Engineering Ethics and Self-Organizing Models of Human Development: Opportunities and Challenges

Bhaskar Chanda Stem Cell Incorporating engineering ethics early during the planning stages of organoid and gastruloid research may help prevent future confusion about the moral status of complex models of human development. However, the intrinsic self-organizing behavior of organoids and gastruloids may pose a slight challenge to this novel ethical approach.

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Generation of Mouse and Human Organoid-Forming Intestinal Progenitor Cells by Direct Lineage Reprogramming

Bhaskar Chanda Stem Cell Miura and Suzuki describe direct conversion of mouse fibroblasts to cells resembling fetal intestine-derived progenitor cells that can give rise to intestinal stem cell organoids and reconstitute injured colonic tissues after transplantation. They also show that a similar approach can work to make human induced intestinal progenitor cells.

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Nup153 Interacts with Sox2 to Enable Bimodal Gene Regulation and Maintenance of Neural Progenitor Cells

Bhaskar Chanda Stem Cell Toda et al. demonstrate that the nucleoporin Nup153 interacts and cooperates with Sox2 to regulate the cellular state of neural progenitor cells. Nup153 binds both the 5′ and 3′ ends of genes, and the direction of gene regulation by Nup153 varies with the binding position of Nup153.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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