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reprogramming of MLL-AF9 leukemia cells into pluripotent stem cells

LEUKEMIA 2014年第5期28卷 1071-1080页

作者： Liu, Y. Cheng, H. Gao, S. Lu, X. He, F. Hu, L. Hou, D. Zou, Z. Li, Y. Zhang, H. Xu, J. Kang, L. Wang, Q. Yuan, W. Gao, S. Cheng, T. Chinese Acad Med Sci Inst Hematol State Key Lab Expt Hematol Tianjin 300020 Peoples R China Chinese Acad Med Sci Blood Dis Hosp Ctr Stem Cell Med Tianjin 300020 Peoples R China Peking Union Med Coll Tianjin 300020 Peoples R China Natl Inst Biol Sci Beijing Peoples R China Chinese Acad Sci Beijing Inst Genom CAS Key Lab Genome Sci & Informat Beijing Peoples R China Univ Chinese Acad Sci Beijing Peoples R China

The 'Yamanaka factors' (Oct4, Sox2, Klf4 and c-Myc) are able to generate induced pluripotent stem (iPS) cells from different cell types. However, to what degree primary malignant cells can be reprogrammed into a pluripotent state has not been vigorously assessed. We established an acute myeloid leukemia (AML) model by overexpressing the human mixed-lineage leukemia-AF9 (MLL-AF9) fusion gene in mouse hematopoietic cells that carry Yamanaka factors under the control of doxycycline (Dox). On addition of Dox to the culture, the transplantable leukemia cells were efficiently converted into iPS cells that could form teratomas and produce chimeras. Interestingly, most chimeric mice spontaneously developed the same type of AML. Moreover, both iPS reprogramming and leukemia reinitiation paths could descend from the same leukemia-initiating cell. RNA-seq analysis showed reversible global gene expression patterns between these interchangeable leukemia and iPS cells on activation or reactivation of MLL-AF9, suggesting a sufficient epigenetic force in driving the leukemogenic process. This study represents an important step for further defining the potential interplay between oncogenic molecules and reprogramming factors during MLL leukemogenesis. More importantly, our reprogramming approach may be expanded to characterize a range of hematopoietic malignancies in order to develop new strategies for clinical diagnosis and treatment.

关键词： iPS cells MLL-AF9 primary leukemia cells reprogramming

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reprogramming the genome to totipotency in mouse embryos

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TRENDS IN CELL BIOLOGY 2015年第2期25卷 82-91页

作者： Zhou, Li-quan Dean, Jurrien NIDDK Lab Cellular & Dev Biol NIH Bethesda MD 20892 USA

Despite investigative interest, the artificial derivation of pluripotent stem cells remains inefficient and incomplete reprogramming hinders its potential as a reliable tool in regenerative medicine. By contrast, fusion of terminally differentiated gametes at fertilization activates efficient epigenetic reprogramming to ensure totipotency of early embryos. Understanding the epigenetic mechanisms required for the transition from the fertilized egg to the embryo can improve efforts to reprogram differentiated cells to pluripotent/totipotent cells for therapeutic use. We review recent discoveries that are providing insight into the molecular mechanisms required for epigenetic reprogramming to totipotency in vivo.

关键词： reprogramming totipotency epigenetic modification embryonic genome activation preimplantation development

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reprogramming of Neural Progenitor Cells into Induced Pluripotent Stem Cells in the Absence of Exogenous Sox2 Expression

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STEM CELLS 2008年第10期26卷 2467-2474页

作者： Eminli, Sarah Utikal, Jochen Arnold, Katrin Jaenisch, Rudolf Hochedlinger, Konrad Massachusetts Gen Hosp Ctr Canc Boston MA 02114 USA Massachusetts Gen Hosp Ctr Regenerat Med Boston MA 02114 USA Free Univ Berlin Dept Biol Chem & Pharm D-1000 Berlin Germany MIT Dept Biol Cambridge MA USA MIT Whitehead Inst Cambridge MA USA

Expression of the transcription factors Oct4, Sox2, Klf4, and c-Myc in mesodermal and endodermal derivatives, including fibroblasts, lymphocytes, liver, stomach, and beta cells, generates induced pluripotent stem (iPS) cells. It remains unknown, however, whether cell types of the ectodermal lineage are equally amenable to reprogramming into iPS cells by the same combination of factors. To test this, we have isolated genetically marked neural progenitor cells (NPCs) from neonatal mouse brains and infected them with viral vectors expressing Oct4, Sox2, Klf4, and c-Myc. Infected NPCs gave rise to iPS cells that expressed markers of embryonic stem cells, showed demethylation of pluripotency genes, formed teratomas, and contributed to viable chimeras. In contrast to other somatic cell types, NPCs expressed high levels of endogenous Sox2 and thus did not require viral Sox2 expression for reprogramming into iPS cells. Our data show that in addition to mesoderm- and endoderm-derived cell types, neural progenitor cells of the ectodermal lineage can be reprogrammed into iPS cells, suggesting that in vitro reprogramming is a universal process. These results also imply that the combination of factors necessary for reprogramming is dependent on cellular context. STEM CELLS 2008;26: 2467-2474

关键词： reprogramming Neural progenitor cells Induced pluripotent stem cells Sox2 Oct4

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reprogramming cell fates: insights from combinatorial approaches

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HEMATOPOIETIC STEM CELLS VIII 2012年第1期1266卷 7-17页

作者： Pereira, Carlos-Filipe Lemischka, Ihor R. Moore, Kateri Mt Sinai Sch Med Dept Dev & Regenerat Biol Black Family Stem Cell Inst New York NY 10029 USA

Epigenetic reprogramming can be achieved in different ways, including nuclear transfer, cell fusion, or the expression of transcription factors (TFs). Combinatorial overexpression provides an opportunity to define the minimal core network of TFs that instructs specific cell fates. This approach has been employed to induce mouse and human pluripotency and differentiated cell types from cells that can be also as distant as cells from different germ layers. This suggests the possibility that any specific cell type may be directly converted into another if the appropriate reprogramming TF core is determined. Herein, we review the factors used for reprogramming multiple cell identities and raise the question of whether there is a common underlying blueprint for reprogramming factors. In addition to the generation of human cell types of interest for cell-replacement therapies, we propose that the TF-mediated conversion of differentiated cell types, especially somatic stem cells, will have an impact on our understanding of their biological development.

关键词： reprogramming transcription factor induced pluripotency transdetermination iPS direct conversion

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reprogramming of chimpanzee fibroblasts into a multipotent cancerous but not fully pluripotent state by transducing iPSC factors in 2i/LIF culture

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DIFFERENTIATION 2020年 112卷 67-76页

作者： Lin, Zachary Yu-Ching Nakai, Risako Hirai, Hirohisa Kozuka, Daiki Katayama, Seiya Nakamura, Shin-ichiro Okada, Sawako Kitajima, Ryunosuke Imai, Hiroo Okano, Hideyuki Imamura, Masanori Keio Univ Sch Med Dept Physiol Shinjuku Ku 35 Shinanomachi Tokyo 1608582 Japan Kyoto Univ Primate Res Inst Dept Cellular & Mol Biol Mol Biol Sect Inuyama Aichi 4848506 Japan Kanazawa Univ Coll Sci & Engn Biol Course Kakuma Machi Kanazawa Ishikawa 9201192 Japan Shiga Univ Med Sci Res Ctr Anim Life Sci Seta Tsukinowa Cho Otsu Shiga 5202192 Japan

To induce and maintain naive pluripotency in mouse embryonic and induced pluripotent stem cells (ESCs/iPSCs), chemically defined N2B27 medium with PD0325901, CHIR99021, and leukemia inhibitory factor (2i/LIF) is a classic and simple condition. However, this method cannot be simply extrapolated to human ESCs/iPSCs that are principally stabilized in primed pluripotency and become primitive neuroepithelium-like cells in N2B27 + 2i/LIF culture. Here, we assessed iPSC reprogramming of fibroblasts from chimpanzee, our closest living relative, in N2B27 +2i/LIF culture. Under this condition, chimpanzee cells formed alkaline phosphatasepositive dome-shaped colonies. The colony-forming cells could be stably expanded by serial passaging without a ROCK inhibitor. However, their gene expression was distinct from iPSCs and neuroepithelium. They expressed the OCT3/4 transgene and a subset of transcripts associated with pluripotency, mesenchymal-epithelial transition, and neural crest formation. These cells exhibited a differentiation potential into the three germ layers in vivo and in vitro. The current study demonstrated that iPSC reprogramming in N2B27 + 2i/LIF culture converted chimpanzee fibroblasts into a multipotent cancerous state with unique gene expression, but not fully pluripotent stem cells.

关键词： Chimpanzee reprogramming Pluripotency iPSC

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reprogramming of Chromatin Accessibility in Somatic Cell Nuclear Transfer Is DNA Replication Independent

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CELL REPORTS 2018年第7期23卷 1939-1947页

作者： Djekidel, Mohamed Nadhir Inoue, Azusa Matoba, Shogo Suzuki, Tsukasa Zhang, Chunxia Lu, Falong Jiang, Lan Zhang, Yi Boston Childrens Hosp Howard Hughes Med Inst Boston MA 02115 USA Boston Childrens Hosp Program Cellular & Mol Med Boston MA 02115 USA Boston Childrens Hosp Div Hematol Oncol Dept Pediat Boston MA 02115 USA Harvard Med Sch Dept Genet Boston MA 02115 USA Harvard Stem Cell Inst WAB 149G200 Longwood Ave Boston MA 02115 USA RIKEN Ctr Integrat Med Sci Yokohama Kanagawa 2300045 Japan RIKEN Bioresource Ctr Tsukuba Ibaraki 3050074 Japan Chinese Acad Sci Inst Genet & Dev Biol State Key Lab Mol Dev Biol Beijing 100101 Peoples R China

Mammalian oocytes have the ability to reset the transcriptional program of differentiated somatic cells into that of totipotent embryos through somatic cell nuclear transfer (SCNT). However, the mechanisms underlying SCNT-mediated reprogramming are largely unknown. To understand the mechanisms governing chromatin reprogramming during SCNT, we profiled DNase I hypersensitive sites (DHSs) in donor cumulus cells and one-cell stage SCNT embryos. To our surprise, the chromatin accessibility landscape of the donor cells is drastically changed to recapitulate that of the in vitro fertilization (IVF)-derived zygotes within 12 hr. Interestingly, this DHS reprogramming takes place even in the presence of a DNA replication inhibitor, suggesting that SCNT-mediated DHS reprogramming is independent of DNA replication. Thus, this study not only reveals the rapid and drastic nature of the changes in chromatin accessibility through SCNT but also establishes a DNA replication-independent model for studying cellular reprogramming.

关键词： SCNT DNase I hypersensitive sites reprogramming DNA replication

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reprogramming of mesenchymal stem cells by oncogenes

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SEMINARS IN CANCER BIOLOGY 2015年第0期32卷 18-31页

作者： Eid, Josiane E. Garcia, Christina B. Vanderbilt Univ Med Ctr Dept Canc Biol Nashville TN 37232 USA Baylor Coll Med Dept Pediat Nutr Houston TX 77030 USA

Mesenchymal stem cells (MSCs) originate from embryonic mesoderm and give rise to the multiple lineages of connective tissues. Transformed MSCs develop into aggressive sarcomas, some of which are initiated by specific chromosomal translocations that generate fusion proteins with potent oncogenic properties. The sarcoma oncogenes typically prime MSCs through aberrant reprogramming. They dictate commitment to a specific lineage but prevent mature differentiation, thus locking the cells in a state of proliferative precursors. Deregulated expression of lineage-specific transcription factors and controllers of chromatin structure play a central role in MSC reprogramming and sarcoma pathogenesis. This suggests that reversing the epigenetic aberrancies created by the sarcoma oncogenes with differentiation-related reagents holds great promise as a beneficial addition to sarcoma therapies. (C) 2014 Elsevier Ltd. All rights reserved.

关键词： reprogramming Mesenchymal Stem Sarcoma Oncogene

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reprogramming progeria fibrob epigenetic landscape

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AGING CELL 2017年第4期16卷 870-887页

作者： Chen, Zhaoyi Chang, Wing Y. Etheridge, Alton Strickfaden, Hilmar Jin, Zhigang Palidwor, Gareth Cho, Ji-Hoon Wang, Kai Kwon, Sarah Y. Dore, Carole Raymond, Angela Hotta, Akitsu Ellis, James Kandel, Rita A. Dilworth, F. Jeffrey Perkins, Theodore J. Hendzel, Michael J. Galas, David J. Stanford, William L. Ottawa Hosp Res Inst Regenerat Med Program Sprott Ctr Stem Cell Res Ottawa ON K1H 8L6 Canada Univ Ottawa Dept Cellular & Mol Med Ottawa ON Canada Pacific Northwest Diabet Res Inst 720 Broadway Seattle WA 98103 USA Univ Alberta Cross Canc Inst Edmonton AB T6G 1Z2 Canada Univ Alberta Dept Expt Oncol Fac Med & Dent Edmonton AB T6G 1Z2 Canada Ottawa Hosp Res Inst Sprott Ctr Stem Cell Res Ottawa Bioinformat Core Facil Ottawa ON K1H 8L6 Canada Univ Toronto Dept Chem Engn Toronto ON Canada Kyoto Univ Ctr iPS Cell Res & Applicat CiRA Kyoto Japan Hosp Sick Children Program Dev & Stem Cell Biol Toronto ON Canada Univ Toronto Dept Mol Genet Toronto ON Canada Mt Sinai Hosp Pathol & Expt Med Toronto ON Canada Univ Ottawa Dept Biochem Microbiol & Immunol Ottawa ON Canada Ottawa Inst Syst Biol Ottawa ON Canada

Ideally, disease modeling using patient-derived induced pluripotent stem cells (iPSCs) enables analysis of disease initiation and progression. This requires any pathological features of the patient cells used for reprogramming to be eliminated during iPSC generation. Hutchinson-Gilford progeria syndrome (HGPS) is a segmental premature aging disorder caused by the accumulation of the truncated form of Lamin A known as Progerin within the nuclear lamina. Cellular hallmarks of HGPS include nuclear blebbing, loss of peripheral heterochromatin, defective epigenetic inheritance, altered gene expression, and senescence. To model HGPS using iPSCs, detailed genome-wide and structural analysis of the epigenetic landscape is required to assess the initiation and progression of the disease. We generated a library of iPSC lines from fibroblasts of patients with HGPS and controls, including one family trio. HGPS patient-derived iPSCs are nearly indistinguishable from controls in terms of pluripotency, nuclear membrane integrity, as well as transcriptional and epigenetic profiles, and can differentiate into affected cell lineages recapitulating disease progression, despite the nuclear aberrations, altered gene expression, and epigenetic landscape inherent to the donor fibroblasts. These analyses demonstrate the power of iPSC reprogramming to reset the epigenetic landscape to a revitalized pluripotent state in the face of widespread epigenetic defects, validating their use to model the initiation and progression of disease in affected cell lineages.

关键词： aging epigenetics induced pluripotent stem cells Lamin A lamina progeria reprogramming

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reprogramming fibroblast into human iBlastoids

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NATURE PROTOCOLS 2024年第8期19卷 2298-2316页

作者： Tan, Jia Ping Liu, Xiaodong Polo, Jose M. Monash Univ Dept Anat & Dev Biol Clayton Vic Australia Monash Biomed Discovery Inst Dev & Stem Cells Program Clayton Vic Australia Monash Univ Australian Regenerat Med Inst Clayton Vic Australia Westlake Univ Sch Life Sci Hangzhou Zhejiang Peoples R China Westlake Univ Res Ctr Ind Future Hangzhou Peoples R China Westlake Lab Life Sci & Biomed Hangzhou Zhejiang Peoples R China Westlake Inst Adv Study Hangzhou Zhejiang Peoples R China Univ Adelaide Sch Biomed Fac Hlth & Med Sci Adelaide Ctr Epigenet Adelaide SA Australia Univ Adelaide Fac Hlth & Med Sci South Australian Immunogen Canc Inst Adelaide SA Australia

The study of early human embryogenesis has relied on the use of blastocysts donated to research or simple stem cell culture systems such as pluripotent and trophoblast stem cells, which have been seminal in shedding light on many key developmental processes. However, simple culture systems lack the necessary complexity to adequately model the spatiotemporal, cellular and molecular dynamics occurring during the early phases of embryonic development. As such, an in vitro model of the human blastocyst is advantageous in many aspects to decipher human embryogenesis. Here we describe a step-by-step protocol for the generation of induced blastoids (iBlastoids), an in vitro integrated model of the human blastocyst derived via somatic reprogramming. This protocol details the workflow for reprogramming of human dermal fibroblasts and subsequent generation of iBlastoids using the reprogramming intermediates, which together takes similar to 27 days (21 days for reprogramming and 6 days for iBlastoid generation). We also discuss several characterization/functional assays that can be used on the iBlastoids. We believe that a person trained in cell culture with similar to 1 year of experience with human somatic cell and reprogramming/cell differentiation assays would be able to perform this protocol. In short, the iBlastoids present an alternative tool as a model to the blastocyst to facilitate the scientific community in the exploration of early human development.

关键词： Cell culture Embryonic induction reprogramming

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reprogramming-derived gene cocktail increases cardiomyocyte proliferation for heart regeneration

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EMBO MOLECULAR MEDICINE 2017年第2期9卷 251-264页

作者： Cheng, Yuan-Yuan Yan, Yu-Ting Lundy, David J. Lo, Annie H. A. Wang, Yu-Ping Ruan, Shu-Chian Lin, Po-Ju Hsieh, Patrick C. H. Natl Def Med Ctr Grad Inst Life Sci Taipei Taiwan Acad Sinica Inst Biomed Sci Taipei Taiwan Natl Taiwan Univ & Hosp Inst Clin Med Inst Med Genom & Prote Dept Surg Taipei Taiwan

Although remnant cardiomyocytes (CMs) possess a certain degree of proliferative ability, efficiency is too low for cardiac regeneration after injury. In this study, we identified a distinct stage within the initiation phase of CM reprogramming before the MET process, and microarray analysis revealed the strong up-regulation of several mitosis-related genes at this stage of reprogramming. Several candidate genes were selected and tested for their ability to induce CM proliferation. Delivering a cocktail of three genes, FoxM1, Id1, and Jnk3-shRNA (FIJs), induced CMs to re-enter the cell cycle and complete mitosis and cytokinesis invitro. More importantly, this gene cocktail increased CM proliferation invivo and significantly improved cardiac function and reduced fibrosis after myocardial infarction. Collectively, our findings present a cocktail FIJs that may be useful in cardiac regeneration and also provide a practical strategy for probing reprogramming assays for regeneration of other tissues.

关键词： cardiomyocyte proliferation gene therapy heart regeneration myocardial infarction reprogramming

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