Cancer stem cells are critical for cancer initiation, development, and treatment resistance. Our understanding of these processes, and how they relate to glioblastoma heterogeneity, is limited. To ...overcome these limitations, we performed single-cell RNA sequencing on 53586 adult glioblastoma cells and 22637 normal human fetal brain cells, and compared the lineage hierarchy of the developing human brain to the transcriptome of cancer cells. We find a conserved neural tri-lineage cancer hierarchy centered around glial progenitor-like cells. We also find that this progenitor population contains the majority of the cancer's cycling cells, and, using RNA velocity, is often the originator of the other cell types. Finally, we show that this hierarchal map can be used to identify therapeutic targets specific to progenitor cancer stem cells. Our analyses show that normal brain development reconciles glioblastoma development, suggests a possible origin for glioblastoma hierarchy, and helps to identify cancer stem cell-specific targets.
Tumors are not simply a chaotic mass of mutated cells but can follow complex organizational principles, including in space. In this issue of Cell, Mathur and colleagues reconstruct a 3D genomic, ...epigenomic, and transcriptomic spatial cartograph of glioblastoma, offering a “whole-tumor” perspective with patterns of clonal expansion that are embedded in neurodevelopmental hierarchy.
Tumors are not simply a chaotic mass of mutated cells but can follow complex organizational principles, including in space. In this issue of Cell, Mathur and colleagues reconstruct a 3D genomic, epigenomic, and transcriptomic spatial cartograph of glioblastoma, offering a “whole-tumor” perspective with patterns of clonal expansion that are embedded in neurodevelopmental hierarchy.
The existence of neural stem cells (NSCs) in adult human brain neurogenic regions remains unresolved. To address this, we created a cell atlas of the adult human subventricular zone (SVZ) derived ...from fresh neurosurgical samples using single-cell transcriptomics. We discovered 2 adult radial glia (RG)-like populations, aRG1 and aRG2. aRG1 shared features with fetal early RG (eRG) and aRG2 were transcriptomically similar to fetal outer RG (oRG). We also captured early neuronal and oligodendrocytic NSC states. We found that the biological programs driven by their transcriptomes support their roles as early lineage NSCs. Finally, we show that these NSCs have the potential to transition between states and along lineage trajectories. These data reveal that multipotent NSCs reside in the adult human SVZ.
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•We created a single-cell atlas of the adult human SVZ derived from fresh samples•We discovered 2 adult radial glia cell types similar to fetal outer radial glia•We also captured early neuronal and oligodendrocytic neural stem cell states•We show NSCs can transition between states and along lineage trajectories
Molecular biology; Cell biology; Omics; Transcriptomics
We have determined the protective effects of Thymus serpyllum (TS) extract and nanoparticle-loaded TS on hydrogen peroxide-induced cell death of mesenchymal stromal cells (MSCs) in vitro. Gas ...chromatography–mass spectroscopy confirmed the spectrum of active components in the extract. Out of the three different extracts, the hexane extract showed significant free radical scavenging activity. Treatment of MSCs with H2O2 (hydrogen peroxide) significantly increased intracellular cell death; however, pretreatment with TS extract and nanoparticle-loaded TS (200 μg/ml) suppressed H2O2-induced elevation of Cyt-c and MMP13 and increased the survival rates of MSCs. H2O2-induced (0.1 mM) changes in cytokines were attenuated in the extract and nanoparticles by pretreatment and cotreatment at two time points (p<0.05). H2O2 increased cell apoptosis. In contrast, treatment with nanoparticle-loaded TS suppressed the percentage of apoptosis considerably (p<0.05). Therefore, TS may be considered as a potential candidate for enhancing the effectiveness of MSC transplantation in cell therapy.
Brain cancers, including Glioblastoma (a lethal grade IV brain cancer) are the most complex and challenging of all cancers in terms of treatment, morbidity, and mortality. These tumors exhibit ...genomic heterogeneity and are nurtured by a complex ecosystem of various cell types. From a genomic perspective, these tumors are constituted by genetically diverse populations of abnormal cells and this genomic complexity has remained a bottleneck in our understanding of the disease and, therefore, hindered any therapeutic attempts. However, recent transcriptomic studies have exposed a cellular order to these tumors. These studies have not only revealed parallels between neurodevelopment and gliomagenesis but also hinted at potential involvement of evolutionarily conserved neurodevelopmental programs. As per this theory, these tumors follow fundamental neurodevelopmental framework, a cellular hierarchy that originates with the stem cells and ends with differentiated/specialized cell types. Cancer stem cell (CSC) hypothesis lies at the core of this theory which is rooted in the functional similarities between cancer and non-neoplastic stem cells, making adult neural stem cells (NSCs) ideal candidates for cancer stem cell. Nevertheless, this notion is compounded by controversies surrounding the existence of adult neural stem cells in the human adult neurogenic zone, subventricular zone (SVZ). In pursuing the role of adult human NSCs in the origin and maintenance of GBM, we explored the existence and identity of human adult NSCs by performing comprehensive cellular census of the human adult SVZ using singlecell RNA-sequencing (scRNAseq) technology and charted the cellular constituents of the adult SVZ in glioma patients. By using well-annotated fetal progenitor populations as our framework, we uncovered lineage-related gene signature bearing adult NSC subpopulations – neuronal (nNSC), astrocytic (aNSC) and oligodendrocytic (oNSC). Moreover, an early radial glia-like (eRG) subpopulation - early NSC (eNSC) – that shared transcriptomic features with fetal eRG was also discovered. Additional molecular processes/pathway analysis further confirmed lineagespecific identity of adult NSC sub-populations and revealed neurodegenerative, brain repair and injury response-associated programs and migratory nature of nNSCs and oNSCs only. Contrary to the abundance of these lineage-specific progenitors in glioma patients, these adult NSC progenitors were rarely observed in normal autopsy adult brain SVZ. Computational lineage inference approach further revealed dynamic relationship between adult subpopulations where eNSC preceded all other progenitor populations on the trajectory scale. Copy number variation (CNV) analysis subsequently revealed glioma related CNV signature in adult NSC progenitors only. Taken together, this study has brought to light the status of human adult neural stem cells (NSCs) in the SVZ and the likelihood of these NSCs to give rise to and maintain the tumor. More importantly, presence of lineage-specific progenitors and injury response programs in glioma patients further reinforces the role of developmental programs in gliomagenesis and necessitates the need to re-examine the significance of a perpetual role of SVZ in gliomagenesis for early intervention and targeted therapy.
With the increasing number of Muslim migrants coming to North America and the rising prevalence rates of psychological disorders among this population, it is essential to investigate the cultural ...beliefs, resulting parental beliefs, and quality-of-life functioning of American Muslim adolescents experiencing psychological distress. Thus the current study employed a mixed methods design to examine (1) the difference between parent and self-reports of quality-of-life functioning of American Muslim Adolescents who have experienced psychological distress (2) the differences between the quality-of-life functioning of American Muslim adolescent males and females experiencing psychological distress per parent and adolescent report (3) the relationship between the level of acculturation and the quality-of-life functioning of American Muslim adolescents who have experienced psychological distress (4) how belief systems regarding mental health and psychological distress based on demographics and (5) how families describe and understand help-seeking patterns. 32 Muslim parent and adolescent duos completed a survey collecting demographic data, the Peds QL 4.0, and the Stephenson Multigroup Acculturation Scale. Based on significant findings, eight parent and adolescent duos were invited to participate in semi-structured interviews. A related samples t-test revealed no statistical difference in quality-of-life functioning scores between raters (parents and adolescents). Additionally, a two-factor mixed ANOVA indicated no significant interaction between the effects of gender and rater, or main effects of gender or rater. Also, a linear regression suggested that acculturation significantly impacts the quality-of-life functioning scores of American Muslim adolescents. Moreover, an applied thematic analysis, used to analyze the qualitative data derived from the semi structured interviews, highlighted four major themes ‘I don’t know,’ ‘family is everything,’ ‘help yourself,’ and ‘mental health is as important as physical well-being,’ which gave insight into the results obtained from the quantitative analyses. Findings support the need for psychoeducation programs and increased conversations about mental health in the American Muslim community, delivered within religious (ex: mosques) or cultural (ex: community centers) setting given the hesitancy of the population to discuss such taboo topics with outside voices.
Abstract
Background
Glioblastoma is a treatment-resistant brain cancer. Its hierarchical cellular nature and its tumor microenvironment (TME) before, during, and after treatments remain unresolved.
...Methods
Here, we used single-cell RNA sequencing to analyze new and recurrent glioblastoma and the nearby subventricular zone (SVZ).
Results
We found 4 glioblastoma neural lineages are present in new and recurrent glioblastoma with an enrichment of the cancer mesenchymal lineage, immune cells, and reactive astrocytes in early recurrences. Cancer lineages were hierarchically organized around cycling oligodendrocytic and astrocytic progenitors that are transcriptomically similar but distinct to SVZ neural stem cells (NSCs). Furthermore, NSCs from the SVZ of patients with glioblastoma harbored glioblastoma chromosomal anomalies. Lastly, mesenchymal cancer cells and TME reactive astrocytes shared similar gene signatures which were induced by radiotherapy in a myeloid-dependent fashion in vivo.
Conclusion
These data reveal the dynamic, immune-dependent nature of glioblastoma’s response to treatments and identify distant NSCs as likely cells of origin.
Morphological and emerging molecular studies have provided evidence for heterogeneity within the oligodendrocyte population. To address the regional and age‐related heterogeneity of human mature ...oligodendrocytes (MOLs) we applied single‐cell RNA sequencing to cells isolated from cortical/subcortical, subventricular zone brain tissue samples, and thoracolumbar spinal cord samples. Unsupervised clustering of cells identified transcriptionally distinct MOL subpopulations across regions. Spinal cord MOLs, but not microglia, exhibited cell‐type‐specific upregulation of immune‐related markers compared to the other adult regions. SVZ MOLs showed an upregulation of select number of development‐linked transcription factors compared to other regions; however, pseudotime trajectory analyses did not identify a global developmental difference. Age‐related analysis of cortical/subcortical samples indicated that pediatric MOLs, especially from under age 5, retain higher expression of genes linked to development and to immune activity with pseudotime analysis favoring a distinct developmental stage. Our regional and age‐related studies indicate heterogeneity of MOL populations in the human CNS that may reflect developmental and environmental influences.
Main Points
scRNA sequencing identified regionally distinct mature oligodendrocytes (OL) sub populations in the adult human CNS, including relative expression of immune markers.
Pediatric OLs retain higher expression of genes linked to development and to immune activity.
Abstract
Intratumoral and interpatient heterogeneity are characteristics of glioblastoma and constitute important challenges in overcoming treatment resistance and developing new, more effective ...therapies. Using single-cell RNA sequencing, we characterized 60 933 cells from 4 developing fetal brains and 8 glioblastomas. By using fetal brain development as a road map, we show a tri-lineage (astrocytic, oligodendrocytic, and neuronal) hierarchical organization in all glioblastomas. In each patient, a population of progenitor cancer cells was found at the apex of this hierarchy. These cells were enriched in our patient-derived glioma stem cell samples, and, like progenitors in the developing brain, were the main dividing cell population within the cancer. Using expression signatures obtained from single-cell RNA-sequencing, we isolated progenitor cancer cells and compared them to other glioblastoma cell types. We showed the progenitors are the most resistant to chemotherapy and the most tumorigenic in mouse xenograft models. This newly found conserved developmental organization points to the cell of origin and suggests new therapeutic approaches.
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