Volume 23, Issue 1, Page 1-166
About the Cover:
, Jing Qu1,2,*
, Guang-Hui Liu1,2
and Juan Carlos Izpisua Belmonte1,3
Cell Research (2013) 23:3-5. doi:10.1038/cr.2012.131; published online 11 September 2012
Efficient generation of functional human vascular endothelial cells and smooth muscle cells from pluripotent stem cells is an extensively studied topic and of great interest in the stem cell field. Though thought to be technically complex and difficult, substantial progress has been made towards this direction. Here we aim to summarize and discuss the most recent advances in this topic and their future perspective in research and clinic.
, Sundeep Kalantry2
and Anjana Rao1
Cell Research (2013) 23:6-9. doi:10.1038/cr.2012.117; published online 7 August 2012
In zygotes, a global loss of DNA methylation occurs selectively in the paternal pronucleus before the first cell division, concomitantly with the appearance of modified forms of 5-methylcytosine. The adjacent maternal pronucleus and certain paternally-imprinted loci are protected from this process. Nakamura et al. recently clarified the molecular mechanism involved: PGC7/Stella/Dppa3 binds to dimethylated histone 3 lysine 9 (H3K9me2), thereby blocking the activity of the Tet3 methylcytosine oxidase in the maternal genome as well as at certain imprinted loci in the paternal genome.
Ling Li and Ravi Bhatia
Cell Research (2013) 23:10-12. doi:10.1038/cr.2012.112; published online 31 July 2012
Sirtuins are NAD-dependent deacetylases that are conserved from yeast to mammals. A new report sheds light on the function of SIRT7, the least understood member of the Sirtuin family by identifying its locus-specific H3K18 deacetylase activity, and linking it to maintenance of cellular transformation in malignancies.
David J Konieczkowski1,2
and Levi A Garraway1,2,3
Cell Research (2013) 23:13-14. doi:10.1038/cr.2012.115; published online 31 July 2012
Two recent papers identify KRAS activation as a mechanism of acquired resistance to EGFR blockade in colorectal cancer. In doing so, they suggest that resistance to single-agent EGFR blockade will be unavoidable because these alterations exist as latent subclones within the tumor even prior to the initiation of therapy.
Manuela Villion and Sylvain Moineau
Cell Research (2013) 23:15-17. doi:10.1038/cr.2012.124; published online 4 September 2012
A recent paper gives the details on how specific small RNAs can program a protein to cleave an undesired piece of DNA and to provide immunity to a microbial cell.
and Minoo Rassoulzadegan1,2,3
Cell Research (2013) 23:18-19. doi:10.1038/cr.2012.181; published online 25 December 2012
Transcriptionally silent sperm contains a variety of RNA fragments of both coding and non-coding transcripts. A recent article by Peng and colleagues reveals several new families of small RNAs enriched in sperm, which are derived from the same locus as tRNAs. The finding of these short fragments of tRNA in the sperm raises once again the question of the possible function(s) of such a miniaturized form of information carried by the spermatozoon.
and Huck-Hui Ng1,2,3,4,5
Cell Research (2013) 23:20-32. doi:10.1038/cr.2012.172; published online 11 December 2012
The defining features of embryonic stem cells (ESCs) are their self-renewing and pluripotent capacities. Indeed, the ability to give rise into all cell types within the organism not only allows ESCs to function as an ideal in vitro tool to study embryonic development, but also offers great therapeutic potential within the field of regenerative medicine. However, it is also this same remarkable developmental plasticity that makes the efficient control of ESC differentiation into the desired cell type very difficult. Therefore, in order to harness ESCs for clinical applications, a detailed understanding of the molecular and cellular mechanisms controlling ESC pluripotency and lineage commitment is necessary. In this respect, through a variety of transcriptomic approaches, ESC pluripotency has been found to be regulated by a system of ESC-associated transcription factors; and the external signalling environment also acts as a key factor in modulating the ESC transcriptome. Here in this review, we summarize our current understanding of the transcriptional regulatory network in ESCs, discuss how the control of various signalling pathways could influence pluripotency, and provide a future outlook of ESC research.
Samantha A Morris1,2,3
and George Q Daley1,2,3
Cell Research (2013) 23:33-48. doi:10.1038/cr.2013.1; published online 1 January 2013
Human diseases such as heart failure, diabetes, neurodegenerative disorders, and many others result from the deficiency or dysfunction of critical cell types. Strategies for therapeutic tissue repair or regeneration require the in vitro manufacture of clinically relevant quantities of defined cell types. In addition to transplantation therapy, the generation of otherwise inaccessible cells also permits disease modeling, toxicology testing and drug discovery in vitro. In this review, we discuss current strategies to manipulate the identity of abundant and accessible cells by differentiation from an induced pluripotent state or direct conversion between differentiated states. We contrast these approaches with recent advances employing partial reprogramming to facilitate lineage switching, and discuss the mechanisms underlying the engineering of cell fate. Finally, we address the current limitations of the field and how the resulting cell types can be assessed to ensure the production of medically relevant populations.
and Yi Zhang1,2,3,4,5
Cell Research (2013) 23:49-69. doi:10.1038/cr.2012.175; published online 18 December 2012
Pluripotent stem cells, like embryonic stem cells (ESCs), have specialized epigenetic landscapes, which are important for pluripotency maintenance. Transcription factor-mediated generation of induced pluripotent stem cells (iPSCs) requires global change of somatic cell epigenetic status into an ESC-like state. Accumulating evidence indicates that epigenetic mechanisms not only play important roles in the iPSC generation process, but also affect the properties of reprogrammed iPSCs. Understanding the roles of various epigenetic factors in iPSC generation contributes to our knowledge of the reprogramming mechanisms.
and Hideyuki Okano2
Cell Research (2013) 23:70-80. doi:10.1038/cr.2012.171; published online 11 December 2012
Stimulated by the 2012 Nobel Prize in Physiology or Medicine awarded for Shinya Yamanaka and Sir John Gurdon, there is an increasing interest in the induced pluripotent stem (iPS) cells and reprograming technologies in medical science. While iPS cells are expected to open a new era providing enormous opportunities in biomedical sciences in terms of cell therapies and regenerative medicine, safety-related concerns for iPS cell-based cell therapy should be resolved prior to the clinical application of iPS cells. In this review, the pre-clinical investigations of cell therapy for spinal cord injury (SCI) using neural stem/progenitor cells derived from iPS cells, and their safety issues in vivo, are outlined. We also wish to discuss the strategy for the first human trails of iPS cell-based cell therapy for SCI patients.
, Kai Jiang2
, Wanguo Wei3
, Yan Shi4
and Sheng Ding2
Cell Research (2013) 23:81-91. doi:10.1038/cr.2012.182; published online 25 December 2012
Stem cells, including both pluripotent stem cells and multipotent somatic stem cells, hold great potential for interrogating the mechanisms of tissue development, homeostasis and pathology, and for treating numerous devastating diseases. Establishment of in vitro platforms to faithfully maintain and precisely manipulate stem cell fates is essential to understand the basic mechanisms of stem cell biology, and to translate stem cells into regenerative medicine. Chemical approaches have recently provided a number of small molecules that can be used to control cell self-renewal, lineage differentiation, reprogramming and regeneration. These chemical modulators have been proven to be versatile tools for probing stem cell biology and manipulating cell fates toward desired outcomes. Ultimately, this strategy is promising to be a new frontier for drug development aimed at endogenous stem cell modulation.
, Wenjian Lv1,*
, Xiaoying Ye2
, Lingbo Wang1
, Man Zhang1
, Hui Yang1
, Maja Okuka3
, Chikai Zhou1
, Xuan Zhang1
, Lin Liu2
Cell Research (2013) 23:92-106. doi:10.1038/cr.2012.157; published online 13 November 2012
Induced pluripotent stem (iPS) cells generated using Yamanaka factors have great potential for use in autologous cell therapy. However, genomic abnormalities exist in human iPS cells, and most mouse iPS cells are not fully pluripotent, as evaluated by the tetraploid complementation assay (TCA); this is most likely associated with the DNA damage response (DDR) occurred in early reprogramming induced by Yamanaka factors. In contrast, nuclear transfer can faithfully reprogram somatic cells into embryonic stem (ES) cells that satisfy the TCA. We thus hypothesized that factors involved in oocyte-induced reprogramming may stabilize the somatic genome during reprogramming, and improve the quality of the resultant iPS cells. To test this hypothesis, we screened for factors that could decrease DDR signals during iPS cell induction. We determined that Zscan4, in combination with the Yamanaka factors, not only remarkably reduced the DDR but also markedly promoted the efficiency of iPS cell generation. The inclusion of Zscan4 stabilized the genomic DNA, resulting in p53 downregulation. Furthermore, Zscan4 also enhanced telomere lengthening as early as 3 days post-infection through a telomere recombination-based mechanism. As a result, iPS cells generated with addition of Zscan4 exhibited longer telomeres than classical iPS cells. Strikingly, more than 50% of iPS cell lines (11/19) produced via this “Zscan4 protocol” gave rise to live-borne all-iPS cell mice as determined by TCA, compared to 1/12 for lines produced using the classical Yamanaka factors. Our findings provide the first demonstration that maintaining genomic stability during reprogramming promotes the generation of high quality iPS cells.
, Yi Liu2,*
, Peyman Kelk2
, Cunye Qu2
, Kentaro Akiyama2
, Chider Chen2
, Ikiru Atsuta2
, WanJun Chen3
, Yanheng Zhou1
and Songtao Shi2
Cell Research (2013) 23:107-121. doi:10.1038/cr.2012.179; published online 25 December 2012
Bone marrow mesenchymal stem cells (MSCs) comprise a heterogeneous population of postnatal progenitor cells with profound immunomodulatory properties, such as upregulation of Foxp3+ regulatory T cells (Tregs) and downregulation of Th17 cells. However, it is unknown whether different MSC subpopulations possess the same range of immunomodulatory function. Here, we show that a subset of single colony-derived MSCs producing IL-17 is different from bulk MSC population in that it cannot upregulate Tregs, downregulate Th17 cells, or ameliorate disease phenotypes in a colitis mouse model. Mechanistically, we reveal that IL-17, produced by these MSCs, activates the NFκB pathway to downregulate TGF-β production in MSCs, resulting in abolishment of MSC-based immunomodulation. Furthermore, we show that NFκB is able to directly bind to TGF-β promoter region to regulate TGF-β expression in MSCs. Moreover, these IL-17+ MSCs possess anti-Candida albicans growth effects in vitro and therapeutic effect in C. albicans-infected mice. In summary, this study shows that MSCs contain an IL-17+ subset capable of inhibiting C. albicans growth, but attenuating MSC-based immunosuppression via NFκB-mediated downregulation of TGF-β.
, Jinzhao Wang1,2
and Yi Zhang1,2
Cell Research (2013) 23:122-130. doi:10.1038/cr.2012.119; published online 21 August 2012
Definitive endoderm differentiation is crucial for generating respiratory and gastrointestinal organs including pancreas and liver. However, whether epigenetic regulation contributes to this process is unknown. Here, we show that the H3K27me3 demethylases KDM6A and KDM6B play an important role in endoderm differentiation from human ESCs. Knockdown of KDM6A or KDM6B impairs endoderm differentiation, which can be rescued by sequential treatment with WNT agonist and antagonist. KDM6A and KDM6B contribute to the activation of WNT3 and DKK1 at different differentiation stages when WNT3 and DKK1 are required for mesendoderm and definitive endoderm differentiation, respectively. Our study not only uncovers an important role of the H3K27me3 demethylases in definitive endoderm differentiation, but also reveals that they achieve this through modulating the WNT signaling pathway.
, Quan Wang2
, Yuan Long2
, Ru Zhang1
, Xiaoyuan Wei1
, Mingzhe Xing1
, Haifeng Gu2
and Xin Xie1,2
Cell Research (2013) 23:131-141. doi:10.1038/cr.2012.143; published online 9 October 2012
Environmental stress-mediated adaptation plays essential roles in the evolution of life. Cellular adaptation mechanisms usually involve the regulation of chromatin structure, transcription, mRNA stability and translation, which eventually lead to efficient changes in gene expression. Global epigenetic change is also involved in the reprogramming of somatic cells into induced pluripotent stem (iPS) cells by defined factors. Here we report that environmental stress such as hyperosmosis not only facilitates four factor-mediated reprogramming, but also enhances two or one factor-induced iPS cell generation. Hyperosmosis-induced p38 activation plays a critical role in this process. Constitutive active p38 mimics the positive effect of hyperosmosis, while dominant negative p38 and p38 inhibitor block the effect of hyperosmosis. Further study indicates stress-mediated p38 activation may promote reprogramming by reducing the global DNA methylation level and enhancing the expression of pluripotency genes. Our results demonstrate how simple environmental stress like hyperosmosis helps to alter the fate of cells via intracellular signaling and epigenetic modulation.
Xudong Guo1,*, Qidong Liu1,*, Guiying Wang1, Songcheng Zhu1, Longfei Gao1, Wujun Hong1, Yafang Chen1, Minjuan Wu2, Houqi Liu2, Cizhong Jiang1
Cell Research (2013) 23:142-156. doi:10.1038/cr.2012.180; published online 25 December 2012
Fibroblasts can be reprogrammed into induced pluripotent stem cells (iPSCs) by the application of Yamanaka factors (OSKM), but the mechanisms underlying this reprogramming remain poorly understood. Here, we report that Sox2 directly regulates endogenous microRNA-29b (miR-29b) expression during iPSC generation and that miR-29b expression is required for OSKM- and OSK-mediated reprogramming. Mechanistic studies show that Dnmt3a and Dnmt3b are in vivo targets of miR-29b and that Dnmt3a and Dnmt3b expression is inversely correlated with miR-29b expression during reprogramming. Moreover, the effect of miR-29b on reprogramming can be blocked by Dnmt3a or Dnmt3b overexpression. Further experiments indicate that miR-29b-DNMT signaling is significantly involved in the regulation of DNA methylation-related reprogramming events, such as mesenchymal-to-epithelial transition (MET) and Dlk1-Dio3 region transcription. Thus, our studies not only reveal that miR-29b is a novel mediator of reprogramming factor Sox2 but also provide evidence for a multistep mechanism in which Sox2 drives a miR-29b-DNMT signaling axis that regulates DNA methylation-related events during reprogramming.
, Song Chen1,2,*
, Shuguang Duo1
, Chengang Xiang1,3
, Jun Jia1,3
, Mina Guo1
, Wei Lai4
, Shichun Lu4
and Hongkui Deng1,2,3
Cell Research (2013) 23:157-161. doi:10.1038/cr.2012.144; published online 16 October 2012
Nana Fan1,2,*, Jijun Chen3,4,*, Zhouchun Shang5,*, Hongwei Dou6, Guangzhen Ji7, Qingjian Zou1,2, Lu Wu3,4, Lixiazi He3,4, Fang Wang7, Kai Liu7
Cell Research (2013) 23:162-166. doi:10.1038/cr.2012.176; published online 18 December 2012