowan C A, Daley G Q (2015). A comparison of non-integrating reprogramming methods. Nat Biotechnol, 33(1): 58–63

60 Shi Y, Desponts C, Do J T, Hahm H S, Scholer H R, Ding S (2008). Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds. Cell Stem Cell, 3(5): 568–574

61 Shu J, Wu C, Wu Y, Li Z, Shao S, Zhao W, Tang X, Yang H, Shen L, Zuo X, Yang W, Shi Y, Chi X, Zhang H, Gao G, Shu Y, Yuan K, He W, Tang C, Zhao Y, Deng H (2013). Induction of pluripotency in mouse somatic cells with lineage specifiers. Cell, 153(5): 963–975

62 Silva M, Daheron L, Hurley H, Bure K, Barker R, Carr A J, Williams D, Kim H W, French A, Coffey P J, Cooper-White J J, Reeve B, Rao M, Snyder E Y, Ng K S, Mead B E, Smith J A, Karp J M, Brindley D A, Wall I (2015). Generating iPSCs: Translating Cell Reprogramming Science into Scalable and Robust Biomanufacturing Strategies. Cell Stem Cell, 16(1): 13–17

63 Soldner F, Hockemeyer D, Beard C, Gao Q, Bell G W, Cook E G, Hargus G, Blak A, Cooper O, Mitalipova M, Isacson O, Jaenisch R (2009). Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell, 136(5): 964–977

64 Stadtfeld M, Apostolou E, Ferrari F, Choi J, Walsh R M, Chen T, Ooi S S, Kim S Y, Bestor T H, Shioda T, Park P J, Hochedlinger K, (2012). Ascorbic acid prevents loss of Dlk1-Dio3 imprinting and facilitates generation of all-iPS cell mice from terminally differentiated B cells. Nat Genet, 44: 398–405, S391–392

65 Stadtfeld M, Nagaya M, Utikal J, Weir G, Hochedlinger K (2008). Induced pluripotent stem cells generated without viral integration. Science, 322(5903): 945–949

66 Su J B, Pei D Q, Qin B M (2013). Roles of small molecules in somatic cell reprogramming. Acta Pharmacol Sin, 34(6): 719–724

67 Sugiura M, Kasama Y, Araki R, Hoki Y, Sunayama M, Uda M, Nakamura M, Ando S, Abe M (2014). Induced Pluripotent Stem Cell Generation-Associated Point Mutations Arise during the Initial Stages of the Conversion of These Cells. Stem Cell Rep, 2(1): 52–63

68 Takahashi K, Tanabe K, Ohnuki M, Narita M, Sasaki A, Yamamoto M, Nakamura M, Sutou K, Osafune K, Yamanaka S (2014). Induction of pluripotency in human somatic cells via a transient state resembling primitive streak-like mesendoderm. Nat Commun, 5: 3678

69 Takahashi K, Yamanaka S (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4): 663–676

70 Tomaru Y, Hasegawa R, Suzuki T, Sato T, Kubosaki A, Suzuki M, Kawaji H, Forrest A R R, Hayashizaki Y, Consortium F, Shin J W, Suzuki H (2014). A transient disruption of fibroblastic transcriptional regulatory network facilitates trans-differentiation. Nucleic Acids Res, 42(14): 8905–8913

71 Valamehr B, Robinson M, Abujarour R, Rezner B, Vranceanu F, Le T, Medcalf A, Lee T T, Fitch M, Robbins D, Flynn P (2014). Platform for Induction and Maintenance of Transgene-free hiPSCs Resembling Ground State Pluripotent Stem Cells. Stem Cell Rep, 2(3): 366–381

72 Vidal S E, Amlani B, Chen T, Tsirigos A, Stadtfeld M (2014). Combinatorial Modulation of Signaling Pathways Reveals Cell-Type-Specific Requirements for Highly Efficient and Synchronous iPSC Reprogramming. Stem Cell Rep, 3(4): 574–584

73 Wang T, Chen K, Zeng X, Yang J, Wu Y, Shi X, Qin B, Zeng L, Esteban M A, Pan G, Pei D (2011). The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner. Cell Stem Cell, 9(6): 575–587

74 Warren L, Manos P D, Ahfeldt T, Loh Y H, Li H, Lau F, Ebina W, Mandal P K, Smith Z D, Meissner A, Daley G Q, Brack A S, Collins J J, Cowan C, Schlaeger T M, Rossi D J (2010). Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell, 7(5): 618– 630

75 Woltjen K, Michael I P, Mohseni P, Desai R, Mileikovsky M, Hamalainen R, Cowling R, Wang W, Liu P, Gertsenstein M, Kaji K, Sung H K, Nagy A (2009). piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature, 458(7239): 766–770

76 Xu J, Du Y, Deng H (2015). Direct Lineage Reprogramming: Strategies, Mechanisms, and Applications. Cell Stem Cell, 16(2): 119–134

77 Ye J, Ge J, Zhang X, Cheng L, Zhang Z, He S, Wang Y, Lin H, Yang W, Liu J, Zhao Y, Deng H (2016). Pluripotent stem cells induced from mouse neural stem cells and small intestinal epithelial cells by small molecule compounds. Cell Res, 26(1): 34–45

78 Yu C, Liu K, Tang S, Ding S (2014). Chemical approaches to cell reprogramming. Curr Opin Genet Dev, 28: 50–56

79 Yu J, Chau K F, Vodyanik M A, Jiang J, Jiang Y (2011). Efficient feeder-free episomal reprogramming with small molecules. PLoS ONE, 6(3): e17557

80 Yu J, Hu K, Smuga-Otto K, Tian S, Stewart R, Slukvin I I, Thomson J A (2009). Human induced pluripotent stem cells free of vector and transgene sequences. Science, 324(5928): 797–801

81 Zhang L, Yin J C, Yeh H, Ma N X, Lee G, Chen X A, Wang Y, Lin L, Chen L, Jin P, Wu G Y, Chen G (2015). Small Molecules Efficiently Reprogram Human Astroglial Cells into Functional Neurons. Cell Stem Cell, 17(6): 735–747

82 Zhao Y, Zhao T, Guan J, Zhang X, Fu Y, Ye J, Zhu J, Meng G, Ge J, Yang S, Cheng L, Du Y, Zhao C, Wang T, Su L, Yang W, Deng H (2015). A XEN-like State Bridges Somatic Cells to Pluripotency during Chemical Reprogramming. Cell, 163(7): 1678–1691

83 Zhou H, Wu S, Joo J Y, Zhu S, Han D W, Lin T, Trauger S, Bien G, Yao S, Zhu Y, Siuzdak G, Scholer H R, Duan L, Ding S (2009). Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell, 4(5): 381–384

84 Zhou Y y, Zeng F (2013). Integration-free Methods for Generating Induced Pluripotent Stem Cells. Genomics Proteomics Bioinformatics, 11(5): 284–287

85 Zhu S, Li W, Zhou H, Wei W, Ambasudhan R, Lin T, Kim J, Zhang K, Ding S (2010). Reprogramming of human primary somatic cells by OCT4 and chemical compounds. Cell Stem Cell, 7(6): 651–655