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Biomater Sci 2021 Apr 20. Epub 2021 Apr 20.

Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China. and School of Engineering Science, University of Chinese Academy of Sciences, Beijing 100049, China.

Mechanical or physical cues are associated with the growth and differentiation of embryonic stem cells (ESCs). While the substrate stiffness or topography independently affects the differentiation of ESCs, their cooperative regulation on lineage-specific differentiation remains largely unknown. Here, four topographical configurations on stiff or soft polyacrylamide hydrogel were combined to direct hepatic differentiation of human H1 cells via a four-stage protocol, and the coupled impacts of stiffness and topography were quantified at distinct stages. Read More

J Biol Chem 2021 Jan 8;296:100264. Epub 2021 Jan 8.

Department of Cell and Molecular Biology, The University of Southern Mississippi, Hattiesburg, Mississippi, USA. Electronic address:

Recent studies have demonstrated that embryonic stem cells (ESCs) are deficient in expressing type I interferons (IFN), the cytokines that play key roles in antiviral responses. However, the underlying molecular mechanisms and biological implications of this finding are poorly understood. In this study, we developed a synthetic RNA-based assay that can simultaneously assess multiple forms of antiviral responses. Read More

Proc Natl Acad Sci U S A 2021 Apr;118(15)

The State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, 010070 Hohhot, China;

Embryonic stem cells (ESCs) and induced pluripotent stem cells have the potential to differentiate to all cell types of an adult individual and are useful for studying development and for translational research. However, extrapolation of mouse and human ESC knowledge to deriving stable ESC lines of domestic ungulates and large livestock species has been challenging. In contrast to ESCs that are usually established from the blastocyst, mouse expanded potential stem cells (EPSCs) are derived from four-cell and eight-cell embryos. Read More

Stem Cells Int 2021 10;2021:8818356. Epub 2021 Mar 10.

Stem Cell Laboratory, Department of Genomic Science, Krishna Building, Central University of Kerala, Tejaswini Hills, Periye. P. O, Kasaragod District, Kerala 671316, India.

Mouse embryonic stem cells (mESCs) and mouse epiblast stem cells (mEpiSCs) are the pluripotent stem cells (PSCs), derived from the inner cell mass (ICM) of preimplantation embryos at embryonic day 3.5 (E3.5) and postimplantation embryos at E5. Read More

Nat Cell Biol 2021 Apr 5;23(4):424-436. Epub 2021 Apr 5.

Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, USA.

Although high-throughput RNA sequencing (RNA-seq) has greatly advanced small non-coding RNA (sncRNA) discovery, the currently widely used complementary DNA library construction protocol generates biased sequencing results. This is partially due to RNA modifications that interfere with adapter ligation and reverse transcription processes, which prevent the detection of sncRNAs bearing these modifications. Here, we present PANDORA-seq (panoramic RNA display by overcoming RNA modification aborted sequencing), employing a combinatorial enzymatic treatment to remove key RNA modifications that block adapter ligation and reverse transcription. Read More

Mater Sci Eng C Mater Biol Appl 2021 Apr 5;123:112012. Epub 2021 Mar 5.

Department of Mechanical Engineering, Faculty of Science & Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa, 223-8522, Japan. Electronic address:

Culturing pluripotent stem cells effectively requires substrates coated with feeder cell layers or cell-adhesive matrices. It is difficult to employ pluripotent stem cells as resources for regenerative medicine due to risks of culture system contamination by animal-derived factors, or the large costs associated with the use of adhesive matrices. To enable a coating-free culture system, we focused on UV/ozone surface modification and atmospheric pressure plasma treatment for polystyrene substrates, to improve adhesion and proliferation of pluripotent stem cells. Read More

Front Cell Dev Biol 2021 16;9:638815. Epub 2021 Mar 16.

Institute of Stem Cell and Regenerative Medicine, School of Medicine, Xiamen University, Xiamen, China.

Self-renewal of embryonic stem cells (ESCs) is orchestrated by a vast number of genes at the transcriptional and translational levels. However, the molecular mechanisms of post-translational regulatory factors in ESC self-renewal remain unclear. Histidine phosphorylation, also known as hidden phosphorylation, cannot be detected by conventional experimental methods. Read More

Cell Death Dis 2021 Apr 1;12(4):343. Epub 2021 Apr 1.

Department of Life Science, University of Seoul, Seoul, 130-743, Republic of Korea.

Transcription factor EB (TFEB), a well-known master regulator of autophagy and lysosomal biogenesis, is a member of the microphthalmia family of transcription factors (MiT family). Over the years, TFEB has been shown to have diverse roles in various physiological processes such as clearance for intracellular pathogenic factors and having developmental functions such as dendritic maturation, as well as osteoclast, and endoderm differentiation. However, in the present study, we propose a novel mechanism for TFEB governing pluripotency of mouse ESCs (mESCs) by regulating the pluripotency transcriptional network (PTN) in these cells. Read More

Stem Cell Reports 2021 Apr 25;16(4):851-867. Epub 2021 Mar 25.

Laboratory for Retinal Regeneration, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan; RIKEN Program for Drug Discovery and Medical Technology Platforms (DMP), RIKEN Cluster for Science, Technology and Innovation Hub, Saitama 351-0198, Japan. Electronic address:

ESC- and iPSC-derived retinal transplantation is a promising therapeutic approach for disease with end-stage retinal degeneration, such as retinitis pigmentosa and age-related macular degeneration. We previously showed medium- to long-term survival, maturation, and light response of transplanted human ESC- and iPSC-retina in mouse, rat, and monkey models of end-stage retinal degeneration. Because the use of patient hiPSC-derived retina with a disease-causing gene mutation is not appropriate for therapeutic use, allogeneic transplantation using retinal tissue/cells differentiated from a stocked hESC and iPSC line would be most practical. Read More

Nat Commun 2021 03 25;12(1):1863. Epub 2021 Mar 25.

Proteomics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

Embryonic stem cells (ESCs) can be maintained in the naïve state through inhibition of Mek1/2 and Gsk3 (2i). A relevant effect of 2i is the inhibition of Cdk8/19, which are negative regulators of the Mediator complex, responsible for the activity of enhancers. Inhibition of Cdk8/19 (Cdk8/19i) stimulates enhancers and, similar to 2i, stabilizes ESCs in the naïve state. Read More

Genome Res 2021 Apr 12;31(4):564-575. Epub 2021 Mar 12.

Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, M5S 3G5, Canada.

Transcriptional enhancers are critical for development and phenotype evolution and are often mutated in disease contexts; however, even in well-studied cell types, the sequence code conferring enhancer activity remains unknown. To examine the enhancer regulatory code for pluripotent stem cells, we identified genomic regions with conserved binding of multiple transcription factors in mouse and human embryonic stem cells (ESCs). Examination of these regions revealed that they contain on average 12. Read More

Stem Cell Res Ther 2021 Mar 11;12(1):172. Epub 2021 Mar 11.

Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, 050017, Hebei Province, China.

Background: Spinal cord injury (SCI) is a common disease that results in motor and sensory disorders and even lifelong paralysis. The transplantation of stem cells, such as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), or subsequently generated stem/progenitor cells, is predicted to be a promising treatment for SCI. In this study, we aimed to investigate effect of human iPSC-derived neural stem cells (hiPSC-NSCs) and umbilical cord-derived MSCs (huMSCs) in a mouse model of acute SCI. Read More

Biochim Biophys Acta Gene Regul Mech 2021 Mar 8;1864(4-5):194702. Epub 2021 Mar 8.

Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Germany; DZHK, German Centre for Cardiovascular Research, Partner Site Heidelberg/Mannheim, Germany. Electronic address:

The homeodomain transcription factor SHOX2 is involved in the development and function of the heart's primary pacemaker, the sinoatrial node (SAN), and has been associated with cardiac conduction-related diseases such as atrial fibrillation and sinus node dysfunction. To shed light on Shox2-dependent genetic processes involved in these diseases, we established a murine embryonic stem cell (ESC) cardiac differentiation model to investigate Shox2 pathways in SAN-like cardiomyocytes. Differential RNA-seq-based expression profiling of Shox2 and Shox2 ESCs revealed 94 dysregulated transcripts in Shox2 ESC-derived SAN-like cells. Read More

Am J Respir Crit Care Med 2021 Mar 11. Epub 2021 Mar 11.

Cincinnati Children's Hospital Medical Center, Pediatrics, Division of Pulmonary Biology, Cincinnati, Ohio, United States;

Rationale: While pulmonary endothelial progenitor cells (EPCs) hold promise for cell-based therapies for neonatal pulmonary disorders, whether EPCs can be derived from pluripotent embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) remains unknown.

Objective: To investigate heterogeneity of pulmonary EPCs and derive functional EPCs from pluripotent ESCs.

Methods: Single cell RNA sequencing of neonatal human and mouse lung was used to identify the heterogeneity of pulmonary EPCs. Read More

Stem Cells Int 2021 22;2021:6674283. Epub 2021 Feb 22.

Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China.

The RNA-binding protein Lin28 regulates neurogliogenesis in mammals, independently of the let-7 microRNA. However, the detailed regulatory mechanism remains obscured. Here, we established Lin28a or Lin28b overexpression mouse embryonic stem cells (ESCs) and found that these cells expressed similar levels of the core pluripotent factors, such as Oct4 and Sox2, and increased Yap1 but decreased lineage-specific markers compared to the control ESCs. Read More

EMBO J 2021 Apr 9;40(8):e105776. Epub 2021 Mar 9.

Max Perutz Laboratories Vienna, University of Vienna, Vienna Biocenter, Vienna, Austria.

In the mammalian embryo, epiblast cells must exit the naïve state and acquire formative pluripotency. This cell state transition is recapitulated by mouse embryonic stem cells (ESCs), which undergo pluripotency progression in defined conditions in vitro. However, our understanding of the molecular cascades and gene networks involved in the exit from naïve pluripotency remains fragmentary. Read More

Hum Cell 2021 May 8;34(3):847-861. Epub 2021 Mar 8.

Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Hezar Jerib Ave, Azadi Square, 81746, Isfahan, Iran.

Fibronectin type III domain-containing-5 (Fndc5) is a trans-membrane protein which is involved in a variety of cellular events including neural differentiation of mouse embryonic stem cells (mESCs) as its knockdown and overexpression diminishes and facilitates this process, respectively. However, downstream targets of Fndc5 in neurogenesis are still unclear. Neurotrophins including NGF, BDNF, NT-3, and NT-4 are the primary regulators of neuronal survival, growth, differentiation, and repair. Read More

Genomics Proteomics Bioinformatics 2021 Mar 3. Epub 2021 Mar 3.

Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore; The State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China. Electronic address:

Chromatin modification contributes to pluripotency maintenance in embryonic stem cells (ESCs). However, the related mechanisms remain obscure. Here, we show that Npac, a "reader" of histone H3 lysine 36 trimethylation (H3K36me3), is required to maintain mouse ESC (mESC) pluripotency since knockdown of Npac causes mESC differentiation. Read More

Stem Cell Reports 2021 Apr 4;16(4):727-740. Epub 2021 Mar 4.

MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK. Electronic address:

Apelin receptor (APLNR/AGTRLl1/APJ) marks a transient cell population during the differentiation of hematopoietic stem and progenitor cells (HSPCs) from pluripotent stem cells, but its function during the production and maintenance of hematopoietic stem cells is not clear. We generated an Aplnr-tdTomato reporter mouse embryonic stem cell (mESC) line and showed that HSPCs are generated exclusively from mesodermal cells that express Aplnr-tdTomato. HSPC production from mESCs was impaired when Aplnr was deleted, implying that this pathway is required for their production. Read More

Stem Cell Reports 2021 Mar 25;16(3):582-596. Epub 2021 Feb 25.

The State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, Hohhot 010020, China; Research Center for Animal Genetic Resources of Mongolia Plateau, College of Life Sciences, Inner Mongolia University, Hohhot 010020, China. Electronic address:

Naive pluripotency can be maintained in medium with two inhibitors plus leukemia inhibitory factor (2i/LIF) supplementation, which primarily affects canonical WNT, FGF/ERK, and JAK/STAT3 signaling. However, whether one of these three supplements alone is sufficient to maintain naive self-renewal remains unclear. Here we show that LIF alone in medium is sufficient for adaptation of 2i/L-ESCs to embryonic stem cells (ESCs) in a hypermethylated state (L-ESCs). Read More

Nanomedicine 2021 Feb 20;34:102375. Epub 2021 Feb 20.

Liaoning Provincial Center for Clinical Research on Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China; Liaoning Provincial Key Laboratory for Research on the Pathogenic Mechanisms of Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China. Electronic address:

MicroRNA132 (miR132) negatively regulates the differentiation of mouse embryonic stem cells (ESCs) into dopaminergic (DAergic) neurons; in contrast, antisense oligonucleotide against miR132 (miR132-ASO) effectively blocks the activity of endogenous miR132 and thereafter promotes the differentiation of DAergic neurons. However, it is difficult for miR132-ASO to enter cells without a suitable delivery system. Tetrahedral DNA nanostructures (TDNs), as a new type of DNA-based nanocarrier, have great potential in biomedical applications and even have been reported to promote stem cell differentiation. Read More

Cell Res 2021 Feb 19. Epub 2021 Feb 19.

State Key Laboratory of Stem Cell and Reproductive Biology, Innovation Academy for Stem Cell and Regeneration, Beijing Institute for Stem Cell and Regenerative Medicine, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 100101, China.

The pluripotency of mammalian early and late epiblast could be recapitulated by naïve embryonic stem cells (ESCs) and primed epiblast stem cells (EpiSCs), respectively. However, these two states of pluripotency may not be sufficient to reflect the full complexity and developmental potency of the epiblast during mammalian early development. Here we report the establishment of self-renewing formative pluripotent stem cells (fPSCs) which manifest features of epiblast cells poised for gastrulation. Read More

J Endocr Soc 2021 Mar 2;5(3):bvaa188. Epub 2020 Dec 2.

Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan.

The hypothalamus and pituitary have been identified to play essential roles in maintaining homeostasis. Various diseases can disrupt the functions of these systems, which can often result in serious lifelong symptoms. The current treatment for hypopituitarism involves hormone replacement therapy. Read More

Front Cell Dev Biol 2020 25;8:533543. Epub 2021 Jan 25.

State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China.

Embryonic Sertoli cells (eSCs) possess multiple supporting functions and research value in gonadal development and sex determination. However, the limitation of acquiring quality eSCs had hindered the further application. Herein, we successfully derived non-genetically modified (non-GM)-induced embryonic Sertoli-like cells (eSLCs) from mouse embryonic stem cells (ESCs) with a TM4 cell-derived conditioned medium containing recombinant endogenous protein factors , , , , , and . Read More

Dev Growth Differ 2021 Feb 22;63(2):104-115. Epub 2021 Mar 22.

Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.

Forty years have passed since the first pluripotent stem cells (PSCs), mouse embryonic stem cells (ESCs), were established. Since then, several PSCs have been reported, including human ESCs in 1998, mouse epiblast stem cells (EpiSCs) in 2007, induced PSCs (iPSCs) in 2006 and 2007, and naïve human PSCs in 2014. Naïve PSCs are thought to correspond to pre-implantation epiblast cells, whereas conventional (or primed) human PSCs correspond to post-implantation epiblast cells. Read More

Blood Adv 2021 Feb;5(3):829-842

Centre for Inflammation Research, The University of Edinburgh, Edinburgh, United Kingdom.

Integrated molecular signals regulate cell fate decisions in the embryonic aortic endothelium to drive hematopoietic stem cell (HSC) generation during development. The G-protein-coupled receptor 56 (Gpr56, also called Adgrg1) is the most highly upregulated receptor gene in cells that take on hematopoietic fate and is expressed by adult bone marrow HSCs. Despite the requirement for Gpr56 in hematopoietic stem/progenitor cell (HS/PC) generation in zebrafish embryos and the highly upregulated expression of GPR56 in treatment-resistant leukemic patients, its function in normal mammalian hematopoiesis remains unclear. Read More

Int J Mol Sci 2021 Feb 2;22(3). Epub 2021 Feb 2.

Laboratory of Neurobiology, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.

Restraint stress causes various maternal diseases during pregnancy. β-Adrenergic receptor (β-AR) and Forkhead transcription factor class O 1 (FOXO1) are critical factors not only in stress, but also in reproduction. However, the role of FOXO1 in restraint stress, causing changes in the β-AR pathway in pregnant mice, has been unclear. Read More

ACS Infect Dis 2021 02 3;7(2):293-308. Epub 2021 Feb 3.

Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, United States.

The increasing prevalence of strains exhibiting decreased susceptibility to extended-spectrum cephalosporins (ESCs) presents a challenge for the successful treatment of gonorrhea infections. To address this challenge, we evaluated a panel of 23 cephalosporins against penicillin-binding protein 2 (PBP2) from the ESC-resistant (ESC) strain H041 to determine which molecular features are important for antimicrobial activity. Structure-activity relationships (SARs) developed from acylation rate constants against PBP2 and antimicrobial susceptibilities against the H041 strain of , and interpreted against docking models, reveal that cephalosporins possessing large, lipophilic R side chains and electronegative R side chains with planar groups are associated with higher acylation rates against PBP2, but also that these same amphipathic features can lower antimicrobial activity. Read More

Nat Genet 2021 02 1;53(2):215-229. Epub 2021 Feb 1.

Department of Molecular Medicine, Medical School, University of Padua, Padua, Italy.

Naive epiblast and embryonic stem cells (ESCs) give rise to all cells of adults. Such developmental plasticity is associated with genome hypomethylation. Here, we show that LIF-Stat3 signaling induces genomic hypomethylation via metabolic reconfiguration. Read More

Sci Adv 2021 Jan 20;7(4). Epub 2021 Jan 20.

State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China.

Polycomb group (PcG) proteins form multiprotein complexes that affect stem cell identity and fate decisions by still largely unexplored mechanisms. Here, by performing a CRISPR-based loss-of-function screen in embryonic stem cells (ESCs), we identify PcG gene involved in the repression of endodermal transcription factor We report that deletion of results in peri-implantation embryonic lethality in mice. We further demonstrate that -null ESCs exhibit impaired self-renewal and spontaneous differentiation to primitive endoderm (PE). Read More