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ScienceDirect Editorial overview: Cell reprogramming, regeneration and repair Jose´ C R Silva and Renee A Reijo Pera Current Opinion in Genetics & Development 2014, 28:v–vi For a complete overview see the Issue http://dx.doi.org/10.1016/j.gde.2014.11.003 0959-437X/Crown Copyright # 2014 Published by Elsevier Ltd. All rights reserved.
Jose´ C R Silva Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK e-mail: [email protected] Jose´ Silva is a senior group leader at the Cambridge Stem Cell Institute, University of Cambridge. He is a biologist with an interest in the nuclear reprogramming of differentiated cells back into pluripotency. His current focus is to understand at the molecular level how reprogramming works.
Renee A Reijo Pera Montana State University, Department of Cell Biology and Neuroscience, Bozeman, MT 59711-2460, USA e-mail: [email protected] Renee Reijo Pera is the vice president for research, creativity and technology transfer at Montana State. Previously she was the Director of the Human Embryonic Stem Cell Research and Education. Her research is aimed at understanding the genetics of human embryo growth and development and in characterizing the basic properties of human embryonic stem cells, especially their ability to differentiate to all cell types including germ cells.
This issue of Current Opinion in Genetics and Development is focused on cell reprogramming, regeneration and repair. The field of cell reprogramming is rapidly evolving and entering into a new and exciting phase in which we are beginning to address, and understand, fundamental aspects of the process. This promises to not only provide new insights into biological processes but also may enable generation of higher quality iPS cells which may deliver much-desired applications in stem cell medicine. The seminal work of Kazutoshi Takahashi and Shinya Yamanaka has shown that the exogenous expression of a small group of transcription factors involved in the maintenance of pluripotent stem cells can mediate reprogramming of differentiated cells back into pluripotent stem cells. Subsequent developments have found that additional transcription factors associated with the maintenance of pluripotent cells also have reprogramming capacity. As discussed in this issue by Niwa, this highlights a strong parallel between the transcription factor network governing the maintenance of pluripotent cells and reprogramming. It is known that the transcriptional context of differentiated cells differs greatly from that of the target pluripotent cells. Analysis of the interactomes of transcription factors regulating reprogramming have found numerous cofactors which when manipulated in a reprogramming context could either boost or block the process of induced pluripotency. In addition, and as discussed by Wang and Huang, these interactome studies highlighted the presence of numerous chromatin regulators as high confidence interactors of the key transcriprion factors mediating reprogramming, thus linking transcription factor function in reprogramming with the epigenetic machinery. One aspect of reprogramming which has gained increased significance is the importance of the culture environment for this process to take place. Several signaling pathways, including the inhibition of some of these, have now been identified to play a role in reprogramming. As discussed by Ying and colleagues, the investigation of how these pathways induce and maintain pluripotency in the mouse system is aiding the pursuit of equivalent pluripotent stem cells in other mammals including humans. Such pluripotent cells could represent a significant improvement over current human ESCs and iPSCs for the development of the stem cell field. As a testimony to the relevance of this, research in this area has seen a great expansion in the last year. As discussed by Cooke and colleagues recent studies show that efficient induction of pluripotency requires the activation of innate immunity. Recent reports on newly generated human iPSCs are also generating
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Current Opinion in Genetics & Development 2014, 28:v–vi
vi Cell reprogramming, regeneration and repair
a great interest in terms of understanding the status of the X chromosome in female human pluripotent cells. One would expect that like the murine system, human pluripotent cells have not yet made a choice as to which X chromosome to silence considering that women present a random X inactivation pattern in their tissues and cell types. The implications of the reactivation of the silent Xchromosome in female iPS cells and the potential use of these for studying the process of X-inactivation in humans is discussed in this issue by Reijo Pera and Briggs. Insights into the biology of reprogramming are also originating from the use of small molecules acting not only in signaling pathways but also on epigenetic enzymes, nuclear receptors and metabolic regulators. Again, the fact that these small molecules, which are added to the medium, are found to facilitate reprogramming, reinforce the role played by the culture environment in this process. The potential mechanisms by which these small molecules contribute to reprogramming are discussed in this issue by Ding and colleagues. The application of new technologies is also aiding the fast development of the study of the process of induced pluripotency as discussed by Liu and colleagues. This includes the modulation of gene expression by designer transcription factors generated by different platforms, namely Transcription activator-like Effector (TALE), Zinc Finger Effector (ZFE) and Clustered Regularly Interspaced Short Palindromic Repeats Effector (CRISPRE). Another topical area to reprogramming is the question regarding the route that cells take to reach a pluripotent state. Evidence is growing that there is a certain order to this process. The current knowledge aiming at characterizing the route taken by cells during reprogramming is discussed in this issue by Kaji and Ruetz. The process of induced pluripotency is also a great cell system to understand how cell identity changes take place. This is not well understood. Potential models for how cells change identity during reprogramming in light of recent evidence suggesting that transcription factors associated with lineage specification can also induce pluripotency, are discussed in this issue by Izpisua Belmonte and colleagues. One key cell identity change taking place during the reprogramming of fibroblasts into pluripotent stem cells is the transition from a mesenchymal identity into an epithelial identity. This follows the reverse order of normal development and is seen as a major step for successful reprogramming. The latest advances in our understanding of the function and the
Current Opinion in Genetics & Development 2014, 28:v–vi
regulation of this event in reprogramming is discussed in this issue by Pei and Shu. Furthermore, in the review by Huo, Baylin and Zambidis, the relationship between epigenetic changes in human pluripotent stem cells (hPSCs) and cancer are discussed with a focus on the potential for tumorigenicity following differentiation. Epigenetic alterations that are observed in hPSCs include those of promoter DNA hypermethylation, histone modifications, and X chromosome inactivation. Importantly, several studies suggest that abnormalities of epigenetic programs can be minimized with use of preferential methods to reprogram to produce lines that may be more optimal for diverse basic, translational and/ or clinical applications. The review of Sebastiano and Au further describes the identification of a remarkable set of new genetic loci that are expressed specifically in hESCs and are likely to intersect with the epigenetic programs of stem cells in vitro and in vivo during development. Comparisons of reprogramming in vitro and that which occurs during formation of the germ cell lineage in both mouse and humans is the subject of the review by Simo´n and colleagues. In this review, current knowledge regarding germ line development is contrasted in the mouse and human with a focus on genetic and epigenetic determinants of germ line fate. Studies that seek to model germ line development in both species, in vitro, are then compared and contrasted. Lee and colleagues describe elegant methods of in vivo imaging that are increasingly being used to track stem cell fate following transplantation. Discussion of reporter gene technologies, structural and functional brain imaging, and imaging of biomarkers provides key material at the intersection of stem cell biology, engineering and translational science that may contribute to promising directions for future research at the interface of stem cell therapies and neuroimaging. In conclusion, the topics covered in this issue are laying the foundation for a comprehensive understanding of how reprogramming works. This is of paramount importance as generated pluripotent cells represent the base for the design of future applications in stem cell medicine. A solid step toward the latter is therefore dependent on the continued support for research aiming at the fundamental understanding of the basic biology underlying reprogramming.
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ScienceDirect Editorial overview: Cell reprogramming, regeneration and repair Jose´ C R Silva and Renee A Reijo Pera Current Opinion in Genetics & Development 2014, 28:v–vi For a complete overview see the Issue http://dx.doi.org/10.1016/j.gde.2014.11.003 0959-437X/Crown Copyright # 2014 Published by Elsevier Ltd. All rights reserved.
Jose´ C R Silva Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK e-mail: [email protected] Jose´ Silva is a senior group leader at the Cambridge Stem Cell Institute, University of Cambridge. He is a biologist with an interest in the nuclear reprogramming of differentiated cells back into pluripotency. His current focus is to understand at the molecular level how reprogramming works.
Renee A Reijo Pera Montana State University, Department of Cell Biology and Neuroscience, Bozeman, MT 59711-2460, USA e-mail: [email protected] Renee Reijo Pera is the vice president for research, creativity and technology transfer at Montana State. Previously she was the Director of the Human Embryonic Stem Cell Research and Education. Her research is aimed at understanding the genetics of human embryo growth and development and in characterizing the basic properties of human embryonic stem cells, especially their ability to differentiate to all cell types including germ cells.
This issue of Current Opinion in Genetics and Development is focused on cell reprogramming, regeneration and repair. The field of cell reprogramming is rapidly evolving and entering into a new and exciting phase in which we are beginning to address, and understand, fundamental aspects of the process. This promises to not only provide new insights into biological processes but also may enable generation of higher quality iPS cells which may deliver much-desired applications in stem cell medicine. The seminal work of Kazutoshi Takahashi and Shinya Yamanaka has shown that the exogenous expression of a small group of transcription factors involved in the maintenance of pluripotent stem cells can mediate reprogramming of differentiated cells back into pluripotent stem cells. Subsequent developments have found that additional transcription factors associated with the maintenance of pluripotent cells also have reprogramming capacity. As discussed in this issue by Niwa, this highlights a strong parallel between the transcription factor network governing the maintenance of pluripotent cells and reprogramming. It is known that the transcriptional context of differentiated cells differs greatly from that of the target pluripotent cells. Analysis of the interactomes of transcription factors regulating reprogramming have found numerous cofactors which when manipulated in a reprogramming context could either boost or block the process of induced pluripotency. In addition, and as discussed by Wang and Huang, these interactome studies highlighted the presence of numerous chromatin regulators as high confidence interactors of the key transcriprion factors mediating reprogramming, thus linking transcription factor function in reprogramming with the epigenetic machinery. One aspect of reprogramming which has gained increased significance is the importance of the culture environment for this process to take place. Several signaling pathways, including the inhibition of some of these, have now been identified to play a role in reprogramming. As discussed by Ying and colleagues, the investigation of how these pathways induce and maintain pluripotency in the mouse system is aiding the pursuit of equivalent pluripotent stem cells in other mammals including humans. Such pluripotent cells could represent a significant improvement over current human ESCs and iPSCs for the development of the stem cell field. As a testimony to the relevance of this, research in this area has seen a great expansion in the last year. As discussed by Cooke and colleagues recent studies show that efficient induction of pluripotency requires the activation of innate immunity. Recent reports on newly generated human iPSCs are also generating
www.sciencedirect.com
Current Opinion in Genetics & Development 2014, 28:v–vi
vi Cell reprogramming, regeneration and repair
a great interest in terms of understanding the status of the X chromosome in female human pluripotent cells. One would expect that like the murine system, human pluripotent cells have not yet made a choice as to which X chromosome to silence considering that women present a random X inactivation pattern in their tissues and cell types. The implications of the reactivation of the silent Xchromosome in female iPS cells and the potential use of these for studying the process of X-inactivation in humans is discussed in this issue by Reijo Pera and Briggs. Insights into the biology of reprogramming are also originating from the use of small molecules acting not only in signaling pathways but also on epigenetic enzymes, nuclear receptors and metabolic regulators. Again, the fact that these small molecules, which are added to the medium, are found to facilitate reprogramming, reinforce the role played by the culture environment in this process. The potential mechanisms by which these small molecules contribute to reprogramming are discussed in this issue by Ding and colleagues. The application of new technologies is also aiding the fast development of the study of the process of induced pluripotency as discussed by Liu and colleagues. This includes the modulation of gene expression by designer transcription factors generated by different platforms, namely Transcription activator-like Effector (TALE), Zinc Finger Effector (ZFE) and Clustered Regularly Interspaced Short Palindromic Repeats Effector (CRISPRE). Another topical area to reprogramming is the question regarding the route that cells take to reach a pluripotent state. Evidence is growing that there is a certain order to this process. The current knowledge aiming at characterizing the route taken by cells during reprogramming is discussed in this issue by Kaji and Ruetz. The process of induced pluripotency is also a great cell system to understand how cell identity changes take place. This is not well understood. Potential models for how cells change identity during reprogramming in light of recent evidence suggesting that transcription factors associated with lineage specification can also induce pluripotency, are discussed in this issue by Izpisua Belmonte and colleagues. One key cell identity change taking place during the reprogramming of fibroblasts into pluripotent stem cells is the transition from a mesenchymal identity into an epithelial identity. This follows the reverse order of normal development and is seen as a major step for successful reprogramming. The latest advances in our understanding of the function and the
Current Opinion in Genetics & Development 2014, 28:v–vi
regulation of this event in reprogramming is discussed in this issue by Pei and Shu. Furthermore, in the review by Huo, Baylin and Zambidis, the relationship between epigenetic changes in human pluripotent stem cells (hPSCs) and cancer are discussed with a focus on the potential for tumorigenicity following differentiation. Epigenetic alterations that are observed in hPSCs include those of promoter DNA hypermethylation, histone modifications, and X chromosome inactivation. Importantly, several studies suggest that abnormalities of epigenetic programs can be minimized with use of preferential methods to reprogram to produce lines that may be more optimal for diverse basic, translational and/ or clinical applications. The review of Sebastiano and Au further describes the identification of a remarkable set of new genetic loci that are expressed specifically in hESCs and are likely to intersect with the epigenetic programs of stem cells in vitro and in vivo during development. Comparisons of reprogramming in vitro and that which occurs during formation of the germ cell lineage in both mouse and humans is the subject of the review by Simo´n and colleagues. In this review, current knowledge regarding germ line development is contrasted in the mouse and human with a focus on genetic and epigenetic determinants of germ line fate. Studies that seek to model germ line development in both species, in vitro, are then compared and contrasted. Lee and colleagues describe elegant methods of in vivo imaging that are increasingly being used to track stem cell fate following transplantation. Discussion of reporter gene technologies, structural and functional brain imaging, and imaging of biomarkers provides key material at the intersection of stem cell biology, engineering and translational science that may contribute to promising directions for future research at the interface of stem cell therapies and neuroimaging. In conclusion, the topics covered in this issue are laying the foundation for a comprehensive understanding of how reprogramming works. This is of paramount importance as generated pluripotent cells represent the base for the design of future applications in stem cell medicine. A solid step toward the latter is therefore dependent on the continued support for research aiming at the fundamental understanding of the basic biology underlying reprogramming.
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