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https://www.readbyqxmd.com/read/29593328/deconstructing-the-pluripotency-gene-regulatory-network
#1
REVIEW
Mo Li, Juan Carlos Izpisua Belmonte
Pluripotent stem cells can be isolated from embryos or derived by reprogramming. Pluripotency is stabilized by an interconnected network of pluripotency genes that cooperatively regulate gene expression. Here we describe the molecular principles of pluripotency gene function and highlight post-transcriptional controls, particularly those induced by RNA-binding proteins and alternative splicing, as an important regulatory layer of pluripotency. We also discuss heterogeneity in pluripotency regulation, alternative pluripotency states and future directions of pluripotent stem cell research...
April 2018: Nature Cell Biology
https://www.readbyqxmd.com/read/29564204/roadblocks-in-the-path-of-ipsc-to-the-clinic
#2
REVIEW
Elena Garreta, Sonia Sanchez, Jeronimo Lajara, Nuria Montserrat, Juan Carlos Izpisua Belmonte
Purpose of Review: The goal of this paper is to highlight the major challenges in the translation of human pluripotent stem cells into a clinical setting. Recent Findings: Innate features from human induced pluripotent stem cells (hiPSCs) positioned these patient-specific cells as an unprecedented cell source for regenerative medicine applications. Immunogenicity of differentiated iPSCs requires more research towards the definition of common criteria for the evaluation of innate and host immune responses as well as in the generation of standardized protocols for iPSC generation and differentiation...
2018: Current Transplantation Reports
https://www.readbyqxmd.com/read/29560089/kidney-organoids-for-disease-modeling
#3
EDITORIAL
Elena Garreta, Nuria Montserrat, Juan Carlos Izpisua Belmonte
No abstract text is available yet for this article.
February 27, 2018: Oncotarget
https://www.readbyqxmd.com/read/29554588/generation-of-two-induced-pluripotent-stem-cell-ipsc-lines-from-p-f508del-cystic-fibrosis-patients
#4
Aarne Fleischer, Iván M Lorenzo, Esther Palomino, Trond Aasen, Fernando Gómez, Miguel Servera, Víctor J Asensio, Víctor Gálvez, Juan Carlos Izpisúa-Belmonte, Daniel Bachiller
Cystic Fibrosis (CF) is a monogenic, lethal disease caused by mutations in the cystic fibrosis transmembrane conductance (CFTR) gene. Here we report the production of CF-iPS cell lines from two different p.F508del homozygous female patients (Table 1). Two different primary cell types, skin fibroblasts and keratinocytes, were transfected with retroviral cocktails containing four: c-MYC, KLF4, OCT4 and SOX2 (MKOS) or three: KLF4, OCT4 and SOX2 (KOS) reprogramming factors. Two fibroblast-derived MKOS lines are described in the main text...
March 11, 2018: Stem Cell Research
https://www.readbyqxmd.com/read/29476423/differential-stem-cell-aging-kinetics-in-hutchinson-gilford-progeria-syndrome-and-werner-syndrome
#5
Zeming Wu, Weiqi Zhang, Moshi Song, Wei Wang, Gang Wei, Wei Li, Jinghui Lei, Yu Huang, Yanmei Sang, Piu Chan, Chang Chen, Jing Qu, Keiichiro Suzuki, Juan Carlos Izpisua Belmonte, Guang-Hui Liu
Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A (LMNA) gene, resulting in the production of a truncated protein product-progerin. WS is caused by mutations in WRN gene, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells (ESCs) with heterozygous (G608G/+) or homozygous (G608G/G608G) LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively...
April 2018: Protein & Cell
https://www.readbyqxmd.com/read/29440377/efficient-derivation-of-stable-primed-pluripotent-embryonic-stem-cells-from-bovine-blastocysts
#6
Yanina Soledad Bogliotti, Jun Wu, Marcela Vilarino, Daiji Okamura, Delia Alba Soto, Cuiqing Zhong, Masahiro Sakurai, Rafael Vilar Sampaio, Keiichiro Suzuki, Juan Carlos Izpisua Belmonte, Pablo Juan Ross
Embryonic stem cells (ESCs) are derived from the inner cell mass of preimplantation blastocysts. From agricultural and biomedical perspectives, the derivation of stable ESCs from domestic ungulates is important for genomic testing and selection, genome engineering, and modeling human diseases. Cattle are one of the most important domestic ungulates that are commonly used for food and bioreactors. To date, however, it remains a challenge to produce stable pluripotent bovine ESC lines. Employing a culture system containing fibroblast growth factor 2 and an inhibitor of the canonical Wnt-signaling pathway, we derived pluripotent bovine ESCs (bESCs) with stable morphology, transcriptome, karyotype, population-doubling time, pluripotency marker gene expression, and epigenetic features...
February 27, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29301845/elixir-of-life-thwarting-aging-with-regenerative-reprogramming
#7
REVIEW
Ergin Beyret, Paloma Martinez Redondo, Aida Platero Luengo, Juan Carlos Izpisua Belmonte
All living beings undergo systemic physiological decline after ontogeny, characterized as aging. Modern medicine has increased the life expectancy, yet this has created an aged society that has more predisposition to degenerative disorders. Therefore, novel interventions that aim to extend the healthspan in parallel to the life span are needed. Regeneration ability of living beings maintains their biological integrity and thus is the major leverage against aging. However, mammalian regeneration capacity is low and further declines during aging...
January 5, 2018: Circulation Research
https://www.readbyqxmd.com/read/29224783/in-vivo-target-gene-activation-via-crispr-cas9-mediated-trans-epigenetic-modulation
#8
Hsin-Kai Liao, Fumiyuki Hatanaka, Toshikazu Araoka, Pradeep Reddy, Min-Zu Wu, Yinghui Sui, Takayoshi Yamauchi, Masahiro Sakurai, David D O'Keefe, Estrella Núñez-Delicado, Pedro Guillen, Josep M Campistol, Cheng-Jang Wu, Li-Fan Lu, Concepcion Rodriguez Esteban, Juan Carlos Izpisua Belmonte
Current genome-editing systems generally rely on inducing DNA double-strand breaks (DSBs). This may limit their utility in clinical therapies, as unwanted mutations caused by DSBs can have deleterious effects. CRISPR/Cas9 system has recently been repurposed to enable target gene activation, allowing regulation of endogenous gene expression without creating DSBs. However, in vivo implementation of this gain-of-function system has proven difficult. Here, we report a robust system for in vivo activation of endogenous target genes through trans-epigenetic remodeling...
December 14, 2017: Cell
https://www.readbyqxmd.com/read/29215090/in-vivo-genome-editing-via-the-hiti-method-as-a-tool-for-gene-therapy
#9
REVIEW
Keiichiro Suzuki, Juan Carlos Izpisua Belmonte
Using genome-editing technologies to correct specific mutations represents a potentially transformative new approach for treating genetic disorders. Despite rapid advances in the field of genome editing, it is still unclear whether the long-standing goal of in vivo targeted transgene integration is feasible. This is primarily because current tools are inefficient. In particular, current technologies are incapable of targeted gene knock-in in non-dividing cells, the major building blocks of adult tissues. This poses a significant barrier for developing therapeutic strategies to treat a broad range of devastating genetic disorders...
February 2018: Journal of Human Genetics
https://www.readbyqxmd.com/read/28985523/human-embryo-editing-opportunities-and-importance-of-transnational-cooperation
#10
Duanqing Pei, David W Beier, Ephrat Levy-Lahad, Gary Marchant, Janet Rossant, Juan Carlos Izpisua Belmonte, Robin Lovell-Badge, Rudolf Jaenisch, Alta Charo, David Baltimore
A recent National Academies report articulates a path forward for research, ethics, and governance of clinical applications involving genome editing. In light of recent human embryo editing developments, scientists and stakeholders from all nations should cooperate to take advantage of this historic opportunity for medicine and also basic human biology.
October 5, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28920955/mir-25-93-mediates-hypoxia-induced-immunosuppression-by-repressing-cgas
#11
Min-Zu Wu, Wei-Chung Cheng, Su-Feng Chen, Shin Nieh, Carolyn O'Connor, Chia-Lin Liu, Wen-Wei Tsai, Cheng-Jang Wu, Lorena Martin, Yaoh-Shiang Lin, Kou-Juey Wu, Li-Fan Lu, Juan Carlos Izpisua Belmonte
The mechanisms by which hypoxic tumours evade immunological pressure and anti-tumour immunity remain elusive. Here, we report that two hypoxia-responsive microRNAs, miR-25 and miR-93, are important for establishing an immunosuppressive tumour microenvironment by downregulating expression of the DNA sensor cGAS. Mechanistically, miR-25/93 targets NCOA3, an epigenetic factor that maintains basal levels of cGAS expression, leading to repression of cGAS during hypoxia. This allows hypoxic tumour cells to escape immunological responses induced by damage-associated molecular pattern molecules, specifically the release of mitochondrial DNA...
October 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28888991/lrrk2-functions-as-a-scaffolding-kinase-of-ask1-mediated-neuronal-cell-death
#12
Ji-Hye Yoon, Jung-Soon Mo, Mi-Yeon Kim, Eun-Jung Ann, Ji-Seon Ahn, Eun-Hye Jo, Hye-Jin Lee, Young Chul Lee, Wongi Seol, Sergiy M Yarmoluk, Thomas Gasser, Philipp J Kahle, Guang-Hui Liu, Juan Carlos Izpisua Belmonte, Hee-Sae Park
Leucine-rich repeat kinase 2 (LRRK2), a multi-domain protein, is a key causative factor in Parkinson's disease (PD). Identification of novel substrates and the molecular mechanisms underlying the effects of LRRK2 are essential for understanding the pathogenesis of PD. In this study, we showed that LRRK2 played an important role in neuronal cell death by directly phosphorylating and activating apoptosis signal-regulating kinase 1 (ASK1). LRRK2 phosphorylated ASK1 at Thr832 that is adjacent to Thr845, which serves as an autophosphorylation site...
December 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28874671/crispr-cas9-mediated-one-step-disabling-of-pancreatogenesis-in-pigs
#13
Jun Wu, Marcela Vilarino, Keiichiro Suzuki, Daiji Okamura, Yanina Soledad Bogliotti, Insung Park, Joan Rowe, Bret McNabb, Pablo Juan Ross, Juan Carlos Izpisua Belmonte
Genome editing using programmable nucleases has revolutionized biomedical research. CRISPR-Cas9 mediated zygote genome editing enables high efficient production of knockout animals suitable for studying development and relevant human diseases. Here we report efficient disabling pancreatogenesis in pig embryos via zygotic co-delivery of Cas9 mRNA and dual sgRNAs targeting the PDX1 gene, which when combined with chimeric-competent human pluriopotent stem cells may serve as a suitable platform for the xeno-generation of human tissues and organs in pigs...
September 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28826795/regulation-of-stem-cell-aging-by-metabolism-and-epigenetics
#14
REVIEW
Ruotong Ren, Alejandro Ocampo, Guang-Hui Liu, Juan Carlos Izpisua Belmonte
Stem cell aging and exhaustion are considered important drivers of organismal aging. Age-associated declines in stem cell function are characterized by metabolic and epigenetic changes. Understanding the mechanisms underlying these changes will likely reveal novel therapeutic targets for ameliorating age-associated phenotypes and for prolonging human healthspan. Recent studies have shown that metabolism plays an important role in regulating epigenetic modifications and that this regulation dramatically affects the aging process...
September 5, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28802034/keeping-the-rhythm-while-changing-the-lyrics-circadian-biology-in-aging
#15
COMMENT
Fumiyuki Hatanaka, Alejandro Ocampo, Juan Carlos Izpisua Belmonte
Aging and circadian rhythms have been linked for decades, but their molecular interplay has remained obscure. Sato et al. and Solanas et al. now reveal that, while core clock components remain nearly unaltered, aging is associated with tissue-specific rewiring, which can be prevented by calorie restriction.
August 10, 2017: Cell
https://www.readbyqxmd.com/read/28783728/correction-of-a-pathogenic-gene-mutation-in-human-embryos
#16
Hong Ma, Nuria Marti-Gutierrez, Sang-Wook Park, Jun Wu, Yeonmi Lee, Keiichiro Suzuki, Amy Koski, Dongmei Ji, Tomonari Hayama, Riffat Ahmed, Hayley Darby, Crystal Van Dyken, Ying Li, Eunju Kang, A-Reum Park, Daesik Kim, Sang-Tae Kim, Jianhui Gong, Ying Gu, Xun Xu, David Battaglia, Sacha A Krieg, David M Lee, Diana H Wu, Don P Wolf, Stephen B Heitner, Juan Carlos Izpisua Belmonte, Paula Amato, Jin-Soo Kim, Sanjiv Kaul, Shoukhrat Mitalipov
Genome editing has potential for the targeted correction of germline mutations. Here we describe the correction of the heterozygous MYBPC3 mutation in human preimplantation embryos with precise CRISPR-Cas9-based targeting accuracy and high homology-directed repair efficiency by activating an endogenous, germline-specific DNA repair response. Induced double-strand breaks (DSBs) at the mutant paternal allele were predominantly repaired using the homologous wild-type maternal gene instead of a synthetic DNA template...
August 24, 2017: Nature
https://www.readbyqxmd.com/read/28728561/understanding-the-genetics-behind-complex-human-disease-with-large-scale-ipsc-collections
#17
Amanda E Yamasaki, Athanasia D Panopoulos, Juan Carlos Izpisua Belmonte
Three recent studies analyzing large-scale collections of human induced pluripotent stem cell lines provide valuable insight into how genetic regulatory variation affects cellular and molecular traits.
July 20, 2017: Genome Biology
https://www.readbyqxmd.com/read/28685772/genetic-enhancement-in-cultured-human-adult-stem-cells-conferred-by-a-single-nucleotide-recoding
#18
Jiping Yang, Jingyi Li, Keiichiro Suzuki, Xiaomeng Liu, Jun Wu, Weiqi Zhang, Ruotong Ren, Weizhou Zhang, Piu Chan, Juan Carlos Izpisua Belmonte, Jing Qu, Fuchou Tang, Guang-Hui Liu
No abstract text is available yet for this article.
September 2017: Cell Research
https://www.readbyqxmd.com/read/28586330/gathering-by-the-red-sea-highlights-links-between-environment-and-epigenetics
#19
Mo Li, Emiliana Borrelli, Pierre J Magistretti, Juan Carlos Izpisua Belmonte, Paolo Sassone-Corsi, Valerio Orlando
No abstract text is available yet for this article.
June 6, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28473583/integration-of-cpg-free-dna-induces-de-novo-methylation-of-cpg-islands-in-pluripotent-stem-cells
#20
Yuta Takahashi, Jun Wu, Keiichiro Suzuki, Paloma Martinez-Redondo, Mo Li, Hsin-Kai Liao, Min-Zu Wu, Reyna Hernández-Benítez, Tomoaki Hishida, Maxim Nikolaievich Shokhirev, Concepcion Rodriguez Esteban, Ignacio Sancho-Martinez, Juan Carlos Izpisua Belmonte
CpG islands (CGIs) are primarily promoter-associated genomic regions and are mostly unmethylated within highly methylated mammalian genomes. The mechanisms by which CGIs are protected from de novo methylation remain elusive. Here we show that insertion of CpG-free DNA into targeted CGIs induces de novo methylation of the entire CGI in human pluripotent stem cells (PSCs). The methylation status is stably maintained even after CpG-free DNA removal, extensive passaging, and differentiation. By targeting the DNA mismatch repair gene MLH1 CGI, we could generate a PSC model of a cancer-related epimutation...
May 5, 2017: Science
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