The applications of induced pluripotent stem (iPS) cells in drug development

Abstract

The introduction of induced pluripotent stem (iPS) cells has been a milestone in the field of regenerative medicine and drug discovery. iPS cells can provide a continuous and individualized source of stem cells and are considered to hold great potential for economically feasible personalized stem cell therapy. Various diseases might potentially be cured by iPS cell-based therapy including Parkinson’s disease, Alzheimer’s disease, Huntington disease, ischemic heart disease, diabetes and so on. Moreover, iPS cells derived from patients suffering from unique incurable diseases can be developed into patient- and disease-specific cell lines. These cells can be used as an effective approach to study the mechanisms of diseases, providing useful tools for drug discovery, development and evaluation. The development of suitable methods for the culture and expansion of iPS cells and their differentiated progenies make feasible modern drug discovery techniques such as high-throughput screening. Furthermore, iPS cells can be applied in the field of toxicological and pharmacokinetics tests. This review focuses on the applications of iPS cells in the field of pharmaceutical industry.

Keywords

induced pluripotent stem (iPS) cells / drug discovery

References

[1] Barbaric I, Gokhale P J, Andrews P W (2010). High-content screening of small compounds on human embryonic stem cells. Biochem Soc Trans, 38(4): 1046–1050

[2] Bass A J, Watanabe H, Mermel C H, Yu S, Perner S, Verhaak R G, Kim S Y, Wardwell L, Tamayo P, Gat-Viks I, Ramos A H, Woo M S, Weir B A, Getz G, Beroukhim R, O’Kelly M, Dutt A, Rozenblatt-Rosen O, Dziunycz P, Komisarof J, Chirieac L R, Lafargue C J, Scheble V, Wilbertz T, Ma C, Rao S, Nakagawa H, Stairs D B, Lin L, Giordano T J, Wagner P, Minna J D, Gazdar A F, Zhu C Q, Brose M S, Cecconello I, Jr U R, Marie S K, Dahl O, Shivdasani R A, Tsao M S, Rubin M A, Wong K K, Regev A, Hahn W C, Beer D G, Rustgi A K, Meyerson M (2009). SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat Genet, 41(11): 1238–1242

[3] Baxter M A, Rowe C, Alder J, Harrison S, Hanley K P, Park B K, Kitteringham N R, Goldring C E, Hanley N A (2010). Generating hepatic cell lineages from pluripotent stem cells for drug toxicity screening. Stem Cell Res (Amst), 5(1): 4–22

[41] Centofanti M (2010). Models of the stem cell kind. ALS Alert Newsletter, News, <OrgAddress>http://www.alscenter.org/news/newsletter/2010/November/models_of_the_stem_cell_kind.html</OrgAddress>

[4] Chu L H, Chen B S (2008). Comparisons of robustness and sensitivity between cancer and normal cells by microarray data. Cancer Inform, 6: 165–181

[5] Crook J M, Kobayashi N R (2008). Human stem cells for modeling neurological disorders: accelerating the drug discovery pipeline. J Cell Biochem, 105(6): 1361–1366

[6] 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, Wichterle H, Henderson C E, Eggan K (2008). Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science, 321(5893): 1218–1221

[7] Doss M X, Sachinidis A, Hescheler J (2008). Human ES cell derived cardiomyocytes for cell replacement therapy: a current update. Chin J Physiol, 51(4): 226–229

[8] Duinsbergen D, Salvatori D, Eriksson M, Mikkers H (2009). Tumors originating from induced pluripotent stem cells and methods for their prevention. Ann N Y Acad Sci, 1176(1): 197–204

[9] Ebert A D, Svendsen C N (2010). Human stem cells and drug screening: opportunities and challenges. Nat Rev Drug Discov, 9(5): 367–372

[10] Ebert A D, Yu J, Rose F F Jr, Mattis V B, Lorson C L, Thomson J A, Svendsen C N (2009). Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature, 457(7227): 277–280

[11] Foster K W, Frost A R, McKie-Bell P, Lin C Y, Engler J A, Grizzle W E, Ruppert J M (2000). Increase of GKLF messenger RNA and protein expression during progression of breast cancer. Cancer Res, 60(22): 6488–6495

[12] Gunaseeli I, Doss M X, Antzelevitch C, Hescheler J, Sachinidis A (2010). Induced pluripotent stem cells as a model for accelerated patient- and disease-specific drug discovery. Curr Med Chem, 17(8): 759–766

[13] Hanna J, Wernig M, Markoulaki S, Sun C W, Meissner A, Cassady J P, Beard C, Brambrink T, Wu L C, Townes T M, Jaenisch R (2007). Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science, 318(5858): 1920–1923

[14] Heng B C, Richards M, Shu Y, Gribbon P (2009). Induced pluripotent stem cells: a new tool for toxicology screening? Arch Toxicol, 83(7): 641–644

[15] 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

[16] Huangfu D, Maehr R, Guo W, Eijkelenboom A, Snitow M, Chen A E, Melton D A (2008a). Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat Biotechnol, 26(7): 795–797

[17] Huangfu D, Osafune K, Maehr R, Guo W, Eijkelenboom A, Chen S, Muhlestein W, Melton D A (2008b). Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol, 26(11): 1269–1275

[18] 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

[19] Jeter C R, Badeaux M, Choy G, Chandra D, Patrawala L, Liu C, Calhoun-Davis T, Zaehres H, Daley G Q, Tang D G (2009). Functional evidence that the self-renewal gene NANOG regulates human tumor development. Stem Cells, 27(5): 993–1005

[20] Kaitin K I (2008). Obstacles and opportunities in new drug development. Clin Pharmacol Ther, 83(2): 210–212

[21] Lee G, Papapetrou E P, Kim H, Chambers S M, Tomishima M J, Fasano C A, Ganat Y M, Menon J, Shimizu F, Viale A, Tabar V, Sadelain M, Studer L (2009). Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature, 461(7262): 402–406

[22] 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

[23] Maehr R, Chen S, Snitow M, Ludwig T, Yagasaki L, Goland R, Leibel R L, Melton D A (2009). Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci USA, 106(37): 15768–15773

[24] Mauritz C, Schwanke K, Reppel M, Neef S, Katsirntaki K, Maier L S, Nguemo F, Menke S, Haustein M, Hescheler J, Hasenfuss G, Martin U (2008). Generation of functional murine cardiac myocytes from induced pluripotent stem cells. Circulation, 118(5): 507–517

[25] Meyer N, Penn L Z (2008). Reflecting on 25 years with MYC. Nat Rev Cancer, 8(12): 976–990

[26] Nakagawa M, Takizawa N, Narita M, Ichisaka T, Yamanaka S (2010). Promotion of direct reprogramming by transformation-deficient Myc. Proc Natl Acad Sci USA, 107(32): 14152–14157

[27] Nakao Y, Narazaki G, Hoshino T, Maeda S, Yoshida M, Maejima H, Yamashita J K (2008). Evaluation of antiangiogenic activity of azumamides by the in vitro vascular organization model using mouse induced pluripotent stem (iPS) cells. Bioorg Med Chem Lett, 18(9): 2982–2984

[42] Neveu P, Kye M J, Qis, Buchholz D E, Clegg D O, Sahin M, Park I H, Kim K S, Daley G Q, Kornblum H I, Shraiman B I, Kossk K S (2010). MicroRNA profiling reveals two distinct p53-related human pluripotent stem cells states. Cell Stem Cell, 7(6): 671–681

[28] Schüle B, Pera R A, Langston J W (2009). Can cellular models revolutionize drug discovery in Parkinson’s disease? Biochim Biophys Acta, 1792(11): 1043–1051

[29] Shi Y, Do J T, Desponts C, Hahm H S, Schöler H R, Ding S (2008). A combined chemical and genetic approach for the generation of induced pluripotent stem cells. Cell Stem Cell, 2(6): 525–528

[30] 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

[31] Sollano J A, Kirsch J M, Bala M V, Chambers M G, Harpole L H (2008). The economics of drug discovery and the ultimate valuation of pharmacotherapies in the marketplace. Clin Pharmacol Ther, 84(2): 263–266

[32] Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131(5): 861–872

[33] 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

[34] Viswanathan S R, Powers J T, Einhorn W, Hoshida Y, Ng T L, Toffanin S, O’Sullivan M, Lu J, Phillips L A, Lockhart V L, Shah S P, Tanwar P S, Mermel C H, Beroukhim R, Azam M, Teixeira J, Meyerson M, Hughes T P, Llovet J M, Radich J, Mullighan C G, Golub T R, Sorensen P H, Daley G Q (2009). Lin28 promotes transformation and is associated with advanced human malignancies. Nat Genet, 41(7): 843–848

[35] Vojnits K, Bremer S (2010). Challenges of using pluripotent stem cells for safety assessments of substances. Toxicology, 270(1): 10–17

[36] Wernig M, Lengner C J, Hanna J, Lodato M A, Steine E, Foreman R, Staerk J, Markoulaki S, Jaenisch R (2008a). A drug-inducible transgenic system for direct reprogramming of multiple somatic cell types. Nat Biotechnol, 26(8): 916–924

[37] Wernig M, Zhao J P, Pruszak J, Hedlund E, Fu D, Soldner F, Broccoli V, Constantine-Paton M, Isacson O, Jaenisch R (2008b). Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease. Proc Natl Acad Sci USA, 105(15): 5856–5861

[38] 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, Slukvin I I, Thomson J A (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science, 318(5858): 1917–1920

[39] Zhao Y, Yin X, Qin H, Zhu F, Liu H, Yang W, Zhang Q, Xiang C, Hou P, Song Z, Liu Y, Yong J, Zhang P, Cai J, Liu M, Li H, Li Y, Qu X, Cui K, Zhang W, Xiang T, Wu Y, Zhao Y, Liu C, Yu C, Yuan K, Lou J, Ding M, Deng H (2008). Two supporting factors greatly improve the efficiency of human iPSC generation. Cell Stem Cell, 3(5): 475–479

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

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