PATH-14. ALPHA CARDIAC ACTIN EXPRESSION IS OBSERVED IN AGGRESSIVE GLIOMA SUBTYPES AND GLIOBLASTOMA STEM CELLS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi117-vi117
Author(s):  
Rahul Suresh ◽  
Sophie Fiola ◽  
Jamie Beaulieu ◽  
Roberto Diaz
Keyword(s):  
Stem Cells ◽  
Protein Expression ◽  
Brain Regions ◽  
Specific Pattern ◽  
Adult Brain ◽  
Normal Brain ◽  
Mrna Levels ◽  
Glioblastoma Stem Cells ◽  
Subunit Expression ◽  
Multiple Glioma

Abstract BACKGROUND Alterations in actin subunit expression have previously been observed in multiple cancers. In glioblastoma (GBM), the expression of ACTC1 has been associated with a more invasive phenotype and with shorter survival. We sought to explore the diversity of actin subunit expression across glioma subtypes and patient derived glioblastoma stem cells (GSCs). METHODS Bioinformatic analysis of multiple glioma databases was performed to profile actin subunit (ACTA1, ACTA2, ACTC1, ACTG1, ACTG2, and ACTB) mRNA levels. Expression levels were also evaluated in normal brain in comparison to liver and heart tissue. Western blot was used to analyze protein expression in GSCs, surgical tissue and human fetal astrocytes. RESULTS The primary actin subunits expressed in normal brain are beta actin (ACTB) and gamma actin (ACTG1). RNA sequencing of tissue from multiple glioma subtypes or different brain regions reveals a global increase in ACTG1 and ACTB abundance in gliomas compared to normal brain. LGG-GCIMP high and LGG-co-deleted glioma subtypes have the lowest ACTC1 expression. LGG-GCIMP low (HR 9.75, P< 0.001), LGG-mesenchymal-like (HR11.1, P< 0.001), LGG-classic-like (HR10.96, P< 0.001) subtypes are associated with ACTC1 expression. ACTC1, ACTCB, and ACTG protein expression was observed in GSCs, freshly resected GBM tissue, and human fetal astrocytes. CONCLUSIONS Gliomas have a specific pattern of actin subunit expression that differs in actin subunit type and abundance when compared to normal adult brain. Expression of ACTC1 is found in aggressive glioma subtypes and is shared by GSCs and human fetal astrocytes. Investigation into the neurodevelopmental role of ACTC1 and its contribution to oncogenic transformation in GBM is warranted.

Very Early Exercise Rehabilitation After Intracerebral Hemorrhage Promotes Inflammation in the Brain

2021 ◽  
pp. 154596832110063
Author(s):  
Keigo Tamakoshi ◽  
Madoka Maeda ◽  
Shinnosuke Nakamura ◽  
Nae Murohashi
Keyword(s):  
Intracerebral Hemorrhage ◽  
Protein Expression ◽  
Brain Regions ◽  
Motor Dysfunction ◽  
Inflammatory Factors ◽  
Mrna Levels ◽  
Exercise Rehabilitation ◽  
Early Exercise ◽  
Polymerase Chain ◽  
To Receive

Background Very early exercise has been reported to exacerbate motor dysfunction; however, its mechanism is largely unknown. Objective This study examined the effect of very early exercise on motor recovery and associated brain damage following intracerebral hemorrhage (ICH) in rats. Methods Collagenase solution was injected into the left striatum to induce ICH. Rats were randomly assigned to receive placebo surgery without exercise (SHAM) or ICH without (ICH) or with very early exercise within 24 hours of surgery (ICH+VET). We observed sensorimotor behaviors before surgery, and after surgery preexercise and postexercise. Postexercise brain tissue was collected 27 hours after surgery to investigate the hematoma area, brain edema, and Il1b, Tgfb1, and Igf1 mRNA levels in the striatum and sensorimotor cortex using real-time reverse transcription polymerase chain reaction. NeuN, PSD95, and GFAP protein expression was analyzed by Western blotting. Results We observed significantly increased skillful sensorimotor impairment in the horizontal ladder test and significantly higher Il1b mRNA levels in the striatum of the ICH+VET group compared with the ICH group. NeuN protein expression was significantly reduced in both brain regions of the ICH+VET group compared with the SHAM group. Conclusion Our results suggest that very early exercise may be associated with an exacerbation of motor dysfunction because of increased neuronal death and region-specific changes in inflammatory factors. These results indicate that implementing exercise within 24 hours after ICH should be performed with caution.

scholarly journals STEM-12. ZIKA VIRUS TARGETS GLIOBLASTOMA STEM CELLS THROUGH A SOX2-INTEGRIN α vβ 5 AXIS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii198-ii199
Author(s):  
Clark Chen ◽  
Sanjay Dhawan ◽  
Zhe Zhu ◽  
Pinar Mesci ◽  
Jeremy Rich
Keyword(s):  
Stem Cells ◽  
Zika Virus ◽  
Oncolytic Virus ◽  
Great Promise ◽  
Normal Brain ◽  
Zikv Infection ◽  
Glioblastoma Stem Cells ◽  
Interferon Stimulated Genes ◽  
Sox2 Expression

Abstract INTRODUCTION Oncolytic virus hold great promise as a platform for glioblastoma therapeutic development. Zika virus (ZIKV) is an oncolytic virus with exquisite selectivity for infecting and killing glioblastoma stem cells (GSCs). Here, we delineate the molecular determinant of this selectivity. METHODS cell-based glioblastoma models, glioblastoma organoid assays, in vivo murine glioblastoma models, ZIKV infectivity assays, gene silencing, ChIP-seq studies. RESULTS In independent models, ZIKV preferentially infected and lysed SOX2+ GSCs. Silencing of SOX2 expression attenuated this preferential infectivity. Of note, ZIKV infection of GSCs was independent of AXL, its putative receptor in normal brain. ChIP-seq experiments revealed that SOX2 bound within the ITGAV locus (encoding the integrin av subunit), and this binding was associated with accumulation of the active chromatin mark H3K27ac. Silencing of SOX2 suppressed ITGAV expression as well as ZIKV infectivity against GSCs, indicating that integrin is required for ZIKV infection. Of integrin b units, only silencing of integrin b5 prevented the killing of GSCs by ZIKV infection, suggesting ZIKV infection required the avb5 integrin. Supporting this hypothesis, blockade of the avb5 integrin substantially reduced ZIKV infection of GSCs in glioblastoma organoid assays and in clinical glioblastoma specimens. Sox2 expression additionally suppress GSC expression of all members of the interferon-stimulated genes (ISG family), thereby suppressing innate anti-viral response to facilitate ZIKV infection. CONCLUSIONS Collectively, our results reveal that ZIKV infection of GSCs is mediated by integrin α vβ 5 leading to SOX2 expression which negatively regulates antiviral immunity thereby facilitating ZIKV infection.

scholarly journals Calcium Channels in Adult Brain Neural Stem Cells and in Glioblastoma Stem Cells

2020 ◽  
Vol 14 ◽  
Author(s):  
Valérie Coronas ◽  
Elodie Terrié ◽  
Nadine Déliot ◽  
Patricia Arnault ◽  
Bruno Constantin
Keyword(s):  
Stem Cells ◽  
Calcium Channels ◽  
Neural Stem Cells ◽  
Adult Brain ◽  
Glioblastoma Stem Cells

scholarly journals HIF2α Upregulates the Migration Factor ODZ1 under Hypoxia in Glioblastoma Stem Cells

2022 ◽  
Vol 23 (2) ◽  
pp. 741
Author(s):  
María Carcelén ◽  
Carlos Velásquez ◽  
Veronica Vidal ◽  
Olga Gutierrez ◽  
Jose L. Fernandez-Luna
Keyword(s):  
Stem Cells ◽  
Transcriptional Control ◽  
Luciferase Reporter ◽  
Mrna Levels ◽  
Consensus Binding Site ◽  
Glioblastoma Stem Cells ◽  
Protein Levels ◽  
Hypoxic Conditions ◽  
Luciferase Reporter Plasmid ◽  
Migration Factor

Background: Glioblastoma (GBM) remains a major clinical challenge due to its invasive capacity, resistance to treatment, and recurrence. We have previously shown that ODZ1 contributes to glioblastoma invasion and that ODZ1 mRNA levels can be upregulated by epigenetic mechanisms in response to hypoxia. Herein, we have further studied the transcriptional regulation of ODZ1 in GBM stem cells (GSCs) under hypoxic conditions and analyzed whether HIF2α has any role in this regulation. Methods: We performed the experiments in three primary GSC cell lines established from tumor specimens. GSCs were cultured under hypoxia, treated with HIF regulators (DMOG, chetomin), or transfected with specific siRNAs, and the expression levels of ODZ1 and HIF2α were analyzed. In addition, the response of the ODZ1 promoter cloned into a luciferase reporter plasmid to the activation of HIF was also studied. Results: The upregulation of both mRNA and protein levels of HIF2α under hypoxia conditions correlated with the expression of ODZ1 mRNA. Moreover, the knockdown of HIF2α by siRNAs downregulated the expression of ODZ1. We found, in the ODZ1 promoter, a HIF consensus binding site (GCGTG) 1358 bp from the transcription start site (TSS) and a HIF-like site (CCGTG) 826 bp from the TSS. Luciferase assays revealed that the stabilization of HIF by DMOG resulted in the increased activity of the ODZ1 promoter. Conclusions: Our data indicate that the HIF2α-mediated upregulation of ODZ1 helps strengthen the transcriptional control of this migration factor under hypoxia in glioblastoma stem cells. The discovery of this novel transcriptional pathway identifies new targets to develop strategies that may avoid GBM tumor invasion and recurrence.

Neuroregenerative Medicine in TBI

Neurotrauma ◽  
2018 ◽  
pp. 359-372
Author(s):  
Jinhui Chen ◽  
Xiaoting Wang ◽  
Xiang Gao
Keyword(s):  
Traumatic Brain Injury ◽  
Stem Cells ◽  
Cell Death ◽  
Large Population ◽  
Brain Regions ◽  
Adult Brain ◽  
Great Promise ◽  
Pathological Changes ◽  
Neural Repair ◽  
Neuroregenerative Medicine

Traumatic brain injury (TBI) is affecting a large population with permanent physical disabilities and neurobehavioral abnormalities worldwide. Cell death in multiple brain regions is one of the most common pathological changes seen after TBI. Neuronal replacement then represents an urgent need for functional recovery. Neural stem cells (NSC) to mediate endogenous neurogenesis in the adult brain holds great promise for neural repair by replacing dead neurons and rebuilding damaged connections. It has been shown that TBI promotes NSC proliferation, detected in both the forebrain and the hippocampus, displaying an intrinsic neuroplasticity in response to injury. Thus, endogenous neurogenesis is an appropriate target for clinical interference aimed at neural repair post-trauma.

scholarly journals New Insights Into the Intricacies of Proneural Gene Regulation in the Embryonic and Adult Cerebral Cortex

2021 ◽  
Vol 14 ◽  
Author(s):  
Ana-Maria Oproescu ◽  
Sisu Han ◽  
Carol Schuurmans
Keyword(s):  
Stem Cells ◽  
Cerebral Cortex ◽  
Protein Interactions ◽  
Neural Progenitor Cells ◽  
Target Genes ◽  
Brain Regions ◽  
Adult Brain ◽  
Mammalian Brain ◽  
Proneural Gene ◽  
Molecular Control

Historically, the mammalian brain was thought to lack stem cells as no new neurons were found to be made in adulthood. That dogma changed ∼25 years ago with the identification of neural stem cells (NSCs) in the adult rodent forebrain. However, unlike rapidly self-renewing mature tissues (e.g., blood, intestinal crypts, skin), the majority of adult NSCs are quiescent, and those that become ‘activated’ are restricted to a few neurogenic zones that repopulate specific brain regions. Conversely, embryonic NSCs are actively proliferating and neurogenic. Investigations into the molecular control of the quiescence-to-proliferation-to-differentiation continuum in the embryonic and adult brain have identified proneural genes encoding basic-helix-loop-helix (bHLH) transcription factors (TFs) as critical regulators. These bHLH TFs initiate genetic programs that remove NSCs from quiescence and drive daughter neural progenitor cells (NPCs) to differentiate into specific neural cell subtypes, thereby contributing to the enormous cellular diversity of the adult brain. However, new insights have revealed that proneural gene activities are context-dependent and tightly regulated. Here we review how proneural bHLH TFs are regulated, with a focus on the murine cerebral cortex, drawing parallels where appropriate to other organisms and neural tissues. We discuss upstream regulatory events, post-translational modifications (phosphorylation, ubiquitinylation), protein–protein interactions, epigenetic and metabolic mechanisms that govern bHLH TF expression, stability, localization, and consequent transactivation of downstream target genes. These tight regulatory controls help to explain paradoxical findings of changes to bHLH activity in different cellular contexts.

scholarly journals Localization patterns of cathepsins K and X and their predictive value in glioblastoma

2018 ◽  
Vol 52 (4) ◽  
pp. 433-442 ◽  
Author(s):  
Barbara Breznik ◽  
Clara Limback ◽  
Andrej Porcnik ◽  
Andrej Blejec ◽  
Miha Koprivnikar Krajnc ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Stem Cell ◽  
Mrna Expression ◽  
Predictive Value ◽  
Cathepsin K ◽  
Mrna Levels ◽  
Glioblastoma Stem Cells ◽  
Glioblastoma Stem Cell ◽  
Cathepsin X

AbstractBackgroundGlioblastoma is a highly aggressive central nervous system neoplasm characterized by extensive infiltration of malignant cells into brain parenchyma, thus preventing complete tumor eradication. Cysteine cathepsins B, S, L and K are involved in cancer progression and are overexpressed in glioblastoma. We report here for the first time that cathepsin X mRNA and protein are also abundantly present in malignant glioma.Materials and methodsGene expression of cathepsins K and X was analyzed using publically-available tran-scriptomic datasets and correlated with glioma grade and glioblastoma subtype. Kaplan-Maier survival analysis was performed to evaluate the predictive value of cathepsin K and X mRNA expression. Cathepsin protein expression was localized and semi-quantified in tumor tissues by immunohistochemistry.ResultsHighest gene expression of cathepsins K and X was found in glioblastoma, in particular in the mesenchymal subtype. Overall, high mRNA expression of cathepsin X, but not that of cathepsin K, correlated with poor patients’ survival. Cathepsin K and X proteins were abundantly and heterogeneously expressed in glioblastoma tissue. Immuno-labeling of cathepsins K and X was observed in areas of CD133-positive glioblastoma stem cells, localized around arterioles in their niches that also expressed SDF-1α and CD68. mRNA levels of both cathepsins K and X correlated with mRNA levels of markers of glioblastoma stem cells and their niches.ConclusionsThe presence of both cathepsins in glioblastoma stem cell niche regions indicates their possible role in regulation of glioblastoma stem cell homing in their niches. The clinical relevance of this data needs to be elaborated in further prospective studies.

scholarly journals Differentiation of Human Amniotic Mesenchymal Stem Cells into Human Anterior Cruciate Ligament Fibroblast Cells by In Vitro Coculture

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Yuwan Li ◽  
Ziming Liu ◽  
Ying Jin ◽  
Xizhong Zhu ◽  
Shengmin Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Anterior Cruciate Ligament ◽  
Protein Expression ◽  
Cruciate Ligament ◽  
Mrna Levels ◽  
Amniotic Mesenchymal Stem Cells ◽  
Anterior Cruciate ◽  
Cellular Components

Anterior cruciate ligament injuries are common in humans, though cellular components of the knee have little regenerative or proliferation potential. This study investigated the differentiation of human amnion-derived mesenchymal stem cells (hAMSCs) into human anterior cruciate ligament fibroblasts (hACLFs) in vitro through induction with bFGF and TGF-β1 with coculture systems. Groups A and B comprised hAMSCs at the 3rd passage cultured with and without bFGF and TGF-β1, respectively; Groups C and D consisted of hAMSCs and hACLFs in monolayer coculture with and without bFGF and TGF-β1, respectively; Groups E and F were composed of hAMSCs and hACLFs in Transwell coculture with and without bFGF and TGF-β1, respectively. Cell morphology and proliferation were recorded. Protein expression and relative mRNA expression were evaluated in each group. Cell proliferation was significantly higher in the induced groups than in the noninduced groups. Protein expression increased over time with the highest expression observed in Group E. mRNA levels were significantly higher in Group E than in other groups. This study is the first to demonstrate the use of the Transwell coculture system for this purpose, and hAMSCs were successfully differentiated into hACLFs. Thus, hAMSCs may be a superior choice for hACLF differentiation via Transwell coculture.

scholarly journals Profiling Anti-Apoptotic BCL-xL Protein Expression in Glioblastoma Tumorspheres

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2853
Author(s):  
Deborah Fanfone ◽  
Ahmed Idbaih ◽  
Jade Mammi ◽  
Mathieu Gabut ◽  
Gabriel Ichim
Keyword(s):  
Stem Cells ◽  
Protein Expression ◽  
Expression Pattern ◽  
Cell Lines ◽  
Tumor Recurrence ◽  
Glioblastoma Stem Cells ◽  
Bh3 Mimetics ◽  
Differentiated Cells

Glioblastoma (GBM) is one of the cancers with the worst prognosis, despite huge efforts to understand its unusual heterogeneity and aggressiveness. This is mainly due to glioblastoma stem cells (GSCs), which are also responsible for the frequent tumor recurrence following surgery, chemotherapy or radiotherapy. In this study, we investigate the expression pattern of the anti-apoptotic BCL-xL protein in several GBM cell lines and the role it might play in GSC-enriched tumorspheres. We report that several GBM cell lines have an increased BCL-xL expression in tumorspheres compared to differentiated cells. Moreover, by artificially modulating BCL-xL expression, we unravel a correlation between BCL-xL and tumorsphere size. In addition, BCL-xL upregulation appears to sensitize GBM tumorspheres to newly developed BH3 mimetics, opening promising therapeutic perspectives for treating GBM patients.

scholarly journals Activation of a neural stem cell transcriptional program in parenchymal astrocytes

2020 ◽  
Author(s):  
Jens P. Magnusson ◽  
Margherita Zamboni ◽  
Giuseppe Santopolo ◽  
Jeff E. Mold ◽  
Mauricio Barrientos-Somarribas ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Subventricular Zone ◽  
Brain Regions ◽  
Adult Brain ◽  
Targeted Interventions ◽  
Physiological Conditions ◽  
Neuronal Lineage ◽  
Epidermal Growth

AbstractNeural stem cells, located in discrete niches in the adult brain, generate new neurons throughout life. These stem cells are specialized astrocytes, but astrocytes in other brain regions do not generate neurons under physiological conditions. After stroke, however, striatal astrocytes undergo neurogenesis in mice, triggered by decreased Notch signaling. We used single-cell RNA sequencing to characterize neurogenesis by Notch-depleted striatal astrocytes in vivo. Striatal astrocytes were located upstream of neural stem cells in the neuronal lineage. As astrocytes initiated neurogenesis, they became transcriptionally very similar to subventricular zone stem cells and progressed through a nearly identical neurogenic program. Surprisingly, in the non- neurogenic cortex, Notch-depleted astrocytes also initiated neurogenesis. Yet, the cortical astrocytes, and many striatal ones, stalled before entering transit- amplifying divisions. Infusion of epidermal growth factor enabled stalled striatal astrocytes to resume neurogenesis. We conclude that parenchymal astrocytes are latent neural stem cells and that targeted interventions can guide them through their neuronal differentiation.

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