1. Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds.
作者:Hou Pingping , Li Yanqin , Zhang Xu , Liu Chun , Guan Jingyang , Li Honggang , Zhao Ting , Ye Junqing , Yang Weifeng , Liu Kang , Ge Jian , Xu Jun , Zhang Qiang , Zhao Yang , Deng Hongkui
期刊:Science (New York, N.Y.)
日期:2013-07-18
DOI :10.1126/science.1239278
Pluripotent stem cells can be induced from somatic cells, providing an unlimited cell resource, with potential for studying disease and use in regenerative medicine. However, genetic manipulation and technically challenging strategies such as nuclear transfer used in reprogramming limit their clinical applications. Here, we show that pluripotent stem cells can be generated from mouse somatic cells at a frequency up to 0.2% using a combination of seven small-molecule compounds. The chemically induced pluripotent stem cells resemble embryonic stem cells in terms of their gene expression profiles, epigenetic status, and potential for differentiation and germline transmission. By using small molecules, exogenous "master genes" are dispensable for cell fate reprogramming. This chemical reprogramming strategy has potential use in generating functional desirable cell types for clinical applications.
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1区Q1影响因子: 45.5
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2. Induction of Pluripotency in Mouse Somatic Cells with Lineage Specifiers.
作者:Shu Jian , Wu Chen , Wu Yetao , Li Zhiyuan , Shao Sida , Zhao Wenhui , Tang Xing , Yang Huan , Shen Lijun , Zuo Xiaohan , Yang Weifeng , Shi Yan , Chi Xiaochun , Zhang Hongquan , Gao Ge , Shu Youmin , Yuan Kehu , He Weiwu , Tang Chao , Zhao Yang , Deng Hongkui
期刊:Cell
日期:2015-05-21
DOI :10.1016/j.cell.2015.05.020
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1区Q1影响因子: 45.5
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3. A XEN-like State Bridges Somatic Cells to Pluripotency during Chemical Reprogramming.
作者:Zhao Yang , Zhao Ting , Guan Jingyang , Zhang Xu , Fu Yao , Ye Junqing , Zhu Jialiang , Meng Gaofan , Ge Jian , Yang Susu , Cheng Lin , Du Yaqin , Zhao Chaoran , Wang Ting , Su Linlin , Yang Weifeng , Deng Hongkui
期刊:Cell
日期:2015-12-10
DOI :10.1016/j.cell.2015.11.017
Somatic cells can be reprogrammed into pluripotent stem cells (PSCs) by using pure chemicals, providing a different paradigm to study somatic reprogramming. However, the cell fate dynamics and molecular events that occur during the chemical reprogramming process remain unclear. We now show that the chemical reprogramming process requires the early formation of extra-embryonic endoderm (XEN)-like cells and a late transition from XEN-like cells to chemically-induced (Ci)PSCs, a unique route that fundamentally differs from the pathway of transcription factor-induced reprogramming. Moreover, precise manipulation of the cell fate transition in a step-wise manner through the XEN-like state allows us to identify small-molecule boosters and establish a robust chemical reprogramming system with a yield up to 1,000-fold greater than that of the previously reported protocol. These findings demonstrate that chemical reprogramming is a promising approach to manipulate cell fates.
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1区Q1影响因子: 45.5
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4. Derivation of Pluripotent Stem Cells with In Vivo Embryonic and Extraembryonic Potency.
作者:Yang Yang , Liu Bei , Xu Jun , Wang Jinlin , Wu Jun , Shi Cheng , Xu Yaxing , Dong Jiebin , Wang Chengyan , Lai Weifeng , Zhu Jialiang , Xiong Liang , Zhu Dicong , Li Xiang , Yang Weifeng , Yamauchi Takayoshi , Sugawara Atsushi , Li Zhongwei , Sun Fangyuan , Li Xiangyun , Li Chen , He Aibin , Du Yaqin , Wang Ting , Zhao Chaoran , Li Haibo , Chi Xiaochun , Zhang Hongquan , Liu Yifang , Li Cheng , Duo Shuguang , Yin Ming , Shen Huan , Belmonte Juan Carlos Izpisua , Deng Hongkui
期刊:Cell
日期:2017-04-06
DOI :10.1016/j.cell.2017.02.005
Of all known cultured stem cell types, pluripotent stem cells (PSCs) sit atop the landscape of developmental potency and are characterized by their ability to generate all cell types of an adult organism. However, PSCs show limited contribution to the extraembryonic placental tissues in vivo. Here, we show that a chemical cocktail enables the derivation of stem cells with unique functional and molecular features from mice and humans, designated as extended pluripotent stem (EPS) cells, which are capable of chimerizing both embryonic and extraembryonic tissues. Notably, a single mouse EPS cell shows widespread chimeric contribution to both embryonic and extraembryonic lineages in vivo and permits generating single-EPS-cell-derived mice by tetraploid complementation. Furthermore, human EPS cells exhibit interspecies chimeric competency in mouse conceptuses. Our findings constitute a first step toward capturing pluripotent stem cells with extraembryonic developmental potentials in culture and open new avenues for basic and translational research. VIDEO ABSTRACT.
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1区Q1影响因子: 19.8
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5. Single-Cell RNA-Seq Reveals Dynamic Early Embryonic-like Programs during Chemical Reprogramming.
作者:Zhao Ting , Fu Yao , Zhu Jialiang , Liu Yifang , Zhang Qian , Yi Zexuan , Chen Shi , Jiao Zhonggang , Xu Xiaochan , Xu Junquan , Duo Shuguang , Bai Yun , Tang Chao , Li Cheng , Deng Hongkui
期刊:Cell stem cell
日期:2018-06-21
DOI :10.1016/j.stem.2018.05.025
Chemical reprogramming provides a powerful platform for exploring the molecular dynamics that lead to pluripotency. Although previous studies have uncovered an intermediate extraembryonic endoderm (XEN)-like state during this process, the molecular underpinnings of pluripotency acquisition remain largely undefined. Here, we profile 36,199 single-cell transcriptomes at multiple time points throughout a highly efficient chemical reprogramming system using RNA-sequencing and reconstruct their progression trajectories. Through identifying sequential molecular events, we reveal that the dynamic early embryonic-like programs are key aspects of successful reprogramming from XEN-like state to pluripotency, including the concomitant transcriptomic signatures of two-cell (2C) embryonic-like and early pluripotency programs and the epigenetic signature of notable genome-wide DNA demethylation. Moreover, via enhancing the 2C-like program by fine-tuning chemical treatment, the reprogramming process is remarkably accelerated. Collectively, our findings offer a high-resolution dissection of cell fate dynamics during chemical reprogramming and shed light on mechanistic insights into the nature of induced pluripotency.
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1区Q1影响因子: 44.7
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6. Long-term functional maintenance of primary human hepatocytes in vitro.
作者:Xiang Chengang , Du Yuanyuan , Meng Gaofan , Soon Yi Liew , Sun Shicheng , Song Nan , Zhang Xiaonan , Xiao Yiwei , Wang Jie , Yi Zhigang , Liu Yifang , Xie Bingqing , Wu Min , Shu Jun , Sun Da , Jia Jun , Liang Zhen , Sun Dong , Huang Yanxiang , Shi Yan , Xu Jun , Lu Fengmin , Li Cheng , Xiang Kuanhui , Yuan Zhenghong , Lu Shichun , Deng Hongkui
期刊:Science (New York, N.Y.)
日期:2019-04-26
DOI :10.1126/science.aau7307
The maintenance of terminally differentiated cells, especially hepatocytes, in vitro has proven challenging. Here we demonstrated the long-term in vitro maintenance of primary human hepatocytes (PHHs) by modulating cell signaling pathways with a combination of five chemicals (5C). 5C-cultured PHHs showed global gene expression profiles and hepatocyte-specific functions resembling those of freshly isolated counterparts. Furthermore, these cells efficiently recapitulated the entire course of hepatitis B virus (HBV) infection over 4 weeks with the production of infectious viral particles and formation of HBV covalently closed circular DNA. Our study demonstrates that, with a chemical approach, functional maintenance of PHHs supports long-term HBV infection in vitro, providing an efficient platform for investigating HBV cell biology and antiviral drug screening.
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1区Q1影响因子: 96.2
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7. CRISPR-Edited Stem Cells in a Patient with HIV and Acute Lymphocytic Leukemia.
作者:Xu Lei , Wang Jun , Liu Yulin , Xie Liangfu , Su Bin , Mou Danlei , Wang Longteng , Liu Tingting , Wang Xiaobao , Zhang Bin , Zhao Long , Hu Liangding , Ning Hongmei , Zhang Yufeng , Deng Kai , Liu Lifeng , Lu Xiaofan , Zhang Tong , Xu Jun , Li Cheng , Wu Hao , Deng Hongkui , Chen Hu
期刊:The New England journal of medicine
日期:2019-09-11
DOI :10.1056/NEJMoa1817426
The safety of CRISPR (clustered regularly interspaced short palindromic repeats)-based genome editing in the context of human gene therapy is largely unknown. is a reasonable but not absolutely protective target for a cure of human immunodeficiency virus type 1 (HIV-1) infection, because -null blood cells are largely resistant to HIV-1 entry. We transplanted CRISPR-edited -ablated hematopoietic stem and progenitor cells (HSPCs) into a patient with HIV-1 infection and acute lymphoblastic leukemia. The acute lymphoblastic leukemia was in complete remission with full donor chimerism, and donor cells carrying the ablated persisted for more than 19 months without gene editing-related adverse events. The percentage of CD4+ cells with ablation increased by a small degree during a period of antiretroviral-therapy interruption. Although we achieved successful transplantation and long-term engraftment of CRISPR-edited HSPCs, the percentage of disruption in lymphocytes was only approximately 5%, which indicates the need for further research into this approach. (Funded by the Beijing Municipal Science and Technology Commission and others; ClinicalTrials.gov number, NCT03164135.).
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1区Q1影响因子: 50.5
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8. Chemical reprogramming of human somatic cells to pluripotent stem cells.
期刊:Nature
日期:2022-04-13
DOI :10.1038/s41586-022-04593-5
Cellular reprogramming can manipulate the identity of cells to generate the desired cell types. The use of cell intrinsic components, including oocyte cytoplasm and transcription factors, can enforce somatic cell reprogramming to pluripotent stem cells. By contrast, chemical stimulation by exposure to small molecules offers an alternative approach that can manipulate cell fate in a simple and highly controllable manner. However, human somatic cells are refractory to chemical stimulation owing to their stable epigenome and reduced plasticity; it is therefore challenging to induce human pluripotent stem cells by chemical reprogramming. Here we demonstrate, by creating an intermediate plastic state, the chemical reprogramming of human somatic cells to human chemically induced pluripotent stem cells that exhibit key features of embryonic stem cells. The whole chemical reprogramming trajectory analysis delineated the induction of the intermediate plastic state at the early stage, during which chemical-induced dedifferentiation occurred, and this process was similar to the dedifferentiation process that occurs in axolotl limb regeneration. Moreover, we identified the JNK pathway as a major barrier to chemical reprogramming, the inhibition of which was indispensable for inducing cell plasticity and a regeneration-like program by suppressing pro-inflammatory pathways. Our chemical approach provides a platform for the generation and application of human pluripotent stem cells in biomedicine. This study lays foundations for developing regenerative therapeutic strategies that use well-defined chemicals to change cell fates in humans.