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In this article, Jiang, Chan, and colleagues show that an in vitro culture strategy through neuronal differentiation and dedifferentiation can reprogram BMSCs with enhanced migratory capacity and homing ability toward cancer, the effect of which is mediated by the H4ac/CCL5/CCR1/ERK pathway.
Pei, Shen, and colleagues demonstrate that human adult astrocytes could be directly converted into neuronal cells by small molecules. The astrocyte-derived neuronal cells exhibited neuronal morphologies, expressed neuronal markers, displayed neuronal electrophysiological properties, shared a similar transcriptome profile with hESC-differentiated neurons, and could survive and become electrophysiologically mature in mice brain.
In this article, Nakamura, Okano, and colleagues report that NSC transplantation therapy is as effective in aged mice as it is in young mice, despite the more severe damage after SCI in aged mice. HGF is a key factor in the enhanced functional recovery after NSC transplantation observed in aged mice with SCI.
In this article, Freude, Zhang, and colleagues describe a patient iPSC-derived neuronal model for FTD3. This cellular model shows endosome abnormalities previously reported in patients. Furthermore, it provides insights into the role of impaired mitochondria function and imbalanced iron homeostasis in FTD3 pathology. All observed phenotypes were rescued in CRISPR/Cas9-edited isogenic controls.
Schapira and colleagues devised a dopaminergic neuronal model from human adipose NCSCs which provided insights into the role of glucocerebrosidase dysfunction in PD pathogenesis. Glucocerebrosidase function enhancement reversed biochemical abnormalities in GBA1 mutant neurons. This method provides a platform to test potential therapeutic compounds for PD treatment.
Brennand, Levy, Carvalho, and colleagues present a systematic evaluation of marker chromosome mosaicism in somatic fibroblasts, hiPSCs, and NPCs. Because this mutation was initially identified as a complex genomic rearrangement rather than as a karyotypic abnormality, it represents a cautionary indication that the precise structure of any genetic mutation should be clarified before moving forward with hiPSC-based studies.
Based on gene profiling data in a stroke model, Momma and colleagues hypothesize a role of calcium signaling in the stem cell injury response. Using a newly established in vitro model they show that astrocytic calcium waves spread to neural stem and progenitor cells, thereby increasing their self-renewal and migration capacity. These effects are mediated by the Notch/Hes1 signaling pathway.
In this article, Wu, Vasilakis, and colleagues demonstrate the infection of primary human fetal brain-derived neural stem cells by a 2015 Mexican strain of ZIKV. They show that ZIKV is cytotoxic and inhibits proliferation independent of different human origins, but inhibits neuronal differentiation and alters gene expression in a cell-strain-dependent manner.
We welcome the opportunity for further discussion of this data, and in the paragraphs below, we briefly address the comments provided by StemCells Inc. (STEM).
The two articles in this issue of Stem Cell Reports authored by UCI researchers are based on sponsor-supported collaborations that were conducted in the effort to develop therapies for serious and debilitating neurological disorders that have no effective therapy: specifically, cervical spinal cord injury (SCI) and Alzheimer’s disease (AD) (Anderson et al., 2017; Marsh et al., 2017).
Temple and Studer discuss two recent studies that raise concerns about cell characterization of a neural stem cell product intended for clinical use. The variability observed between clinical versus research-grade cell lots in pre-clinical studies imply that negative clinical results may have been avoidable by more detailed characterization and mechanism-based potency assays in the final cell product.
(Stem Cell Reports 8, 69–83, January 10, 2017)
In this article, Blurton-Jones and colleagues demonstrate that StemCells, Inc. human neural stem cells (HuCNS-SC), which were originally derived under GMP conditions, failed to improve cognition, synaptic density, or increase BDNF in an immune-deficient AD mouse model. Furthermore, cells formed ectopic ventricular clusters in over a quarter of transplanted animals.
Anderson and colleagues report that preclinical testing of a human neural stem cell line intended for use in a human clinical trial of cervical spinal cord injury (SCI) failed to show efficacy in an animal model of SCI, whereas a research-grade cell line did show efficacy. The human trial proceeded despite the negative data.
Franklin, Kazanis, and colleagues compare the two oligodendrogenic pathways that co-exist in the corpus callosum. They demonstrate that, irrespective of age, adult neural stem cells generate oligodendroblasts; i.e., progenitors with limited self-renewal capacity that respond rapidly to focal demyelination but eventually fail to generate new myelin, which are different to parenchymal oligodendrocyte progenitor cells that drive remyelination.
In mouse testicular seminiferous tubules, Yoshida and colleagues questioned how sperm stem cells follow different fates (to differentiate or to self-renew) in response to homogeneously distributed extracellular signals. They showed that heterogeneous expression of Shisa6, a cell-autonomous Wnt inhibitor, confers resistance to homogeneously distributed differentiation-promoting Wnt signaling. This may be generic for stem cell regulation in a facultative niche.
The use of sera in the preparation of cell-based strategies critically limits the efficacy and reproducibility of the process as it conflicts with cellular responses. Luyten and colleagues present a bioinspired engineering process including serum-free pre-conditioning combined with micro-aggregation and bone morphogenetic protein priming resulting in a self-sustained tissue intermediate that, upon implantation, successfully heals critical long-bone defects.
In this study, Gadue and colleagues studied GATA6 mutant pluripotent stem cells and demonstrate that GATA6 is necessary for human definitive endoderm specification. GATA6 also plays an important role in pancreas specification which could be partially bypassed by retinoic acid signaling. Furthermore, derivative β cells lacked glucose responsiveness in vitro, showing that GATA6 is vital for appropriate human pancreas development.
Tsai and Li use a strategy to identify and evaluate soluble factors of interest in human bone marrow critical to regulation of BMSC activities. They have found that LCN2 and PRL are key factors of bone marrow that delay cellular senescence of BMSCs and prime the cells to enhance the repair of calvarial defects in mice.
Kassem and colleagues have investigated the role of legumain in cell fate decision of human bone marrow stromal cells (BMSCs). Using multidisciplinary in vitro and in vivo approaches, they show that legumain functions as a novel “molecular switch” inhibiting osteoblast and enhancing adipocyte differentiation of BMSCs, through modulation of the ECM protein fibronectin, and that legumain expression is altered in the bone microenvironment of postmenopausal osteoporotic patients.