![]() Bone marrow stem cells, for example, differentiate primarily into blood cells. However, under natural circumstances somatic stem cells can become only a subset of related cell types. Stem cells from the blood and bone marrow are routinely used as a treatment for blood-related diseases. They are important for growth, healing, and replacing cells that are lost through daily wear and tear. These findings have intriguing implications for understanding stem cell biology and the evolution of pathogen resistance.Somatic stem cells (also called adult stem cells) exist naturally in the body. We demonstrate the in vivo importance of intrinsic ISG expression for protecting stem cells and their differentiation potential during viral infection. Importantly, we show that intrinsically expressed ISGs protect stem cells against viral infection. This intrinsic ISG expression varies in a cell-type-specific manner, and many ISGs decrease upon differentiation, at which time cells become IFN responsive, allowing induction of a broad spectrum of ISGs by IFN signaling. We find that, conserved across species, stem cells express a subset of genes previously classified as interferon (IFN) stimulated genes (ISGs) but that expression is intrinsic, as stem cells are refractory to interferon. Here, we analyzed gene expression in mammalian stem cells and cells at various stages of differentiation. Stem cells are highly resistant to viral infection compared to their differentiated progeny however, the mechanism is mysterious. It may be this function, in part, which underlies the neurological disease observed in patients with GRIN2B mutations. Using electrophysiology and calcium imaging, we demonstrate that NMDA receptors are present on neural progenitor cells and that human mutations in GRIN2B can impair calcium influx and membrane depolarization even in a presumed undifferentiated cell state, highlighting an important role for non-synaptic NMDA receptors. Transcriptome analysis revealed extensive increases in genes associated with cell proliferation and decreases in genes associated with neuron differentiation, a result supported by extensive protein analyses. We developed clonal models of GRIN2B deletion and loss-of-function mutations in a region coding for the glutamate binding domain in human cells and generated neurons from a patient harboring a missense mutation in the same domain. Heterozygous loss-of-function mutations in GRIN2B, a subunit of the NMDA receptor, cause intellectual disability and language impairment. These models will serve to study the phenotypic and functional differences between human ventrally and dorsally derived oligodendroglia and to reveal mechanisms of diseases associated with cortical myelin defects. Thus, our organoid models reveal human oligodendrogenesis with ventral and dorsal origins. Furthermore, dorsally derived oligodendroglial cells outcompete ventrally derived oligodendroglia and become dominant in FFOs after long-term culture. Assembling VFOs and DFOs to generate fused forebrain organoids (FFOs) promotes oligodendroglia maturation. ![]() Interestingly, oligodendrogenesis can be induced in both VFOs and DFOs after neuronal maturation. OLIG2/GFP exhibits distinct temporal expression patterns in ventral forebrain organoids (VFOs) versus dorsal forebrain organoids (DFOs). Here we report oligodendrogenesis in forebrain organoids, generated by using OLIG2-GFP knockin human pluripotent stem cell (hPSC) reporter lines. However, it remains unknown whether analogous developmental processes are manifested in the human brain. The process of oligodendrogenesis has been relatively well delineated in the rodent brain. ![]() Tissue and Cell Culture Dissociation Reagents.Work at STEMCELL View Current Opportunities > ![]()
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