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Macrophages are highly plastic multifunctional immune cells that play an essential role in mammalian tissues and their dysregulation is implicated in many pathological conditions. In this article, Buchrieser and colleagues define that iPSC-derived macrophages are of the same ontogeny as mouse tissue-resident macrophages, and are MYB independent. This work lays the foundation for the generation of authentic tissue-specialized macrophage subtypes.
In this resource article, Murphy, Mostoslavsky and colleagues describe a diverse, comprehensive and characterized library of sickle-cell-disease-specific induced pluripotent stem cells from patients of different ethnicities, β-globin gene (HBB) haplotypes, and fetal hemoglobin (HbF) levels. This bank is readily available and accessible to all investigators.
In this article, Yu, Geng, and colleagues reveal a direct repressive effect of nicotine on myocardial differentiation by regulating suppression of two cardiac genes (Gata4 and Tbx5) via promoter DNA hypermethylation, contributing to the etiology of smoking-associated cardiac defects.
In this article, Leutz and colleagues assessed the transdifferentiation potential of four C/EBP transcription factors in B cells. C/EBPβ and C/EBPε stimulated the formation of macrophage and granulocyte-like cells. Transdifferentiation involved endogenous C/EBP activation. High transgene dosage promoted granulocyte versus macrophage outcome. C/EBPβ also elicited a stable GMP-like phenotype that could serve as a model to study cell-fate decision.
Shinozawa and colleagues demonstrate that susceptibility to moxifloxacin-induced QT prolongation is significantly correlated between hiPSC-CMs and the healthy individuals they are derived from, showing no significant differences in any drug target-binding sites or in the hERG channel subunit, and no polymorphisms associated with drug-induced QT prolongation. The data suggest the potential of hiPSC-CMs for intrinsic drug susceptibility testing in healthy humans.
In this article, Stamp, McKeown, and colleagues examined the effects of several candidate factors on enteric neurosphere size and behavior following transplantation in vivo. They show that exposure of enteric neurospheres to GDNF enhances their ability to generate an enteric nervous system following transplantation.
Zweigerdt and colleagues demonstrate that the SK channel modulator EBIO does not induce cardiomyogenic differentiation of human PSCs, in contrast to previous reports using mouse PSCs. Instead the authors show that EBIO, in a time- and dose-dependent manner, enriches for cardiomyocyte subpopulations with overall shortened action potentials. All compound-induced effects are independent of the applied PSC lines and differentiation protocols.
Yanagawa, Yuri, and colleagues describe a serum-free culture system that is capable of propagating ureteric bud progenitor cells in vitro with defined growth factors, and demonstrates the ability to reconstruct ureteric bud-like structures from single ureteric bud cells that retained the original ureteric bud characteristics and integrated into the native embryonic kidneys.
In this article, Lo Nigro and colleagues further dissect the heterogeneity of mESC cultures by using the endogenous and heterogeneous expression of PECAM1 and PDGFRα. By combining the expression of these surface markers, the authors describe a strategy to sort out a subpopulation that exclusively gives rise to extraembryonic endodermal derivatives in vitro and in vivo.
In this article, Mandai and colleagues showed that iPSC retina could develop organized photoreceptor layers in the end-stage degeneration retina (rd1) after transplantation with visualized contact with host retinal cells. These transplanted mice showed light-responsive behaviors, and light responses were recorded from the host retina and host retinal ganglion cells that send output signals to the brain.
G. lucidum is a revered medicinal herb for promoting health. Pei and colleagues found that the polysaccharides from G. lucidum (GLP) promoted neural progenitor proliferation to enhance neurogenesis and ameliorated cognition deficits in transgenic Alzheimer's disease model mice. These findings suggest that GLP could serve as a regenerative therapeutic agent for the treatment of cognitive decline associated with neurodegenerative diseases.
Short and colleagues show overexpression of RAD51 in a poorly differentiated stem-like population of glioma cells and that the homologous DNA double-strand break-repair pathway may represent a specific therapeutic target. RAD51-dependent repair is essential for recovery from radiation and temozolomide-induced DNA damage. Targeting this pathway may provide a tumor cell-specific effect in the context of chemo-radiotherapy.
Eaves and colleagues show five growth factors alone can maintain transplantable human hematopoietic stem cell (HSC) activity for 21 days in vitro, through many divisions and the production of thousands of differentiating progeny. Single-cell tracking showed HSC survival and proliferation are regulated in a combinatorial and tunable manner, with SCF most potently stimulating HSC proliferation, multiple single growth factors promoting survival, and the regenerative activity of HSCs regulated independently of either their proliferation or survival.
Therapeutic use of iPSC is limited due to the genomic alterations that accompany cell reprograming. Huertas, Gómez-Cabello, and colleagues show that DNA resection is essential to avoid such phenomena and that CtIP is critically required for mouse and human cell reprogramming. Indeed, reprogramming in the absence of CtIP has severe consequences for cell maintenance and differentiation.
Dann and colleagues show that GSCs are guarded from pluripotency by ZEB1 and high TGF-β signaling, maintaining GSC's mesenchymal state and constituting a MET barrier. However, rare GSCs exhibit epithelial characteristics, explaining the spontaneous emergence of pluripotent cells. Inhibiting TGF-β signaling, downregulating Zeb1, or isolating rare epithelial GSCs all enhance the reprogramming frequency by boosting GSCs over the MET barrier.
Human iPSC-derived cardiomyocytes (hiPSC-CMs) are typically immature, resembling fetal cardiomyocytes. Three months after transplantation to neonatal and adult rat hearts, hiPSC-CMs enlarged and developed partially mature sarcomeres, with greater maturation in the adult heart. Neonatal rat cardiomyocyte grafts matured fully by 3 months, indicating that the human cells require additional time or environmental factors for full maturation.
Accelerating cell homing after adoptive transfer may expediate recovery after hematopoietic transplant. Lund and colleagues developed a novel zebrafish model utilizing bioluminescent imaging to track hematopoietic cell homing, thus allowing for a functional screening approach of small molecule libraries.
Gazit and colleagues mapped all splicing within mouse hematopoietic stem cells by analysis of microarrays and meta-analysis of RNA-sequencing datasets. They validated co-expression of minor isoforms, variant isoform predominance, multiple isoforms from one gene, and discovery of unannotated splicing. Functionally, variant isoforms may alter the activity of HSC genes, or not. Whole-transcriptome splicing data at nucleotide resolution is providing a useful tool for the community.
How does a DNA repair factor regulate adipogenic differentiation and organismal fat deposition? Grillari, Schosserer and colleagues have shown that the essential splicing and DNA repair factor, SNEVhPrp19/hPso4, modulates pro- and anti-adipogenic signaling pathways and ensures genome integrity during adipocyte differentiation, suggesting a novel failsafe mechanism to avoid accumulation of dysfunctional cells.
In this article, Frye and colleagues show that NSUN2-dependent RNA methylation is crucial for neural stem cell differentiation. Human neuroepithelial stem cells lacking NSUN2 are delayed in responding to differentiation and migrating cues. The impaired migration and differentiation capacity of neural stem cells may explain the reduction of upper-layer neurons and microcephaly in the developing NSUN2−/− mouse brain.