Single-nucleus transcriptomics of IDH1- and TP53-mutant glioma stem cells displays diversified commitment on invasive cancer progenitors.

Glioma is a devastating brain tumor with a high mortality rate attributed to the glioma stem cells (GSCs) possessing high plasticity. Marker mutations in isocitrate dehydrogenase type 1 (IDH1) and tumor protein 53 (TP53) are frequent in gliomas and impact the cell fate decisions. Understanding the GSC heterogeneity within IDH1- and TP53- mutant tumors may elucidate possible treatment targets. Here, we performed single-nucleus transcriptomics of mutant and wild-type glioma samples sorted for Sox2 stem cell marker. For the first time the rare subpopulations of Sox2 + IDH1- and TP53-mutant GSCs were characterized. In general, GSCs contained the heterogeneity root subpopulation resembling active neural stem cells capable of asymmetric division to quiescent and transit amplifying cell branches. Specifically, double-mutant GSCs revealed the commitment on highly invasive oligodendrocyte- and astroglia-like progenitors. Additionally, double-mutant GSCs displayed upregulated markers of collagen synthesis, altered lipogenesis and high migration, while wild-type GSCs expressed genes related to ATP production. Wild-type GSC root population was highly heterogeneous and lacked the signature marker expression, thus glioblastoma treatment should emphasize on establishing differentiation protocol directed against residual GSCs. For the more differentiated IDH1- and TP53-mutant gliomas we suggest therapeutic targeting of migration molecules, such as CD44.

Production of human entorhinal stellate cell-like cells by forward programming shows an important role of Foxp1 in reprogramming.

Stellate cells are principal neurons in the entorhinal cortex that contribute to spatial processing. They also play a role in the context of Alzheimer's disease as they accumulate Amyloid beta early in the disease. Producing human stellate cells from pluripotent stem cells would allow researchers to study early mechanisms of Alzheimer's disease, however, no protocols currently exist for producing such cells. In order to develop novel stem cell protocols, we characterize at high resolution the development of the porcine medial entorhinal cortex by tracing neuronal and glial subtypes from mid-gestation to the adult brain to identify the transcriptomic profile of progenitor and adult stellate cells. Importantly, we could confirm the robustness of our data by extracting developmental factors from the identified intermediate stellate cell cluster and implemented these factors to generate putative intermediate stellate cells from human induced pluripotent stem cells. Six transcription factors identified from the stellate cell cluster including RUNX1T1, SOX5, FOXP1, MEF2C, TCF4, EYA2 were overexpressed using a forward programming approach to produce neurons expressing a unique combination of RELN, SATB2, LEF1 and BCL11B observed in stellate cells. Further analyses of the individual transcription factors led to the discovery that FOXP1 is critical in the reprogramming process and omission of RUNX1T1 and EYA2 enhances neuron conversion. Our findings contribute not only to the profiling of cell types within the developing and adult brain's medial entorhinal cortex but also provides proof-of-concept for using scRNAseq data to produce entorhinal intermediate stellate cells from human pluripotent stem cells in-vitro.

Assessing Sleep Concerns in Individuals With Acquired Brain Injury: The Feasibility of a Smartpad Sleep Tool.

OBJECTIVE: The investigators examined the presence of disrupted sleep in acquired brain injury (ABI) and the utility of a mobile health program, MySleepScript, as an effective clinical tool to detect sleep disturbances. METHODS: A cross-sectional pilot study of MySleepScript, a customizable electronic battery of validated sleep questionnaires, was conducted. Participants were recruited at the Acquired Brain Injury Clinic at Johns Hopkins Bayview Medical Center. RESULTS: Sixty-eight adults with ABI (mean age, 46.3 years [SD=14.8]) participated in the study, with a mean completion time of 16.6 minutes (SD=5.4). Time to completion did not differ on individual completion or staff assistance. The mean score on the Pittsburgh Sleep Quality Index was 9.2 (SD=4.7); 83.9% of individuals had poor sleep quality (defined as a score >5). Insomnia Severity Index scores indicated moderate to severe insomnia in 45% of participants; 36.5% of participants screened positive for symptoms concerning sleep apnea, while 39.3% of individuals screened positive for restless legs syndrome. CONCLUSIONS: Poor sleep quality was highly prevalent in this ABI cohort. MySleepScript may be an effective method of assessing for sleep disturbance in ABI. Further efforts to identify sleep disorders in this patient population should be pursued to optimize ABI management.