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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
Lyndon da Cruz, Kate Fynes, Odysseas Georgiadis, Julie Kerby, Yvonne H Luo, Ahmad Ahmado, Amanda Vernon, Julie T Daniels, Britta Nommiste, Shazeen M Hasan, Sakina B Gooljar, Amanda-Jayne F Carr, Anthony Vugler, Conor M Ramsden, Magda Bictash, Mike Fenster, Juliette Steer, Tricia Harbinson, Anna Wilbrey, Adnan Tufail, Gang Feng, Mark Whitlock, Anthony G Robson, Graham E Holder, Mandeep S Sagoo, Peter T Loudon, Paul Whiting, Peter J Coffey
Age-related macular degeneration (AMD) remains a major cause of blindness, with dysfunction and loss of retinal pigment epithelium (RPE) central to disease progression. We engineered an RPE patch comprising a fully differentiated, human embryonic stem cell (hESC)-derived RPE monolayer on a coated, synthetic basement membrane. We delivered the patch, using a purpose-designed microsurgical tool, into the subretinal space of one eye in each of two patients with severe exudative AMD. Primary endpoints were incidence and severity of adverse events and proportion of subjects with improved best-corrected visual acuity of 15 letters or more...
March 19, 2018: Nature Biotechnology
Mousumi Sahu, Bibekanand Mallick
MicroRNAs (miRNAs) play crucial roles in pluripotency and differentiation of human Embryonic Stem Cells (hESCs). However, synergism among multiple miRNAs and their regulatory effects on stem cells are largely unknown. We investigated the synergistic regulations among miRNAs, which are differentially expressed in hESCs and fibroblasts (Fibs) to gain deeper insights into the regulatory mechanisms of miRNA-miRNA synergism in differentiation of hESCs into Fibs. In this study, we identified miRNA targets incorporating differential expression profiles of miRNAs and genes in hESCs-Fibs as well as miRNA targeting information followed by enrichment analysis...
March 14, 2018: International Journal of Biological Macromolecules
Wasco Wruck, James Adjaye
Induced pluripotent stem cells (iPSCs) and human embryonic stem cells (hESCs) differentiated into hepatocyte-like cells (HLCs) provide a defined and renewable source of cells for drug screening, toxicology and regenerative medicine. We previously reprogrammed human fetal foreskin fibroblast cells (HFF1) into iPSCs employing an episomal plasmid-based integration-free approach, this iPSC-line and the hESC lines H1 and H9 were used to model hepatogenesis in vitro. Biochemical characterisation confirmed glycogen storage, ICG uptake and release, urea and bile acid production, as well as CYP3A4 activity...
March 13, 2018: Scientific Data
Anthony Flamier, Supriya Singh, Theodore P Rasmussen
Human birth defects are relatively common and can be caused by exposure to environmental teratogens or to pharmaceuticals with teratogenic activities. Human embryonic stem cells (hESCs), by virtue of their pluripotent nature, provide an excellent cellular platform for teratogen detection and risk assessment. This unit describes detailed protocols for the preparation and validation of highly pluripotent hESCs, the production of large quantities of aggregated multicellular spheroids composed of hESCs, and these spheroids' differentiation into embryoid bodies (EBs)...
February 21, 2018: Current Protocols in Toxicology
Isabel Saez, Seda Koyuncu, Ricardo Gutierrez-Garcia, Christoph Dieterich, David Vilchez
Human embryonic stem cells (hESCs) exhibit high levels of proteasome activity, an intrinsic characteristic required for their self-renewal, pluripotency and differentiation. However, the mechanisms by which enhanced proteasome activity maintains hESC identity are only partially understood. Besides its essential role for the ability of hESCs to suppress misfolded protein aggregation, we hypothesize that enhanced proteasome activity could also be important to degrade endogenous regulatory factors. Since E3 ubiquitin ligases are responsible for substrate selection, we first define which E3 enzymes are increased in hESCs compared with their differentiated counterparts...
March 6, 2018: Scientific Reports
Thomas Robert, Ines De Mesmaeker, Geert M Stangé, Krista G Suenens, Zhidong Ling, Evert J Kroon, Daniel G Pipeleers
Human stem cells represent a potential source for implants that replace the depleted functional beta cell mass (FBM) in diabetes patients. Human embryonic stem cell-derived pancreatic endoderm (hES-PE) can generate implants with glucose-responsive beta cells capable of reducing hyperglycemia in mice. This study with device-encapsulated hES-PE (4 × 106 cells/mouse) determines the biologic characteristics at which implants establish metabolic control during a 50-week follow-up. A metabolically adequate FBM was achieved by (1) formation of a sufficient beta cell number (>0...
February 22, 2018: Stem Cell Reports
Michael D West, Ivan Labat, Hal Sternberg, Dana Larocca, Igor Nasonkin, Karen B Chapman, Ratnesh Singh, Eugene Makarev, Alex Aliper, Andrey Kazennov, Andrey Alekseenko, Nikolai Shuvalov, Evgenia Cheskidova, Aleksandr Alekseev, Artem Artemov, Evgeny Putin, Polina Mamoshina, Nikita Pryanichnikov, Jacob Larocca, Karen Copeland, Evgeny Izumchenko, Mikhail Korzinkin, Alex Zhavoronkov
Here we present the application of deep neural network (DNN) ensembles trained on transcriptomic data to identify the novel markers associated with the mammalian embryonic-fetal transition (EFT). Molecular markers of this process could provide important insights into regulatory mechanisms of normal development, epimorphic tissue regeneration and cancer. Subsequent analysis of the most significant genes behind the DNNs classifier on an independent dataset of adult-derived and human embryonic stem cell (hESC)-derived progenitor cell lines led to the identification of COX7A1 gene as a potential EFT marker...
January 30, 2018: Oncotarget
Geeta Shroff
Multiple sclerosis (MS), a complex disorder of the central nervous system (CNS), is characterized with axonal loss underlying long-term progressive disability. Currently available therapies for its management are able to slow down the progression but fail to treat it completely. Moreover, these therapies are associated with major CNS and cardiovascular adverse events, and prolonged use of these treatments may cause life-threatening diseases. Recent research has shown that cellular therapies hold a potential for CNS repair and may be able to provide protection from inflammatory damage caused after injury...
2018: Stem Cells and Cloning: Advances and Applications
Koichiro Ogawa, Hidetaka Suga, Chikafumi Ozone, Mayu Sakakibara, Tomiko Yamada, Mayuko Kano, Kazuki Mitsumoto, Takatoshi Kasai, Yu Kodani, Hiroshi Nagasaki, Naoki Yamamoto, Daisuke Hagiwara, Motomitsu Goto, Ryoichi Banno, Yoshihisa Sugimura, Hiroshi Arima
Arginine-vasopressin (AVP) neurons exist in the hypothalamus, a major region of the diencephalon, and play an essential role in water balance. Here, we established the differentiation method for AVP-secreting neurons from human embryonic stem cells (hESCs) by recapitulating in vitro the in vivo embryonic developmental processes of AVP neurons. At first, the differentiation efficiency was improved. That was achieved through the optimization of the culture condition for obtaining dorsal hypothalamic progenitors...
February 26, 2018: Scientific Reports
Bowen Zhang, Lijuan He, Yiming Liu, Jing Zhang, Quan Zeng, Sihan Wang, Zeng Fan, Fang Fang, Lin Chen, Yang Lv, Jiafei Xi, Wen Yue, Yanhua Li, Xuetao Pei
The accurate control of early cell fate specification during differentiation of human embryonic stem cells (hESCs) is critical for acquiring pure therapeutic cell populations of interest. Bone morphogenetic protein 4 (BMP4) is a key mesoderm inducer from ESCs. However, the molecular mechanism of the mesodermal cell fate decision induced by BMP4 remains unclear. Here, we demonstrate the requirement of a bioactive lipid, prostaglandin E2 (PGE2 ), for the mesoderm specification from hESCs by BMP4 induction. We show that BMP4 directly regulates the expression of the key enzyme for PGE2 synthesis, COX-1, and promotes PGE2 production...
February 16, 2018: Stem Cell Reports
Amy Ferreccio, Julie Mathieu, Damien Detraux, Somasundaram Logeshwaran, Christopher Cavanaugh, Bryce Sopher, Karin Fischer, Thomas Bello, Assis M Hussein, Shiri Levy, Savannah Cook, Sonia B Sidhu, Filippo Artoni, Nathan J Palpant, Hans Reinecke, Yuliang Wang, Patrick Paddison, Charles Murry, Suman Jayadev, Carol Ware, Hannele Ruohola-Baker
To easily edit the genome of naïve human embryonic stem cells (hESC), we introduced a dual cassette encoding an inducible Cas9 into the AAVS1 site of naïve hESC (iCas9). The iCas9 line retained karyotypic stability, expression of pluripotency markers, differentiation potential, and stability in 5iLA and EPS pluripotency conditions. The iCas9 line induced efficient homology-directed repair (HDR) and non-homologous end joining (NHEJ) based mutations through CRISPR-Cas9 system. We utilized the iCas9 line to study the epigenetic regulator, PRC2 in early human pluripotency...
February 22, 2018: Cell Cycle
Ekaterina Ovchinnikova, Martijn Hoes, Kirill Ustyantsev, Nils Bomer, Tristan V de Jong, Henny van der Mei, Eugene Berezikov, Peter van der Meer
Cardiac hypertrophy accompanies many forms of cardiovascular diseases. The mechanisms behind the development and regulation of cardiac hypertrophy in the human setting are poorly understood, which can be partially attributed to the lack of a human cardiomyocyte-based preclinical test system recapitulating features of diseased myocardium. The objective of our study is to determine whether human embryonic stem cell-derived cardiomyocytes (hESC-CMs) subjected to mechanical stretch can be used as an adequate in vitro model for studying molecular mechanisms of cardiac hypertrophy...
February 8, 2018: Stem Cell Reports
Yanjiang Xing, Shuang Zhao, Qingxia Wei, Shiqiang Gong, Xin Zhao, Fang Zhou, Rafia Ai-Lamki, Daniel Ortmann, Mingxia Du, Roger Pedersen, Guangdong Shang, Shuyi Si, Nicholas W Morrell, Jun Yang
Genetic defects in bone morphogenetic protein type-II receptor (BMPRII) signalling and inflammation contribute to the pathogenesis of pulmonary arterial hypertension (PAH). The receptor is activated by BMP ligands, which also enhance BMPR2 transcription. A small molecule BMP upregulator with selectivity on vascular endothelium would represent a desirable therapeutic intervention for PAH.We assayed compounds identified in the screening of BMP2 upregulators for their ability to increase expression of Inhibitor of DNA binding 1 (Id1), using a dual reporter driven specifically in human embryonic stem cell (hESC)-derived endothelial cells (ECs)...
February 15, 2018: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
Jieqiong Yang, Yachao Zhang, Jing Tong, Hong Lv, Cong Zhang, Zi-Jiang Chen
Preeclampsia (PE) is a pregnancy-related disorder that occurs after 20 weeks of gestation and affects 3-5% of all human pregnancies worldwide. However, the pathogenesis of PE still remains poorly understood. A deficiency in decidualization is considered a contributing factor to the development of PE. The DNA damage inducible transcript 4 (DDIT4) gene encodes a protein whose main function is inhibiting mammalian target of rapamycin (mTOR) under stress, and several studies have demonstrated that its expression promotes tumor cell apoptosis...
February 13, 2018: Biology of Reproduction
Changbin Sun, Jiawen Zhang, Dongmin Zheng, Jian Wang, Huanming Yang, Xi Zhang
Human embryonic stem cells (hESCs) have the potential to form any cell type in the body, making them attractive cell sources in drug screening, regenerative medicine, disease and developmental processes modeling. However, not all hESC lines have the equal potency to generate desired cell types in vitro. Significant variations have been observed for the differentiation efficiency of various human ESC lines. The precise underpinning molecular mechanisms are still unclear. In this work, we compared transcriptome variations of four hESC lines H7, HUES1, HUES8 and HUES9...
2018: PloS One
Sandra Petrus-Reurer, Hammurabi Bartuma, Monica Aronsson, Sofie Westman, Fredrik Lanner, Anders Kvanta
Geographic atrophy (GA), the late stage of dry age-related macular degeneration is characterized by loss of the retinal pigment epithelial (RPE) layer, which leads to subsequent degeneration of vital retinal structures (e.g., photoreceptors) causing severe vision impairment. Similarly, RPE-loss and decrease in visual acuity is seen in long-term follow up of patients with advanced wet age-related macular degeneration (AMD) receiving intravitreal anti-vascular endothelial growth factor (VEGF) treatment. Therefore, on the one hand, it is fundamental to efficiently derive RPE cells from an unlimited source that could serve as replacement therapy...
January 22, 2018: Journal of Visualized Experiments: JoVE
Yang Wang, Juan Yu, Lvjun Liu, Wen Li, Xingxiang Duan, Yingying Peng, Sicong Zeng, Qi Ouyang, Guangxiu Lu, Ge Lin, Yi Sun
The human embryonic stem cell (hESC) line NERCe003-A-1 was generated by introducing lentiviral-vector-mediated tetracycline-inducible β-catenin expression into a normal hESC line, NERCe003-A. The resulting cell line can overexpress the β-catenin protein, encoded by the CTNNB1 gene, after exposure to doxycycline (Dox). CTNNB1 gene expression was confirmed by quantitative PCR (qPCR) and immunofluorescence assays. Further characterization confirmed that the NERCe003-A-1 cell line expresses typical pluripotency markers and has the ability to form the three germ layers both in vitro and in vivo...
February 3, 2018: Stem Cell Research
Junjie Lu, Anna Baccei, Edroaldo Lummertz da Rocha, Christelle Guillermier, Sean McManus, Lydia A Finney, Cheng Zhang, Matthew L Steinhauser, Hu Li, Paul H Lerou
Differentiation of human pluripotent stem cells towards definitive endoderm (DE) is the critical first step for generating cells comprising organs such as the gut, liver, pancreas and lung. This in-vitro differentiation process generates a heterogeneous population with a proportion of cells failing to differentiate properly and maintaining expression of pluripotency factors such as Oct4. RNA sequencing of single cells collected at four time points during a 4-day DE differentiation identified high expression of metallothionein genes in the residual Oct4-positive cells that failed to differentiate to DE...
January 31, 2018: Stem Cell Research
Qidong Hu, Puja Khanna, Belinda Shu Ee Wong, Zealyn Shi Lin Heng, Charannya Sozheesvari Subhramanyam, Lal Zo Thanga, Sharon Wui Sing Tan, Gyeong Hun Baeg
Reactive oxygen species (ROS) play important roles in fundamental cellular processes such as proliferation and survival. Here we investigated the effect of oxidative stress on stem cell maintenance and neuronal differentiation in a human embryonic stem cell (hESC) model, Ntera2 (NT2). CM-H2DCFDA and DHE assays confirmed that the oxidizing agent paraquat could induce a high level of ROS in NT2 cells. Quantitative PCR, Western blotting and immunocytochemistry showed that paraquat-induced oxidative stress suppressed the expression of stemness markers, including NANOG, OCT4 and TDGF1, whereas it enhanced the spontaneous expression of neuronal differentiation markers such as PAX6, NEUROD1, HOXA1, NCAM, GFRA1 and TUJ1...
January 9, 2018: Oncotarget
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