Aneuploidy is permissive for hepatocyte-like cell differentiation from human induced pluripotent stem cells

BMC Research Notes

Stephen A Duncan¹  Sunil K Mallanna¹  Max A Cayo¹  Jun Cai¹  Megan R Determan¹  Fallon K Noto¹ 

[1] Department of Cell Biology, Neurobiology and Anatomy, The Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA

关键词: Aneuploidy;    Hepatocyte differentiation;    iPSC;   

Others  :  1131976
DOI  :  10.1186/1756-0500-7-437

 received in 2013-11-12, accepted in 2014-06-30,  发布年份 2014

【 摘 要 】

Background

The characterization of induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) routinely includes analyses of chromosomal integrity. The belief is that pluripotent stem cells best suited to the generation of differentiated derivatives should display a euploid karyotype; although, this does not appear to have been formally tested. While aneuploidy is commonly associated with cell transformation, several types of somatic cells, including hepatocytes, are frequently aneuploid and variation in chromosomal content does not contribute to a transformed phenotype. This insight has led to the proposal that dynamic changes in the chromosomal environment may be important to establish genetic diversity within the hepatocyte population and such diversity may facilitate an adaptive response by the liver to various insults. Such a positive contribution of aneuploidy to liver function raises the possibility that, in contrast to existing dogma, aneuploid iPSCs may be capable of generating hepatocyte-like cells that display hepatic activities.

Results

We examined whether a human iPSC line that had multiple chromosomal aberrations was competent to differentiate into hepatocytes and found that loss of normal chromosomal content had little impact on the production of hepatocyte-like cells from iPSCs.

Conclusions

iPSCs that harbor an abnormal chromosomal content retain the capacity to generate hepatocyte–like cells with high efficiency.

【 授权许可】

   
2014 Noto et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Robinton DA, Daley GQ: The promise of induced pluripotent stem cells in research and therapy. Nature 2012, 481:295-305.
• [2]Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S: Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007, 131:861-872.
• [3]Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA: Induced pluripotent stem cell lines derived from human somatic cells. Science 2007, 318:1917-1920.
• [4]Ronen D, Benvenisty N: Genomic stability in reprogramming. Curr Opin Genet Dev 2012, 22:444-449.
• [5]Taapken SM, Nisler BS, Newton MA, Sampsell-Barron TL, Leonhard KA, McIntire EM, Montgomery KD: Karotypic abnormalities in human induced pluripotent stem cells and embryonic stem cells. Nat Biotechnol 2011, 29:313-314.
• [6]Pasi CE, Dereli-Oz A, Negrini S, Friedli M, Fragola G, Lombardo A, Van Houwe G, Naldini L, Casola S, Testa G, Trono D, Pelicci PG, Halazonetis TD: Genomic instability in induced stem cells. Cell Death Differ 2011, 18:745-753.
• [7]Martins-Taylor K, Nisler BS, Taapken SM, Compton T, Crandall L, Montgomery KD, Lalande M, Xu RH: Recurrent copy number variations in human induced pluripotent stem cells. Nat Biotechnol 2011, 29(6):488-491.
• [8]Mayshar Y, Ben-David U, Lavon N, Biancotti JC, Yakir B, Clark AT, Plath K, Lowry WE, Benvenisty N: Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell 2010, 7:521-531.
• [9]Gore A, Li Z, Fung HL, Young JE, Agarwal S, Antosiewicz-Bourget J, Canto I, Giorgetti A, Israel MA, Kiskinis E, Lee JH, Loh YH, Manos PD, Montserrat N, Panopoulos AD, Ruiz S, Wilbert ML, Yu J, Kirkness EF, Izpisua Belmonte JC, Rossi DJ, Thomson JA, Eggan K, Daley GQ, Goldstein LS, Zhang K: Somatic coding mutations in human induced pluripotent stem cells. Nature 2011, 471:63-67.
• [10]Laurent LC, Ulitsky I, Slavin I, Tran H, Schork A, Morey R, Lynch C, Harness JV, Lee S, Barrero MJ, Ku S, Martynova M, Semechkin R, Galat V, Gottesfeld J, Izpisua Belmonte JC, Murry C, Keirstead HS, Park HS, Schmidt U, Laslett AL, Muller FJ, Nievergelt CM, Shamir R, Loring JF: Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture. Cell Stem Cell 2011, 8:106-118.
• [11]Duncan AW, Taylor MH, Hickey RD, Hanlon Newell AE, Lenzi ML, Olson SB, Finegold MJ, Grompe M: The ploidy conveyor of mature hepatocytes as a source of genetic variation. Nature 2010, 467:707-710.
• [12]Duncan AW, Hanlon Newell AE, Smith L, Wilson EM, Olson SB, Thayer MJ, Strom SC, Grompe M: Frequent aneuploidy among normal human hepatocytes. Gastroenterology 2012, 142:25-28.
• [13]Si-Tayeb K, Noto FK, Sepac A, Sedlic F, Bosnjak ZJ, Lough JW, Duncan SA: Generation of human induced pluripotent stem cells by simple transient transfection of plasmid DNA encoding reprogramming factors. BMC Dev Biol 2010, 10:81. BioMed Central Full Text
• [14]Si-Tayeb K, Noto FK, Nagaoka M, Li J, Battle MA, Duris C, North PE, Dalton S, Duncan SA: Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells. Hepatology 2010, 51:297-305.
• [15]Delaforest A, Nagaoka M, Si-Tayeb K, Noto FK, Konopka G, Battle MA, Duncan SA: HNF4A is essential for specification of hepatic progenitors from human pluripotent stem cells. Development 2011, 138:4143-4153.
• [16]Nagaoka M, Si-Tayeb K, Akaike T, Duncan SA: Culture of human pluripotent stem cells using completely defined conditions on a recombinant E-cadherin substratum. BMC Dev Biol 2010, 10:60. BioMed Central Full Text
• [17]Ludwig TE, Bergendahl V, Levenstein ME, Yu J, Probasco MD, Thomson JA: Feeder-independent culture of human embryonic stem cells. Nat Methods 2006, 3:637-646.
• [18]Mallanna SK, Duncan SA: Differentiation of hepatocytes from pluripotent stem cells. Curr Protoc Stem Cell Biol 2013., 26Unit 1G.4
• [19]Cayo MA, Cai J, DeLaForest A, Noto FK, Nagaoka M, Clark BS, Collery RF, Si-Tayeb K, Duncan SA: JD induced pluripotent stem cell-derived hepatocytes faithfully recapitulate the pathophysiology of familial hypercholesterolemia. Hepatology 2012, 56:2163-2171.
• [20]Harwood HJJ, Pellarin LD: Kinetics of low-density lipoprotein receptor activity in Hep-G2 cells: derivation and validation of a Briggs-Haldane-based kinetic model for evaluating receptor-mediated endocytotic processes in which receptors recycle. Biochem J 1997, 323:649-659.
• [21]Jackson KG, Maitin V, Leake DS, Yaqoob P, Williams CM: Saturated fat-induced changes in Sf 60–400 particle composition reduces uptake of LDL by HepG2 cells. J Lipid Res 2006, 47:393-403.