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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.
In this article, Takahashi and colleagues show the allogeneic immune response, such as immune rejection, to iPSC-derived retinal pigment epithelial (RPE) cells by inflammatory cells in vivo. However, the immune reaction does not occur when iPS-RPE cells established from MHC homozygous donors were transplanted.
Lian, Tse, and colleagues reveal the protective effects of iPSC-MSCs against Dox-induced cardiomyopathy by efficacious mitochondrial transfer from iPSC-MSCs to injured cardiomyocytes, independently of MSC paracrine effects, and show that augmentation of Dox-induced cardiomyopathy with iPSC-MSCs is attributed to an intrinsically high level of Miro1 and high sensitivity to TNF-α-induced TNT formation.
Wnt signaling is an established key regulator of vertebrate heart development, but its role in human cardiomyocyte development remains unclear. Here, Hoppler and colleagues use hESCs to study canonical and noncanonical Wnt pathway activity and identify Wnt signal and receptor genes during human cardiomyocyte development. They identify roles for Wnt signaling that are relevant for congenital defects studies and regenerative medicine applications.
Wang and colleagues used a knockin mouse model, CBPS436A, in which the aPKC-CBP pathway is deficient, to show that the aPKC-CBP pathway is required to maintain a sustained rate of hippocampal neurogenesis, hippocampal-dependent fear, and spatial memory, and to retain the interaction between CBP and CREB in response to cellular/molecular changes during early adulthood (3–6 months).
In this article, Rahmig and colleagues report on highly improved reconstitution of human thrombocytes and erythroid cells in a KIT-deficient humanized mouse model, NSGW41 mice. They show that stable human HSC engraftment is sufficient to ensure continuous and robust output of human thrombocytic and erythroid cells. Enucleation of human normoblasts in mice occurs independently of human EPO.
Rossant and colleagues developed a robust embryonic stem cell-based vascular differentiation assay, which was used to screen a small-molecule kinase library. They identified RSK and TTK as angiogenic modulators. Inhibition of these pathways inhibited angiogenesis in embryoid bodies and HUVECs in vitro, and reduced tumor growth and vascular density in an in vivo Lewis lung carcinoma mouse model.
In their work, Benvenisty and colleagues utilize neural progenitor cells (NPCs) derived from five embryonic stem cell lines with trisomy 21 to show the involvement of RUNX1 in the development of the neural phenotype of Down syndrome (DS). Ablation of all three copies of RUNX1 using genome editing led to reduced apoptosis and changes to neuron migration-related genes in DS-NPCs.
In this article, Gao and colleagues generated multiple iPSC lines from patients with MAPT IVS10+16 and tau-A152T mutations and found that significantly higher levels of MMP-9/MMP-2 in patient neurons contribute to stress-induced neuronal cell death. 4R but not 3R tau-A152T activates ERK, which in turn increases MMP-9 expression. These results provide insights into the molecular pathogenesis of FTD.
In this article, Izeta, García-Parra, and colleagues show that the panniculus carnosus (PC) muscle satellite cells originate from a somitic Pax3/7-positive and Myf5-positive lineage, like limb and body wall skeletal muscles. Through lineage tracing, cell sorting, and ablation experiments they unambiguously demonstrate that the only dermal cells with a myogenic potential are the PC satellite cells and their progeny.
Haggarty and colleagues show in-depth phenotypic characterization of a human iPSC-derived neuronal model of tau-A152T associated with FTD. This study reveals upregulation of phospho-tau and detergent-insoluble oligomeric tau, dysregulation of proteostasis pathways, and consequent increased cell vulnerability to stress, unmasking potential disease biomarkers and therapeutic targets. This study further demonstrates that tau toxicity can be rescued by genetic and pharmacological downregulation of tau.
In this report, Balyasnikova and colleagues demonstrate that hypoxic preconditioning or overexpression of CXCR4 in neural stem cells enhances intranasal delivery of oncolytic virus to irradiated glioma, resulting in survival benefits for experimental animals. These findings indicate that intranasal stem cell-based oncolytic virotherapy could be optimized for future clinical applications in the context of brain tumors.
Savatier, Afanassieff, and colleagues report the generation of rabbit ESC lines with gene expression profiles and cell-cycle characteristics closer to those of the rabbit epiblast and mouse ESCs than what was previously reported for rbESC conventional cells. These ESC lines can switch between different states, revealing the dynamics of pluripotency states. Some of these ESC lines acquired the capacity to colonize the rabbit embryo.
In this article, Zhang, Liu, Jin, and colleagues show that two adjacent double-strand breaks are preferentially repaired through precise ligation without insertions/deletions in human pluripotent stem cells. This strategy will thus serve as an efficient way to delete a gene fragment and represents a precise methodology for loss-of-function studies of both coding and non-coding genes in human pluripotent stem cells.
In this article Stanley, Elefanty, and colleagues describe a simple vector system, GAPTrap, for constitutively expressing transgenes in pluripotent stem cells and their differentiated derivatives. GAPTrap vectors target transgenes to the GAPDH locus, ensuring robust and reliable expression in a wide variety of cell types, and providing an ideal base for cell tagging and gene overexpression experiments.