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In this article, Metzger and colleagues present the establishment of physiologically relevant human blood-brain barrier quadruple culture models based on induced pluripotent and multipotent stem cells. The novel model can be used as a powerful tool in pharmaceutical drug research and ADMET studies, which may allow a more reliable translation of promising drug candidates into clinical application.
In this article, Cheng and colleagues isolated primitive neural stem cells from a patient presenting a c.1444-2A>C mutation in TSC2. These iPSC-derived neural cells recapitulated the pathophysiology of TSC2-deficient patients and could be used for screening appropriate drugs for personalized therapies.
In this article, van Leeuwen and colleagues determine high temporal gene expression changes in human mesenchymal stromal cells upon induction of adipocyte and osteoblast differentiation. They identify three early differentiation phases within the first 4 days. Furthermore, novel transcription factors were identified that may control cell fate of hMSCs and should be considered in mechanistic models that clarify bone-anabolic changes.
In this article, Han and colleagues show that miR-342-5p acts as a downstream effector of Notch signaling in the mouse CNS. Notch signal inhibits miR-342-5p expression by regulating its host gene Evl. And with attenuated Notch signal in NSCs, miR-342-5p is upregulated to promote NSCs transition into INPs, and to inhibit astrocyte commitment by targeting GFAP.
In this article, Pawlowski and colleagues report a dual genomic safe harbor targeting approach for optimized inducible transgene expression in human pluripotent stem cells (hPSCs). The optimized inducible expression of reprogramming factors in hPSCs enables deterministic forward programming into mature cell types. This is exemplified by the rapid, single-step generation of neurons, skeletal myocytes, and oligodendrocytes.
In this study Kruitwagen and colleagues establish and characterize a feline liver organoid culture, which has adult stem cell properties and can be differentiated toward hepatocyte-like cells. They propose liver organoids as a tool to model hepatic steatosis and show that feline liver organoids accumulate more lipids than human organoids when provided with excess fatty acids.
Murphy, Schwartz and colleagues report a genome-wide analysis of biological function for endothelial cells and pericytes cultured using 2D or 3D formats. Global gene expression patterns are comparable for vascular cells cultured in synthetic hydrogels or Matrigel during vascular network formation, while cells cultured on tissue-culture polystyrene surfaces adopt a proliferative phenotype that correlates to increased FAK-ERK activity.
Fütterer et al. show that DIDO isoforms regulate symmetric and asymmetric cell division of ESCs. Whereas DIDO3 is involved in centrosome positioning to polarize PE cells, DIDO1 is determinant for their fate identity. Moreover, DIDO3 regulates DIDO1 expression at the onset of ESC differentiation.
In this article, the authors demonstrate that Dicer-dependent miRNAs are required for the generation of new neurons, but not astrocytes, in the adult hippocampus in vivo and in vitro. The authors identify a new set of 11 miRNAs that synergistically converge on multiple targets in different pathways to sustain neurogenic lineage fate commitment in aNSCs.
In this article, Kessel and colleagues demonstrate that the DNA damage response factor MAD2L2 is required for open and accessible chromatin in embryonic stem cells and germ cells. MAD2L2 functions via activation of the Dppa3 gene, an epigenetic regulator known to suppress DNA and histone H3 methylation in early embryogenesis.
In this article, Gentner and colleagues undertake a comprehensive strategy to advance ex vivo genetic engineering of HSCs for gene therapy. They experimentally define an optimal strategy to purify HSCs, which allows uncoupling long-term from short-term hematopoietic reconstitution, and implement ex vivo conditions that best preserve their biological properties applying novel transduction-enhancing compounds and pyrimidoindole derivatives to support HSC expansion.
In this article, Liang and colleagues show that loss of latexin in vivo expands the HSC population and increases their survival and engraftment. Latexin regulates HSC function and hematopoiesis via the Thbs1 signaling pathway.
Mesenchymal stromal cells (MSCs) are promising for cell-based therapy in inflammatory disorders by switching off the immune response. Varin and colleagues demonstrate that MSCs and inflammatory macrophages communicate via an unconventional but functional interaction that strongly increases the immunosuppressive capacities of MSCs. This new communication between the innate immune system and MSCs opens new perspectives for MSC-based cell therapy.
Unlike mammals, zebrafish regenerate following retina damage from a resident adult stem cell (Müller glia). Dissecting the mechanisms that zebrafish use could lead to new therapeutic targets to treat retinal diseases. Patton and colleagues have discovered a mechanism by which decreased GABA levels are sensed by Müller glia to initiate a regenerative response.
In this article, Livesey and colleagues perform a phenotypic drug screen in a human stem cell model of Alzheimer's disease. The anthelminthic avermectins are identified as a family of compounds that increase the production of short Aβ peptides over longer more toxic Aβ forms. The effect is analogous to existing γ-secretase modulators, but is independent of the core γ-secretase complex.
A cancer stem cell (CSC)-enriched malignant mesothelioma (MM) cell subpopulation was identified by an OCT4/SOX2 reporter approach. These EGFP-expressing cells showed an altered sensitivity toward chemotherapeutic drugs and a higher tumor-initiating capacity in vivo in orthotopic xenograft and allograft mouse models. While NF2 overexpression had no effect on proliferation/viability of CSC-enriched MM populations, they were susceptible to downregulation of calretinin.
In this report, Bouchard and colleagues identify a role for the transcription factor Gata3 in mitotic spindle orientation and lineage specification of prostate progenitor cells through the subcellular localization of the polarity protein aPKC. Their results underscore the importance of mitotic spindle orientation for progenitor cell homeostasis and tissue architecture.
In this article, Okano, Nakamura and colleagues report that the iCaspase9 system abolished hiPSC-NS/PCs-derived tumors and controlled adverse events. The iCaspase system may serve as an important countermeasure against post-transplantation adverse events in stem cell transplant therapies.
In this article, Zhou and colleagues demonstrate that miR-375 promotes osteogenic differentiation of hASCs both in vitro and in vivo. They revealed that miR-375 inhibits AKT signaling via directly targeting DEPTOR during the osteogenic differentiation of hASCs. Moreover, they found that YAP1 together with miR-375 forms a negative feedback loop to regulate hASCs osteogenesis.
In this paper, Tse, Esteban and colleagues have generated chimeric mice with human hepatocytes derived from familial hypercholesterolemia (FH) induced pluripotent stem cells. These chimeric mice resemble FH patients in the response to clinical-grade PCSK9 antibodies and statins. These results indicate the utility of this stem cell model for preclinical testing of new LDL-C-lowering therapies for FH patients.