Prostaglandin E1 and Its Analog Misoprostol Inhibit Human CML Stem Cell Self-Renewal via EP4 Receptor Activation and Repression of AP-1
Bhaskar Chanda Stem Cell Xue and colleagues show that prostaglandin E1 (PGE1) inhibits the activity and self-renewal of human CML leukemic stem cells. Combination of PGE1 or an agonist for its receptor EP4 with conventional tyrosine kinase inhibitor treatment can effectively target CML leukemic stem cells and reduce leukemia growth.
Zika-Virus-Encoded NS2A Disrupts Mammalian Cortical Neurogenesis by Degrading Adherens Junction Proteins
Bhaskar Chanda Stem Cell Zika virus infects neural stem cells and causes microcephaly. In this study, Yoon et al. showed that NS2A protein encoded by Zika virus, but not by Dengue virus, impairs proliferation of radial glial cells in both embryonic mouse cortex and human forebrain organoids. Mechanistically, ZIKV-NS2A disrupts adherens junction formation.
Therapy-Related Clonal Hematopoiesis in Patients with Non-hematologic Cancers Is Common and Associated with Adverse Clinical Outcomes
Bhaskar Chanda Stem Cell Coombs et al. examined a large cohort of solid tumor patients who underwent deep-coverage, paired tumor/blood sequencing and demonstrated that clonal hematopoiesis is common and associated with increasing age, tobacco use, and prior radiation therapy and that it predicts an increased risk of hematologic cancers and shorter survival.
Modeling of TREX1-Dependent Autoimmune Disease using Human Stem Cells Highlights L1 Accumulation as a Source of Neuroinflammation
Bhaskar Chanda Stem Cell Thomas et al. used human pluripotent stem cells to dissect the contribution of neurons and glia to the neuroinflammatory disorder Aicardi-Goutières syndrome (AGS). They found that mutant cells accumulate retroviral-like extrachromosomal nucleic acids that trigger a neurotoxic response, and they suggest that anti-retrovirals could potentially provide therapy for this disease.
Open Chromatin Profiling in hiPSC-Derived Neurons Prioritizes Functional Noncoding Psychiatric Risk Variants and Highlights Neurodevelopmental Loci
Bhaskar Chanda Stem Cell Forrest et al. outline an approach for prioritizing noncoding GWAS risk variants using open chromatin analysis in differentiating hiPSCs. They further show that CRISPR/Cas9 editing of prioritized schizophrenia risk SNPs near MIR137 alters gene expression, open chromatin, and neurodevelopment in hiPSC-derived neurons.
Fusion of Regionally Specified hPSC-Derived Organoids Models Human Brain Development and Interneuron Migration
Bhaskar Chanda Stem Cell Xiang and colleagues report a method for generating human medial ganglionic eminence (MGE)-like organoids (hMGEOs) and cortical-like organoids (hCOs), which resemble the developing human MGE and cortex, respectively. By fusing hMGEOs and hCOs, they establish a 3D model to investigate human interneuron migration.
High-Content Screening in hPSC-Neural Progenitors Identifies Drug Candidates that Inhibit Zika Virus Infection in Fetal-like Organoids and Adult Brain
Bhaskar Chanda Stem Cell Chen, Studer, and colleagues utilize human pluripotent stem cell-derived neural progenitors to perform a high-content screen for anti-ZIKV drug discovery. Hippeastrine hydrobromide was identified and shown to eliminate ZIKV in infected human neural progenitors, rescue a ZIKV-induced microcephaly phenotype in human forebrain organoids, and suppress virus propagation in adult mice with active ZIKV infection.
Pathogen-Induced TLR4-TRIF Innate Immune Signaling in Hematopoietic Stem Cells Promotes Proliferation but Reduces Competitive Fitness
Bhaskar Chanda Stem Cell Takizawa et al. show that self-renewing hematopoietic cells directly sense gram-negative bacterial infection through Toll-like receptor 4 (TLR4) activation, which leads to impaired function via proliferative stress. Genetic and pharmacological blockage of the TLR4-TRIF-ROS-p38 axis can maintain HSC function without disrupting emergency granulopoietic responses to infection.
Bhaskar Chanda Stem Cell Goldman and colleagues use mice chimerized with human patient-derived glial progenitor cells to find out whether glia contribute to childhood-onset schizophrenia. The defects in cell differentiation, myelination, and behavior they see strongly suggest that glial cells do, in fact, have a previously unappreciated role in the pathogenesis of this disease.
ASCL1 Reorganizes Chromatin to Direct Neuronal Fate and Suppress Tumorigenicity of Glioblastoma Stem Cells
Bhaskar Chanda Stem Cell Glioblastoma is characterized by a block in cellular differentiation. Park et al. identify a subset of glioblastoma stem cells (GSCs) that express high levels of the proneural transcription factor ASCL1 and differentiate in response to Notch inhibition, effectively abrogating their stemness properties and tumorigenic potential.