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1. Pluripotent transcription factors possess distinct roles in normal versus transformed human stem cells.

Author

Junfeng Ji, Tamra E Werbowetski-Ogilvie, Bonan Zhong, Seok-Ho Hong, and Mickie Bhatia

Subjects
Medicine, Science
Abstract

Cancer and normal stem cells (SCs) share proliferative properties of self-renewal and expression of key transcription factors (TFs). Despite similar TF identities, the functional role of specific TFs responsible for retaining SC state has yet to be examined in cancer.Here, we compare the role of Oct4 and Nanog, two-core pluripotent TFs, in transformed (t-hPSCs), and normal human pluripotent stem cells (hPSCs). Unlike normal SCs, self-renewal and survival of t-hPSCs were found to be independent of Oct4. In contrast, t-hPSCs exhibit hypersensitivity to reduction in Nanog and demonstrate complete loss of self-renewal coupled with apoptosis. Dual and sequential knockdown of Oct4 and Nanog revealed that sensitivity of t-hPSCs to Nanog was Oct4 dependent.Our study indicates a bifurcation for the role of two-core SC and cancer related TFs in self-renewal and survival processes. We suggest that the divergent roles of these TFs establish a paradigm to develop novel therapeutics towards selective destruction of aggressive tumors harboring cancer stem cells (CSCs) with similar molecular signatures.

Published
2009
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2. Engineered zinc-finger transcription factors activate OCT4 (POU5F1), SOX2, KLF4, c-MYC (MYC) and miR302/367

Author

Tamar Dvash, Carol Kreader, Erik R. Eastlund, Ian Lyons, Clyde R. Brown, Ashley L. Fischer, Scott W. Knight, Mark A. Gerber, Bonan Zhong, and Qingzhou Ji

Subjects
Transcriptional Activation, genetic processes, Response element, Kruppel-Like Transcription Factors, Enhancer RNAs, Biology, Protein Engineering, Cell Line, Proto-Oncogene Proteins c-myc, Kruppel-Like Factor 4, Gene expression, Genetics, Humans, natural sciences, Enhancer, Transcription factor, General transcription factor, SOXB1 Transcription Factors, Gene regulation, Chromatin and Epigenetics, fungi, Zinc Fingers, Promoter, Molecular biology, Protein Structure, Tertiary, MicroRNAs, Regulatory sequence, Trans-Activators, Octamer Transcription Factor-3
Abstract

Artificial transcription factors are powerful tools for regulating gene expression. Here we report results with engineered zinc-finger transcription factors (ZF-TFs) targeting four protein-coding genes, OCT4, SOX2, KLF4 and c-MYC, and one noncoding ribonucleic acid (RNA) gene, the microRNA (miRNA) miR302/367 cluster. We designed over 300 ZF-TFs whose targets lie within 1 kb of the transcriptional start sites (TSSs), screened them for increased messenger RNA or miRNA levels in transfected cells, and identified potent ZF-TF activators for each gene. Furthermore, we demonstrate that selected ZF-TFs function with alternative activation domains and in multiple cell lines. For OCT4, we expanded the target range to -2.5 kb and +500 bp relative to the TSS and identified additional active ZF-TFs, including three highly active ZF-TFs targeting distal enhancer, proximal enhancer and downstream from the proximal promoter. Chromatin immunoprecipitation (FLAG-ChIP) results indicate that several inactive ZF-TFs targeting within the same regulatory region bind as well as the most active ZF-TFs, suggesting that efficient binding within one of these regulatory regions may be necessary but not sufficient for activation. These results further our understanding of ZF-TF design principles and corroborate the use of ZF-TFs targeting enhancers and downstream from the TSS for transcriptional activation.

Published
2014
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3. Contributors

Author

Russell C. Addis, Jon D. Ahlstrom, Michal Amit, Peter W. Andrews, Joyce Axelman, M. Azim Surani, Nissim Benvenisty, Mickie Bhatia, Ali H. Brivanlou, Joseph W. Carnwath, Melissa K. Carpenter, Howard Y. Chang, Xin Chen, Tao Cheng, Susana M. Chuva de Sousa Lopes, Gregory O. Clark, Joshua D. Dowell, Jonathan S. Draper, Martin Evans, Loren J. Field, Margaret T. Fuller, Richard L. Gardner, Svetlana Gavrilov, John D. Gearhart, Charles A. Gersbach, Marko E. Horb, Joseph Itskovitz-Eldor, Junfeng Ji, Penny Johnson, D. Leanne Jones, Kathleen C. Kent, Candace L. Kerr, Ali Khademhosseini, Irina Klimanskaya, Jennifer N. Kraszewski, Wilfried A. Kues, Donald W. Landry, Robert Langer, Shulamit Levenberg, John W. Littlefield, Andrea Lucas-Hahn, Anne McLaren, Jill McMahon, M. Martins-Green, Yoav Mayshar, Douglas Melton, Christine L. Mummery, Andras Nagy, Heiner Niemann, Shin-Ichi Nishikawa, Hitoshi Niwa, Keisuke Okita, Virginia E. Papaioannou, Ethan S. Patterson, Alice Pébay, Martin F. Pera, M. Petreaca, Emily N. Price, Jane Rossant, Michael Rubart, David T. Scadden, Thomas Schulz, Michael J. Shamblott, Harvir Singh, David L. Stocum, James A. Thomson, David Tosh, Alan Trounson, Chunhui Xu, Kohei Yamamizu, Shinya Yamanaka, Jun K. Yamashita, Holly Young, Bonan Zhong, Leonard I. Zon, Thomas P. Zwaka, and Robert Zweigerdt

Published
2013
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4. Safeguarding Nonhuman Primate iPS Cells With Suicide Genes

Author

Martin E. Wohlfahrt, Hans-Peter Kiem, Jennifer E. Adair, Korashon L. Watts, Jennifer L. Gori, Joerg Enssle, and Bonan Zhong

Subjects
Cellular differentiation, Genetic Vectors, Green Fluorescent Proteins, Induced Pluripotent Stem Cells, Mutagenesis (molecular biology technique), Mice, SCID, Cell fate determination, Biology, Regenerative Medicine, Regenerative medicine, Cell Line, Insertional mutagenesis, 03 medical and health sciences, Mice, 0302 clinical medicine, Mice, Inbred NOD, Drug Discovery, Genetics, Animals, Humans, Cloning, Molecular, Induced pluripotent stem cell, Molecular Biology, 030304 developmental biology, Cell Proliferation, Pharmacology, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, Lentivirus, Genes, Transgenic, Suicide, Teratoma, Cell Differentiation, Sequence Analysis, DNA, Suicide gene, 3. Good health, Cell biology, Blotting, Southern, Mutagenesis, Insertional, Gene Expression Regulation, Cell culture, 030220 oncology & carcinogenesis, Models, Animal, Molecular Medicine, Macaca, Original Article
Abstract

The development of technology to generate induced pluripotent stem (iPS) cells constitutes one of the most exciting scientific breakthroughs because of the enormous potential for regenerative medicine. However, the safety of iPS cell-related products is a major concern for clinical translation. Insertional mutagenesis, possible oncogenic transformation of iPS cells or their derivatives, or the contamination of differentiated iPS cells with undifferentiated cells, resulting in the formation of teratomas, have remained considerable obstacles. Here, we demonstrate the utility of suicide genes to safeguard iPS cells and their derivatives. We found suicide genes can control the cell fate of iPS cells in vitro and in vivo without interfering with their pluripotency and self-renewal capacity. This study will be useful to evaluate the safety of iPS cell technology in a clinically highly relevant, large animal model and further benefit the clinical use of human iPS cells.

Published
2011

5. Genetic Approaches in Human Embryonic Stem Cells and their Derivatives: Prospects for Regenerative Medicine

Author

Mickie Bhatia, Bonan Zhong, and Junfeng Ji

Subjects
Genetics, Context (language use), Biology, equipment and supplies, biology.organism_classification, Embryonic stem cell, Regenerative medicine, Cell biology, Transplantation, chemistry.chemical_compound, chemistry, embryonic structures, biological phenomena, cell phenomena, and immunity, Homologous recombination, Gene, reproductive and urinary physiology, DNA, Gammaretrovirus
Abstract

This chapter reviews current protocols to maintain human embryonic stem cells (hESCs), genetic approaches to modifying undifferentiated hESCs, differentiation of hESCs into multiple lineages and transplantation of their derivatives, and genetic manipulation of hESC-derived progenies and also discusses the potential applications of genetic modifications of hESCs and their derivatives in the context of regenerative medicine. Knock-in/knockout technologies based on homologous recombination are the most widely used methods to study gene function in most mammals. Homologous recombination in hESCs is important for modifying specific hESC-derived tissues for therapeutic applications in transplantation medicine. In vitro studies of hESCs involved in understanding the pathogenesis of gene disorder diseases such as Wiskott-Aldrich syndrome or cancer also need the loss-and-gain methods. Synthetic chemicals such as cationic lipids are extensively used for the delivery of DNA into hESCs. These chemical approaches are based on the neutralization of cationic lipids to negatively charged DNA followed by the formation of DNA/lipid complexes, which possess an excess of positive charges. These complexes bind to the negatively charged membranes of hESCs and are subsequently taken by the cells through endocytosis. Retroviral vectors are used for stable gene transfer into mammalian cells. They are derived from retroviruses. This family consists of seven genera that include alpharetrovirus, betaretrovirus, gammaretrovirus, deltaretrovirus, epsilonretrovirus, lentivirus, and spumavirus.

Published
2011
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6. Contributors

Author

Tamer Aboushwareb, Jon D. Ahlstrom, Alejandro J. Almarza, James M. Anderson, Judith Arcidiacono, Anthony Atala, Stephen F. Badylak, Jae Hyun Bae, Brian G. Ballios, Ashok Batra, M. Douglas Baumann, Ravi V. Bellamkonda, Nicole M. Bergmann, Mickie Bhatia, Martin A. Birchall, Helen M. Blau, Joel D. Boerckel, Ali H. Brivanlou, Mara Cananzi, Arnold I. Caplan, Joseph W. Carnwath, Grant A. Challen, George J. Christ, Hyun Jung Chung, Maegen Colehour, Michael J. Cooke, V.M. Correlo, Benjamin D. Cosgrove, Stefano Da Sacco, Jiyoung M. Dang, Richard M. Day, Paolo De Coppi, Roger E. De Filippo, Mahesh C. Dodla, Juan Domínguez-Bendala, Ryan P. Dorin, Charles N. Durfor, Rita B. Effros, Jennifer H. Elisseeff, Ewa C.S. Ellis, Juliet A. Emamaullee, Per Fagerholm, Qiang Feng, Donald Fink, Matthew B. Fisher, Andrés J. García, Svetlana Gavrilov, Dan Gazit, Zulma Gazit, Christopher V. Gemmiti, Charles A. Gersbach, Margaret A. Goodell, Deborah Lavoie Grayeski, Ronald M. Green, May Griffith, Robert E. Guldberg, Qiongyu Guo, M.C. Hacker, Joanne Hackett, Joshua M. Hare, Benjamin S. Harrison, Konstantinos E. Hatzistergos, Kevin E. Healy, Stephen L. Hilbert, Jiang Hu, Alexander Huber, H. David Humes, Elizabeth F. Irwin, Brett C. Isenberg, Takanori Iwata, Sam Janes, Lily Jeng, Junfeng Ji, Josephine Johnston, Kimberly A. Johnston, David L. Kaplan, David S. Kaplan, Sinan Karaoglu, Adam J. Katz, Jaehyun Kim, Erin A. Kimbrel, Nadav Kimelman, Jonathan A. Kluge, Chester J. Koh, Yash M. Kolambkar, Makoto Komura, Wilfried A. Kues, Francois Ng kee Kwong, Neil Lagali, Deepak A. Lamba, Donald W. Landry, Robert Lanza, Barrett Larson, Malcolm A. Latorre, Ellen Lazarus, Hyukjin Lee, Mark H. Lee, Sang Jin Lee, Gary G. Leisk, Feng Li, Rui Liang, Kuanyin K. Lin, Xiaohua Liu, Michael T. Longaker, H. Peter Lorenz, Shi-Jiang Lu, Andrea Lucas-Hahn, Peter X. Ma, Paolo Macchiarini, Masood A. Machingal, J.F. Mano, M. Martins-Green, Michael McCall, Richard McFarland, Melissa K. McHale, Alexander F. Mericli, A.G. Mikos, Vivek J. Mukhatyar, Allison Nauta, N.M. Neves, Heiner Niemann, Teruo Okano, Keisuke Okita, J.M. Oliveira, Virginia E. Papaioannou, Tae Gwan Park, Gadi Pelled, Laura Perin, M. Petreaca, Antonello Pileggi, Jacob F. Pollock, Blaise D. Porter, Milica Radisic, Nandini Rao, A.H. Reddi, Thomas A. Reh, R.L. Reis, Camillo Ricordi, Philip Roelandt, Caroline Beth Sangan, Justin M. Saul, David V. Schaffer, Gunter Schuch, Michael V. Sefton, Sarah Selem, A.M. James Shapiro, Heather Sheardown, Dima Sheyn, Molly S. Shoichet, Harvir Singh, Sirinrath Sirivisoot, Daniel Skuk, Shay Soker, Myron Spector, David L. Stocum, Stephen C. Strom, James A. Thomson, David Tosh, Robert T. Tranquillo, Jacques P. Tremblay, Catherine M. Verfaillie, Zhan Wang, Jennifer L. West, Kevin J. Whittlesey, Chrysanthi Williams, David F. Williams, J. Koudy Williams, Celia Witten, Savio L.-Y. Woo, Fiona Wood, Shinya Yamanaka, Masayuki Yamato, Saami K. Yazdani, James J. Yoo, Junying Yu, and Bonan Zhong

Published
2011
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7. Efficient generation of nonhuman primate induced pluripotent stem cells

Author

Hans-Peter Kiem, Aravind Ramakrishnan, Martin E. Wohlfahrt, Bonan Zhong, Xiao-Bing Zhang, Grant D. Trobridge, Korashon L. Watts, and Jennifer E. Adair

Subjects
Male, Risk, Genetic Vectors, Induced Pluripotent Stem Cells, Kruppel-Like Transcription Factors, Biology, Regenerative Medicine, Transfection, Regenerative medicine, Viral vector, Cell Line, Proto-Oncogene Proteins c-myc, Kruppel-Like Factor 4, Mice, SOX2, Original Research Reports, Animals, Humans, Induced pluripotent stem cell, Reverse Transcriptase Polymerase Chain Reaction, SOXB1 Transcription Factors, Cell Differentiation, Cell Biology, Hematology, Fibroblasts, Cellular Reprogramming, Microarray Analysis, Cell biology, Transplantation, KLF4, Immunology, Female, Gammaretrovirus, Macaca nemestrina, Reprogramming, Octamer Transcription Factor-3, Developmental Biology
Abstract

Induced pluripotent stem (iPS) cells have great potential for regenerative medicine and gene therapy. Thus far, iPS cells have typically been generated using integrating viral vectors expressing various reprogramming transcription factors; nonintegrating methods have been less effective and efficient. Because there is a significant risk of malignant transformation and cancer involved with the use of iPS cells, careful evaluation of transplanted iPS cells will be necessary in small and large animal studies before clinical application. Here, we have generated and characterized nonhuman primate iPS cells with the goal of evaluating iPS cell transplantation in a clinically relevant large animal model. We developed stable Phoenix-RD114-based packaging cell lines that produce OCT4, SOX2, c-MYC, and KLF4 (OSCK) expressing gammaretroviral vectors. Using these vectors in combination with small molecules, we were able to efficiently and reproducibly generate nonhuman primate iPS cells from pigtailed macaques (Macaca nemestrina). The established nonhuman primate iPS cells exhibited pluripotency and extensive self-renewal capacity. The facile and reproducible generation of nonhuman primate iPS cells using defined producer cells as a source of individual reprogramming factors should provide an important resource to optimize and evaluate iPS cell technology for studies involving stem cell biology and regenerative medicine.

Published
2010

9. List of Contributors

Author

Jon D. Ahlstrom, Taby Ahsan, Julie Allickson, Alejandro J. Almarza, James M. Anderson, Peter Andrews, Hadi Aslan, Anthony Atala, Stephen F. Badylak, Ashok Batra, M. Douglas Baumann, Ravi V. Bellamkonda, Nicole M. Bergman, Z. Beyhan, Mickie Bhatia, Sangeeta N. Bhatia, Peter M. Black, Helen Blau, Scott D. Boden, Eric M. Brey, Ali H. Brivanlou, Chris R. Brown, Scott P. Bruder, S.M. Chambers, Christopher S. Chen, LiHow Chen, Mike Chen, Sulin Chen, N. Cheng, George J. Christ, Seyung Chung, J.B. Cibelli, Massimo Cimini, Paolo De Coppi, Mahesh C. Dodla, Juan Dominguez-Bendala, AM Doyle, Charles N. Durfor, Yann Echelard, Rita B. Effros, Jennifer Elisseeff, Ewa C.S. Ellis, Juliet A. Emamaullee, Carol A. Erickson, Roger De Filippo, Donald Fink, William H. Fissell, Gary E. Friedlaender, Mark E. Furth, Yossi Gafni, Keneth Gage, Andres Garcia, William Gavin, Daniel Gazit, Zulma Gazit, Christopher S. Gemmiti, Jörg C. Gerlach, Paul J. Gokhale, M.A. Goodell, May Griffith, Louis M. Guenin, Stefano Giuliani, Robert E. Guldberg, M.C. Hacker, Benjamin S. Harrison, Bernd Hartmann, Stephen H. Hilbert, Alexander Hillel, Jason Hipp, Col. J.B. Holcomb, Jeffrey O. Hollinger, Chantal E. Holy, Mariah Hout, Jiang Hu, George T.-J. Huang, Johnny Huard, Elliot E. Hui, H. David Humes, Marcos Intaglietta, Junfeng Ji, Yueha Jiang, Christa Johnen, Josephine Johnston, Akira Joraku, David L. Kaplan, David S. Kaplan, Gilson Khang, Rehan N. Khanzada, Soon Hee Kim, Moon Suk Kim, Nadav Kimelman, Irina Klimanskaya, Jonathan A. Kluge, Yash Kolambkar, Chester J. Koh, Makoto Komura, Douglas Kondziolka, Deniz Konya, Wilfried A. Kues, Francois Ng kee Kwong, Deepak Lamba, Hai Bang Lee, Hyukjin Lee, Gary G. Leisk, Kam W. Leong, Ariel J. Levine, Ren Ke Li, Wan-Ju Li, Grace J. Lim, Yan Lin, William J. Lindblad, Wendy F. Liu, Xiaohua Liu, Andrea Lucas-Hahn, Aernout Luttun, Samuel Lynch, Peter X. Ma, Ellen Maher, Manuela Martins-Green, Randall E. McClelland, Richard McFarland, Larry V. McIntire, Harry Meade, David L. Melican, A.G. Mikos, Fernando Ulloa Montoya, Robert M. Nerem, Heiner Niemann, Aparna Nori, Patrea L. Pabst, Kook In Park, Tae Gwan Park, David P. Patterson, Karen Pauwelyn, Gadi Pelled, Laura Perin, M. Petreaca, Antonello Pileggi, Jason H. Pomerantz, Blaise Porter, Milica Radisic, Buddy D. Ratner, A. Hari Reddi, Thomas A. Reh, Lola M. Reid, Camillo Ricordi, Jeff Ross, Alan J. Russell, Filipe N.C. Santos, John P. Schmitz, Gunter Schuch, Sargis Sedrakyan, Michael V. Sefton, Marta Serafini, Paulesh Shah, A.M. James Shapiro, Heather Sheardown, Molly S. Shoichet, M. Minhaj Siddiqui, Richard L. Sidman, Ronald Silverman, Daniel Skuk, Evan Snyder, Shay Soker, Myron Spector, David L. Stocum, Stephen C. Strom, Doris A. Taylor, Yang D. Teng, James Thomson, Robert T. Tranquillo, Jacques P. Tremblay, Amy Tsai, Rocky S. Tuan, Ross S. Tubo, Mark Van Dyke, Deborah Vavoie, Catherine Verfaillie, F. Jerry Volenec, Sara Wargo, Joseph W. Warnwath, Lawrence Wechsler, Shen Wei, Richard D. Weisel, Jennifer L. West, Chrysanthi Williams, J. Koudy Williams, Celia Witten, Steven E. Wolf, Savio L.-Y. Woo, Jordan H. Wosnick, Christine Wrenzycki, Munira Xaymardan, Hsin-Lei Yao, Saami K. Yazdani, Pamela C. Yelick, James J. Yoo, Junying Yu, Katrin Zeilinger, Lepeng Zeng, Andrey G. Zenovich, Bonan Zhong, Carol A. Ziomek, and Laurie Zoloth

Published
2008
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