Generation of induced pluripotent stem cells without genetic defects by small molecules

被引：22

作者：

Park, Hang-Soo ^{[1
]}

Hwang, Insik ^{[1
]}

Choi, Kyung-Ah ^{[1
]}

Jeong, Hyesun ^{[1
]}

Lee, Ji-Yun ^{[2
]}

Hong, Sunghoi ^{[1
]}

机构：

[1] Korea Univ, Coll Hlth Sci, Sch Biosyst & Biomed Sci, Seoul 136703, South Korea

[2] Korea Univ, Coll Med, Dept Pathol, Seoul 136701, South Korea

来源：

BIOMATERIALS | 2015年 / 39卷

关键词：

Induced pluripotent stem cells; Small molecules; Genomic stability; DNA double-strand breaks; EPIGENETIC MEMORY; COPY NUMBER; HUMAN ESC; MOUSE; DIFFERENTIATION; ZSCAN4; INHIBITORS; CONVERSION; INDUCTION; TIME;

D O I：

10.1016/j.biomaterials.2014.10.055

中图分类号：

R318 [生物医学工程];

学科分类号：

0831 ;

摘要：

The generation of induced pluripotent stem cells (iPSCs) often causes genetic and epigenetic defects, which may limit their clinical applications. Here, we show that reprogramming in the presence of small molecules preserved the genomic stability of iPSCs by inhibiting DNA double-strand breaks (DSBs) and activating Zscan4 gene. Surprisingly, the small molecules protected normal karyotype by facilitating repair of the DSBs that occurred during the early reprogramming process and long-term culture of iPSCs. The stemness and cell growth of iPSCs(+) were normally sustained with high expression of pluripotency genes compared that of iPSCs(-). Moreover, small molecules maintained the differentiation potential of iPSCs(+) for the three germ layers, whereas it was lost in iPSCs(-). Our results demonstrate that the defined small molecules are potent factors for generation of high quality iPSCs with preservation of genomic integrity by facilitating the reprogramming process. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：47 / 58

页数：12

共 50 条

[11] Zscan4:: A novel gene expressed exclusively in late 2-cell embryos and embryonic stem cells [J].

Falco, Geppino ;

Lee, Sung-Lim ;

Stanghellini, Ilaria ;

Bassey, Uwem C. ;

Hamatani, Toshio ;

Ko, Minoru S. H. .

DEVELOPMENTAL BIOLOGY, 2007, 307 (02) :539-550

[12] Somatic coding mutations in human induced pluripotent stem cells [J].

Gore, Athurva ;

Li, Zhe ;

Fung, Ho-Lim ;

Young, Jessica E. ;

Agarwal, Suneet ;

Antosiewicz-Bourget, Jessica ;

Canto, Isabel ;

Giorgetti, Alessandra ;

Israel, Mason A. ;

Kiskinis, Evangelos ;

Lee, Je-Hyuk ;

Loh, Yuin-Han ;

Manos, Philip D. ;

Montserrat, Nuria ;

Panopoulos, Athanasia D. ;

Ruiz, Sergio ;

Wilbert, Melissa L. ;

Yu, Junying ;

Kirkness, Ewen F. ;

Izpisua Belmonte, Juan Carlos ;

Rossi, Derrick J. ;

Thomson, James A. ;

Eggan, Kevin ;

Daley, George Q. ;

Goldstein, Lawrence S. B. ;

Zhang, Kun .

NATURE, 2011, 471 (7336) :63-U76

[13] Zscan4 transiently reactivates early embryonic genes during the generation of induced pluripotent stem cells [J].

Hirata, Tetsuya ;

Amano, Tomokazu ;

Nakatake, Yuhki ;

Amano, Misa ;

Piao, Yulan ;

Hoang, Hien G. ;

Ko, Minoru S. H. .

SCIENTIFIC REPORTS, 2012, 2

[14] Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds [J].

Huangfu, Danwei ;

Maehr, Rene ;

Guo, Wenjun ;

Eijkelenboom, Astrid ;

Snitow, Melinda ;

Chen, Alice E. ;

Melton, Douglas A. .

NATURE BIOTECHNOLOGY, 2008, 26 (07) :795-797

[15] Copy number variation and selection during reprogramming to pluripotency [J].

Hussein, Samer M. ;

Batada, Nizar N. ;

Vuoristo, Sanna ;

Ching, Reagan W. ;

Autio, Reija ;

Narva, Elisa ;

Ng, Siemon ;

Sourour, Michel ;

Hamalainen, Riikka ;

Olsson, Cia ;

Lundin, Karolina ;

Mikkola, Milla ;

Trokovic, Ras ;

Peitz, Michael ;

Bruestle, Oliver ;

Bazett-Jones, David P. ;

Alitalo, Kari ;

Lahesmaa, Riitta ;

Nagy, Andras ;

Otonkoski, Timo .

NATURE, 2011, 471 (7336) :58-U67

[16] A Small-Molecule Inhibitor of Tgf-β Signaling Replaces Sox2 in Reprogramming by Inducing Nanog [J].

Ichida, Justin K. ;

Blanchard, Joel ;

Lam, Kelvin ;

Son, Esther Y. ;

Chung, Julia E. ;

Egli, Dieter ;

Loh, Kyle M. ;

Carter, Ava C. ;

Di Giorgio, Francesco P. ;

Koszka, Kathryn ;

Huangfu, Danwei ;

Akutsu, Hidenori ;

Liu, David R. ;

Rubin, Lee L. ;

Eggan, Kevin .

CELL STEM CELL, 2009, 5 (05) :491-503

[17] Differentiation of human embryonic stem cells into embryoid bodies comprising the three embryonic germ layers [J].

Itskovitz-Eldor, J ;

Schuldiner, M ;

Karsenti, D ;

Eden, A ;

Yanuka, O ;

Amit, M ;

Soreq, H ;

Benvenisty, N .

MOLECULAR MEDICINE, 2000, 6 (02) :88-95

[18] Comparative Analysis of Endoderm Formation Efficiency Between Mouse ES Cells and iPS Cells [J].

Iwamuro, Masaya ;

Komaki, Toshiyuki ;

Kubota, Yasuhiro ;

Seita, Masayuki ;

Kawamoto, Hironobu ;

Yuasa, Takeshi ;

Shahid, Javed M. ;

Hassan, Reham A. R. A. ;

Hassan, Wael A. R. A. ;

Nakaji, Shuhei ;

Nishikawa, Yuriko ;

Kondo, Eisaku ;

Yamamoto, Kazuhide ;

Kobayashi, Naoya .

CELL TRANSPLANTATION, 2010, 19 (6-7) :831-839

[19] Zscan4 promotes genomic stability during reprogramming and dramatically improves the quality of iPS cells as demonstrated by tetraploid complementation [J].

Jiang, Jing ;

Lv, Wenjian ;

Ye, Xiaoying ;

Wang, Lingbo ;

Zhang, Man ;

Yang, Hui ;

Okuka, Maja ;

Zhou, Chikai ;

Zhang, Xuan ;

Liu, Lin ;

Li, Jinsong .

CELL RESEARCH, 2013, 23 (01) :92-106

[20] Epigenetic memory in induced pluripotent stem cells [J].

Kim, K. ;

Doi, A. ;

Wen, B. ;

Ng, K. ;

Zhao, R. ;

Cahan, P. ;

Kim, J. ;

Aryee, M. J. ;

Ji, H. ;

Ehrlich, L. I. R. ;

Yabuuchi, A. ;

Takeuchi, A. ;

Cunniff, K. C. ;

Hongguang, H. ;

Mckinney-Freeman, S. ;

Naveiras, O. ;

Yoon, T. J. ;

Irizarry, R. A. ;

Jung, N. ;

Seita, J. ;

Hanna, J. ;

Murakami, P. ;

Jaenisch, R. ;

Weissleder, R. ;

Orkin, S. H. ;

Weissman, I. L. ;

Feinberg, A. P. ;

Daley, G. Q. .

NATURE, 2010, 467 (7313) :285-U60

← 1 2 3 4 5 →