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Eiges and colleagues characterized two C9/ALS-FTD hESC lines, and compared them with haploidentical and unrelated C9 iPSCs. They show that reprogramming excessively hypermethylates the C9 expansion, and provide evidence that when it is unmethylated the expansion enhances accumulation of repeat-containing mRNAs upon differentiation. Their study supports the potential role of C9 hypermethylation as a neuroprotective mechanism in C9-related ALS.
Stripp and colleagues report that H1N1 influenza virus infection in mice induces distal lung epithelial remodeling marked by the appearance of nascent KRT5+ cells in injured airways and alveoli. Rather than pre-existing basal, club, and alveolar progenitor cells, they traced the cellular origin of these nascent KRT5+ cells to a population of airway-resident SOX2+ Lin− progenitor cells.
In this article, Aguilar and colleagues temporally characterize the in vivo dynamics of chromatin modifications and the coding and noncoding transcriptional landscape in a mouse model of traumatic muscle injury to provide a comprehensive view of the central factors that regulate muscle regeneration.
Pan and colleagues generated GATA2w/eGFP reporter in hESCs, and found that GATA2/eGFP expression defines HECs and HPCs in hESC differentiation. In addition, they showed that CD61 marks HECs and HPCs in hPSC differentiation. Moreover, they revealed that CD61 also marks a small portion of bio-potent HECs in both YS and AGM in E10 mouse embryo.
In this article, Hu and colleagues showed that CNOT3, a component of the Ccr4-Not deadenylase complex, is required for the maintenance of the pluripotent state in mouse epiblast and embryonic stem cells. They found that CNOT3 promotes differentiation gene mRNA deadenylation and degradation, and post-transcriptionally regulates the gene expression program in pluripotent cells.
Stein and colleagues investigated whether phenotypic transcription factors have a role in the initial stages of differentiation of human embryonic stem cells before lineage commitment. They discovered selective and transient upregulation of RUNX1 early in mesendodermal differentiation. Multiple experimental approaches provide evidence that RUNX1 regulates EMT and motility through modulation of TGFB2 signaling.
In this article, Kurre and colleagues demonstrate that FA proteins guard genome integrity during hematopoietic development and balance the inherent stress that coincides with the characteristic rapid fetal cell divisions. FA pathway disruption reveals a unique p53 independent developmental phenotype that constrains proliferative activity and pool expansion without leading to canonical apoptotic attrition seen in experimental models postnatally.
In this article, Spence and colleagues show that WNT/β-CATENIN signaling is dispensable for epithelial progenitor cell proliferation during the pseudostratified stage of intestine development, whereas active signaling is required for proliferation and proper villus formation once villus morphogenesis begins. Mechanistically, WNT/β-CATENIN-mediated proliferation is driven by mesenchymal, but not epithelial, WNT ligand secretion.
In this article, Zhang, Liu, Gao, and colleagues show that SHH-induced ventral neuroprogenitors under EB conditions are fated to MGE, while the AD cells are fated to FP. Wnts/STAT3/p38 pathways are closely involved in MGE and FP specification. GABA, cholinergic, and dopaminergic neurons of either MGE or FP origin could therefore be generated through integration of appropriate differentiation paradigms and signaling regulators.
In this article, Ma and colleagues show that considerable definitive erythroblasts could be generated from hPSCs by co-culturing with AGM-S3 cells. Tracing through serial expression of CD34, GPA, and CD36 on hPSC-derived erythroblasts revealed that they arose from a unique GPA+CD34lowCD36− cell fraction sharing both erythroid and mesodermal endothelium characteristics.
Ocular injury is a major cause of loss of corneal transparency, leading to blindness. Chauhan and colleagues’ data demonstrate that, following ocular injury, corneal transparency can be restored by MSCs, a process that is completely dependent upon HGF secretion by MSCs. Most importantly, they show that HGF alone can restore corneal transparency, a finding that offers a cell-free HGF-based therapeutic approach.
In this article, Sun and colleagues show that Aβ may not be the major factor accounting for impaired adult neurogenesis in mice overexpressing hAPP.
In this article, Leschik and colleagues examine a combination therapy with BDNF-overexpressing neural progenitors as a potential therapy for HD. They compare transplantation in a chemical and two genetic HD mouse models, demonstrate rescue effects in motor function in the QA-lesioned mouse model, and attribute these to enhanced striatal differentiation of transplanted cells.
Tryggvason and colleagues have developed a protocol to differentiate hESCs to endothelial progenitor cells (EPCs) on human recombinant laminin matrices in a chemically defined and xeno-free environment. These hESC-derived cells are functional and express specific markers in the endothelial lineage, holding promise to provide a pure, unlimited source of EPCs for therapeutic purposes and in vitro disease modeling.
Hedgehog (Hh) signaling is implicated in tissue regeneration. Ruat, Boussin, and colleagues show that short-term Hh pathway activation in adult neural stem cells (NSCs) results in increases in activated NSCs. Surprisingly, long-term pathway activation causes a large accumulation of quiescent NSCs and impaired neurogenesis. Thus, the Hh pathway has a novel role in balancing quiescent and activated adult NSC numbers.
γ-Secretase inhibitor (GSI)-treated neural stem/progenitor cells derived from human induced pluripotent stem cells exhibited a reduced proportion of dividing cells and increased neuronal maturation with limited proliferation in vitro. Okano, Nakamura, and colleagues show that GSI treatment prevented tumor-like overgrowth of transplanted cells by inhibiting cell proliferation, thereby resulting in safe and long-lasting functional recovery in vivo.
In this article, Yan and colleagues comprehensively evaluate the properties of mitochondrial and synaptic structure and function during the development of hiPSC-derived dopaminergic (DA) neurons. Their data demonstrate that mitochondria are important in DA neuron maturation and synaptic formation. The model provides a link of mitochondrial alterations to synaptic failure and neurogenesis in the pathogenesis of neurodegenerative diseases including Parkinson’s disease.
Despite the interest in generating iPSCs from human primary acute leukemias for disease modeling, reprogramming leukemias is an extremely inefficient process. In this article, Menéndez, Bueno, and colleagues show that many reprogramming strategies reported to date are not sufficient to generate B-ALL-derived iPSCs. Global transcriptome/DNA methylome profiling suggested a developmental/differentiation refractoriness of B-ALL to reprogramming into pluripotency.
Shim, Studer, and colleagues demonstrate that using a floor-plate-based differentiation strategy, Parkinson's disease (PD) patient iPSC-derived mDA neurons recapitulate several PD phenotypes, including pathogenic protein accumulation, cell-type-specific vulnerability, mitochondrial dysfunction, and abnormal neurotransmitter homeostasis. The authors further propose that these phenotypes form a pathogenic loop contributing to disease.
In this article, Takahashi and colleagues show that the allogeneic immune response to iPSC-derived retinal pigment epithelial (RPE) cells by T cells in vitro. However, HLA-restricted immune reaction (at least HLA-A, -B, and -DRB1-matched) does not occur when iPS-RPE cells established from HLA homozygous donors are used.