ESC & iPSC News Volume 14.24 | Jun 26 2019

TOP STORY

Whsc1 Links Pluripotency Exit with Mesendoderm Specification

Researchers showed that the chromatin-related factor Whsc1 had a dual role in pluripotency exit and germ layer specification of embryonic stem cells. On induction of differentiation, a proportion of Whsc1-depleted ESCs remained entrapped in a pluripotent state and failed to form mesendoderm, although they were still capable of generating neuroectoderm. [Nat Cell Biol] Abstract

(Ranked by impact factor of the journal)

Multi-Organ System for the Evaluation of Efficacy and Off-Target Toxicity of Anticancer Therapeutics

A multi-organ-on-a-chip system housed a multidrug-resistant vulva cancer line, a non-multidrug-resistant breast cancer line, primary hepatocytes, and iPSC-derived cardiomyocytes. Tamoxifen reduced viability of the breast cancer cells only after metabolite generation but did not affect the vulva cancer cells except when coadministered with verapamil, a permeability glycoprotein inhibitor. [Sci Transl Med] Abstract | Press Release

Axonal Pathology in hPSC-Based Models of Parkinson’s Disease Results from Loss of Nrf2 Transcriptional Activity at the Map1b Gene Locus

By employing a combination of human PSCs that harbored the SNCA-A53T mutation contrasted against isogenic controls, the authors evaluated the consequences of α-syn accumulation in human A9-type dopaminergic neurons (hNs). They showed that the early accumulation of α-syn in SNCA-A53T hNs resulted in changes in gene expression consistent with the expression profile of the substantia nigra from Parksinson’s disease patients, analyzed post mortem. [Proc Natl Acad Sci USA] Abstract

KLF4 Protein Stability Regulated by Interaction with Pluripotency Transcription Factors Overrides Transcriptional Control

While investigating transcriptional regulation of the pluripotency transcription factor Kruppel-like factor 4 (Klf4), scientists observed that homozygous deletion of distal enhancers caused a 17-fold decrease in Klf4 transcripts but surprisingly decreased protein levels by less than twofold, indicating that posttranscriptional control of KLF4 protein overode transcriptional control. [Genes Dev] Abstract | Press Release

Induction of Pluripotent Stem Cells from Mouse Embryonic Fibroblasts by Jdp2-Jhdm1b-Mkk6-Glis1-Nanog-Essrb-Sall4

Investigators report that a combination of Jdp2, Jhdm1b, Mkk6, Glis1, Nanog, Essrb, and Sall4 (7F) reprogrammed mouse embryonic fibroblasts to chimera competent iPSCs efficiently. RNA sequencing and ATAC-seq revealed distinct mechanisms for 7F induction of pluripotency. [Cell Rep] Full Article | Graphical Abstract

HSF2BP Interacts with a Conserved Domain of BRCA2 and Is Required for Mouse Spermatogenesis

Researchers identified HSF2BP, a protein previously described as testis specific and not characterized functionally, as an interactor of BRCA2 in mouse embryonic stem cells, where the two proteins form a constitutive complex. HSF2BP was transcribed in all cultured human cancer cell lines tested and elevated in some tumor samples. [Cell Rep] Full Article | Graphical Abstract

Rapid Irreversible Transcriptional Reprogramming in Human Stem Cells Accompanied by Discordance between Replication Timing and Chromatin Compartment

The authors tracked changes in replication timing, gene expression, and chromatin conformation capture A/B compartments over the first two cell cycles during differentiation of human ESCs to definitive endoderm. Remarkably, transcriptional programs were irreversibly reprogrammed within the first cell cycle and were largely but not universally coordinated with replication timing changes. [Stem Cell Reports] Full Article | Press Release

Melanoma Progression Inhibits Pluripotency and Differentiation of Melanoma-Derived iPSCs Produces Cells with Neural-Like Mixed Dysplastic Phenotype

Investigators used reprogramming of melanocytes and melanoma cells to iPSCs to investigate the relationship between cellular plasticity and melanoma progression and mitogen-activated protein kinase (MAPK) inhibitor resistance. They found that melanocyte reprogramming is prevented by the expression of oncogenic BRAF, and in melanoma cells harboring oncogenic BRAF and sensitive to MAPK inhibitors, reprogramming could be restored by inhibition of the activated oncogenic pathway. [Stem Cell Reports] Full Article | Graphical Abstract

Kynurenine Signaling through the Aryl Hydrocarbon Receptor Maintains the Undifferentiated State of Human Embryonic Stem Cells

Researchers report that kynurenine was produced by undifferentiated human (h)ESCs and by iPSCs. In undifferentiated hESCs, kynurenine stimulated the aryl hydrocarbon receptor to promote the expression of self-renewal genes. [Sci Signal] Abstract

Essential Role of PTPN11 Mutation in Enhanced Hematopoietic Differentiation Potential of Induced Pluripotent Stem Cells of Juvenile Myelomonocytic Leukemia

The authors established mutated and non-mutated iPSC clones from a patient with PTPN11-mutated juvenile myelomonocytic leukemia. Both types of iPSCs fulfilled the quality criteria. Mutated iPSC colonies generated significantly more CD34⁺ and CD34⁺CD45⁺ cells compared to non-mutated iPSC colonies in a culture coated with irradiated AGM-S3 cells to which four growth factors were added sequentially or simultaneously. [Br J Haematol] Abstract

Generation of Fully Functional Hepatocyte-Like Organoids from Human Induced Pluripotent Stem Cells Mixed with Endothelial Cells

Using 3D human embryoid bodies formation technology, scientists interlaced human adipose microvascular endothelial cells with hiPSCs, leading to a higher differentiation yield and notable improvements across a wide range of hepatic functions. They conducted a comprehensive gene and protein secretion analysis of our hepatocyte-like clusters’ coagulation factors profile, showing promising results in comparison with human primary hepatocytes. [Sci Rep] Full Article

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Quiescence: Good and Bad of Stem Cell Aging

While protecting stem cell maintenance, quiescence comes at the cost of vulnerability during the process of stem cell activation. The authors discuss molecular and biochemical processes regulating stem cells’ maintenance in and exit from quiescence and how age-related failures of these circuits can contribute to organism aging. [Trends Cell Biol] Full Article

The Convergence of Stem Cell Technologies and Phenotypic Drug Discovery

Investigators analyze the impact of small-molecule phenotypic screens on drug discovery as well as on the investigation of human development and disease biology. They further examine the role of 3D spheroid/organoid structures, microfluidic systems, and miniaturized on-a-chip systems for future discovery strategies. [Cell Chem Biol] Abstract

Visit our reviews page to see a complete list of reviews in the ESC & iPSC research field.

New York Genome Center Awarded $1.5M Chan Zuckerberg Initiative Grant to Develop Integrative Single-Cell Analysis Toolkit for the Human Cell Atlas Project

Scientists at the New York Genome Center and the Icahn School of Medicine at Mount Sinai have been awarded a $1.5 million collaborative grant over three years from the Chan Zuckerberg Initiative to support the development of a toolkit for integrated multimodal cell profiling. [New York Genome Center] Press Release

NORD Awards Ten New Grants in Eight Disease States for Rare Disease Research

The National Organization for Rare Disorders^® (NORD), the leading independent nonprofit organization representing the 25-30 million Americans living with rare diseases, has announced ten new grants as part of its Rare Disease Research Grant Program, which celebrates its 30^th anniversary in 2019. [The National Organization for Rare Disorders^®] Press Release

USPTO Restarts CRISPR Patent Dispute between Broad and UC

The US Court of Appeals for the Federal Circuit ruled last September that patents held by the Broad Institute of MIT and Harvard University were not in conflict with previously submitted patents from the University of California (UC), Berkeley. But the US Patent and Trademark Office (USPTO) has now posted documents declaring interference between them- meaning they may cover overlapping IP. [The Scientist] Editorial

Doctors at Many Stem-Cell Clinics Don’t Have Relevant Training

Many companies offering unproven stem-cell therapies in the United States do not employ clinicians with relevant medical training, an analysis has found. Fewer than half of the 166 businesses analyzed in the study employed physicians whose formal medical training covered the conditions the company claimed to treat, according to the paper, which was published on 25 June in JAMA. [Nature News] Editorial

Embryo Experiments Take ‘Baby Steps’ toward Growing Human Organs in Livestock

The perpetual shortage of human organs for transplant has researchers turning to farm animals. Several biotech companies are genetically engineering pigs to make their organs more compatible with the human body. But some scientists are pursuing a different solution: growing fully human organs in pigs, sheep, or other animals, which could then be harvested for transplants. [ScienceInsider] Editorial

China Organ Transplant Claims Raise Alarm about Research

On 17 June, the China Tribunal, a panel established by the non-governmental organization the International Coalition to End Transplant Abuse in China, concluded that prisoners in China, in particular those imprisoned for their political or religious views, have been killed for their organs for years. It said that the practice — which it branded a crime against humanity – probably still continues. [Nature News] Editorial

Proposal to Close UK Mouse-Research Center Is ‘Major Threat’

Leaders and senior scientists at a national mouse-genetics center in the United Kingdom have written an open letter decrying a recommendation to close the facility’s on-site academic research unit. The closure of the MRC Harwell Institute’s Mammalian Genetics Unit – where scientists study disease using animal models – would be “a major threat to mouse genetics in the UK”, says the letter, organized by 14 senior Harwell scientists. [Nature News] Editorial

NEW American Society of Human Genetics (ASHG) Annual Meeting 2019
October 15-19, 2019
Houston, Texas, United States

Visit our events page to see a complete list of events in the community.

NEW Postdoctoral Researchers – Molecular Embryology and Biology (Cambridge Stem Cell Institute)

Scientist – Stem Cell Metabolism (STEMCELL Technologies Inc.)

Postdoctoral Fellows – Striated Muscle Regeneration (Duke University)

Postdoctoral Fellow – iPSC Models of Diabetes (New York Stem Cell Foundation)

Research Tecnichian – iPSC Generation and Differentiation (The University of Chicago)

Postdoctoral Researcher – Cystic Fibrosis Stem Cell Models (The University of Alabama at Birmingham)

Postdoctoral Associate – RNA Genomics in iPSCs (The Jackson Laboratory)

Postdoctoral Fellow – Stem Cells and Regenerative Medicine (German Research Center for Environmental Health)

Postdoctoral Associate – Stem Cell Differentiation in Immunology (University of Massachusetts Medical School)

Research Assistant – Stem Cells & Regenerative Medicine (Boston Children’s Hospital)

Postdoctoral Fellow – Pluripotent Stem Cells & Joint Tissue Development (Boston Children’s Hospital)

Postdoctoral Fellow – Genetics and Epigenomics of iPSC Biology (Stanford University)

Assistant Associate Professor/Professor in Residence – Stem Cell Program (UC Davis)

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