scholarly journals The white matter is a pro-differentiative microenvironment for glioblastoma

2020 ◽  
Author(s):  
Lucy J. Brooks ◽  
Melanie P. Clements ◽  
Jemima J. Burden ◽  
Daniela Kocher ◽  
Luca Richards ◽  
...  
Keyword(s):  
Stem Cells ◽  
White Matter ◽  
Feedback Loop ◽  
White Matter Injury ◽  
Glioma Stem Cells ◽  
Differentiation Potential ◽  
Tumour Suppression ◽  
Tumour Infiltration ◽  
Proliferation And Invasion

SummaryGlioblastomas are hierarchically organised tumours driven by glioma stem cells that retain partial differentiation potential. Glioma stem cells are maintained in specialised microenvironments, but how they undergo lineage progression outside of these niches remains unclear. Here we identify the white matter as a differentiative niche for glioblastomas with oligodendrocyte lineage competency. Tumour cells in contact with white matter acquire pre-oligodendrocyte-like fate, resulting in decreased proliferation and invasion. Differentiation is a response to white matter injury, which is caused by tumour infiltration itself in a tumoursuppressive feedback loop. Mechanistically, tumour cell differentiation is driven by selective white matter upregulation of SOX10, a master regulator of normal oligodendrogenesis. SOX10 overexpression or treatment with myelination-promoting agents that upregulate endogenous SOX10, mimic this response, leading to white matter-independent pre-oligodendrocyte-like differentiation and tumour suppression in vivo. Thus, glioblastoma recapitulates an injury response and exploiting this latent programme may offer treatment opportunities for a subset of patients.

scholarly journals The white matter is a pro-differentiative niche for glioblastoma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lucy J. Brooks ◽  
Melanie P. Clements ◽  
Jemima J. Burden ◽  
Daniela Kocher ◽  
Luca Richards ◽  
...  
Keyword(s):  
Stem Cells ◽  
White Matter ◽  
Feedback Loop ◽  
White Matter Injury ◽  
Glioma Stem Cells ◽  
Oligodendrocyte Differentiation ◽  
Differentiation Potential ◽  
Tumour Infiltration ◽  
Proliferation And Invasion

AbstractGlioblastomas are hierarchically organised tumours driven by glioma stem cells that retain partial differentiation potential. Glioma stem cells are maintained in specialised microenvironments, but whether, or how, they undergo lineage progression outside of these niches remains unclear. Here we identify the white matter as a differentiative niche for glioblastomas with oligodendrocyte lineage competency. Tumour cells in contact with white matter acquire pre-oligodendrocyte fate, resulting in decreased proliferation and invasion. Differentiation is a response to white matter injury, which is caused by tumour infiltration itself in a tumoursuppressive feedback loop. Mechanistically, tumour cell differentiation is driven by selective white matter upregulation of SOX10, a master regulator of normal oligodendrogenesis. SOX10 overexpression or treatment with myelination-promoting agents that upregulate endogenous SOX10, mimic this response, leading to niche-independent pre-oligodendrocyte differentiation and tumour suppression in vivo. Thus, glioblastoma recapitulates an injury response and exploiting this latent programme may offer treatment opportunities for a subset of patients.

scholarly journals Author Correction: Invasion of white matter tracts by glioma stem cells is regulated by a NOTCH1–SOX2 positive-feedback loop

2019 ◽  
Vol 22 (5) ◽  
pp. 840-840
Author(s):  
Jun Wang ◽  
Sen-Lin Xu ◽  
Jiang-Jie Duan ◽  
Liang Yi ◽  
Yu-Feng Guo ◽  
...  
Keyword(s):  
Stem Cells ◽  
White Matter ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Glioma Stem Cells ◽  
Positive Feedback Loop ◽  
White Matter Tracts

Invasion of white matter tracts by glioma stem cells is regulated by a NOTCH1–SOX2 positive-feedback loop

2018 ◽  
Vol 22 (1) ◽  
pp. 91-105 ◽  
Author(s):  
Jun Wang ◽  
Sen-Lin Xu ◽  
Jiang-Jie Duan ◽  
Liang Yi ◽  
Yu-Feng Guo ◽  
...  
Keyword(s):  
Stem Cells ◽  
White Matter ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Glioma Stem Cells ◽  
Positive Feedback Loop ◽  
White Matter Tracts

scholarly journals Prrx1 promotes stemness and angiogenesis via activating TGF-β/smad pathway and upregulating proangiogenic factors in glioma

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Zetao Chen ◽  
Yihong Chen ◽  
Yan Li ◽  
Weidong Lian ◽  
Kehong Zheng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Therapeutic Strategy ◽  
Critical Role ◽  
Glioma Stem Cells ◽  
Promoter Regions ◽  
Aberrant Expression ◽  
Smad Pathway ◽  
Tgf Β1

AbstractGlioma is one of the most lethal cancers with highly vascularized networks and growing evidences have identified glioma stem cells (GSCs) to account for excessive angiogenesis in glioma. Aberrant expression of paired-related homeobox1 (Prrx1) has been functionally associated with cancer stem cells including GSCs. In this study, Prrx1 was found to be markedly upregulated in glioma specimens and elevated Prrx1 expression was inversely correlated with prognosis of glioma patients. Prrx1 potentiated stemness acquisition in non-stem tumor cells (NSTCs) and stemness maintenance in GSCs, accompanied with increased expression of stemness markers such as SOX2. Prrx1 also promoted glioma angiogenesis by upregulating proangiogenic factors such as VEGF. Consistently, silencing Prrx1 markedly inhibited glioma proliferation, stemness, and angiogenesis in vivo. Using a combination of subcellular proteomics and in vitro analyses, we revealed that Prrx1 directly bound to the promoter regions of TGF-β1 gene, upregulated TGF-β1 expression, and ultimately activated the TGF-β/smad pathway. Silencing TGF-β1 mitigated the malignant behaviors induced by Prrx1. Activation of this pathway cooperates with Prrx1 to upregulate the expression of stemness-related genes and proangiogenic factors. In summary, our findings revealed that Prrx1/TGF-β/smad signal axis exerted a critical role in glioma stemness and angiogeneis. Disrupting the function of this signal axis might represent a new therapeutic strategy in glioma patients.

scholarly journals GAS5 suppresses malignancy of human glioma stem cells via a miR-196a-5p/FOXO1 feedback loop

2017 ◽  
Vol 1864 (10) ◽  
pp. 1605-1617 ◽  
Author(s):  
Xihe Zhao ◽  
Yunhui Liu ◽  
Jian Zheng ◽  
Xiaobai Liu ◽  
Jiajia Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Feedback Loop ◽  
Glioma Stem Cells ◽  
Human Glioma

scholarly journals High glucose induces early senescence in adipose-derived stem cells by accelerating p16 and mTOR

2019 ◽  
Vol 6 (6) ◽  
pp. 3213-3221
Author(s):  
Hieu Liem Pham ◽  
Phuc Van Pham
Keyword(s):  
Stem Cells ◽  
High Glucose ◽  
Glucose Concentration ◽  
Culture Medium ◽  
Diabetic Patients ◽  
Adipose Derived Stem Cells ◽  
Differentiation Potential ◽  
Normal Glucose

Introduction: The senescence of stem cells is the primary reason that causes aging of stem cell-containing tissues. Some hypotheses have suggested that high glucose concentration in diabetic patients is the main factor that causes senescence of cells in those patients. This study aimed to evaluate the effects of high glucose concentrations on the senescence of adipose-derived stem cells (ADSCs). Methods: ADSCs were isolated and expanded from human adipose tissues. They were characterized and confirmed as mesenchymal stem cells (MSCs) by expression of surface markers, their shape, and in vitro differentiation potential. They were then cultured in 3 different media- that contained 17.5 mM, 35 mM, or 55 mM of D-glucose. The senescent status of ADSCs was recorded by the expression of the enzyme beta-galactosidase, cell proliferation, and doubling time. Real-time RT-PCR was used to evaluate the expression of p16, p21, p53 and mTOR. Results: The results showed that high glucose concentrations (35 mM and 55 mM) in the culture medium induced senescence of human ADSCs. The ADSCs could progress to the senescent status quicker than those cultured in the lower glucose-containing medium (17.5 mM). The senescent state was related to the up-regulation of p16 and mTOR genes. Conclusion: These results suggest that high glucose in culture medium can trigger the expression of p16 and mTOR genes which cause early senescence in ADSCs. Therefore, ADSCs should be cultured in low glucose culture medium, or normal glucose concentration, to extend their life in vitro as well as in vivo.  

scholarly journals Endothelial-derived exosomes demonstrate a link between endothelial innate inflammation and brain dysfunction and injury in aging

2019 ◽  
Author(s):  
F.M. Elahi ◽  
D. Harvey ◽  
M. Altendahl ◽  
K.B. Casaletto ◽  
N. Fernandes ◽  
...  
Keyword(s):  
White Matter ◽  
Human Subjects ◽  
Positive Association ◽  
Regulatory Proteins ◽  
White Matter Injury ◽  
White Matter Hyperintensity ◽  
Grey Matter Volume ◽  
Older Individuals ◽  
Significant Positive Association

ABSTRACTWe test the hypothesis that endothelial cells take on an inflammatory phenotype in functionally intact human subjects with radiographic evidence of white matter injury. Markers within all three complement effector pathways and regulatory proteins were quantified from endothelial-derived exosomes (EDE) of subjects (age 70-82) with (n=11) and without (n=16) evidence of white matter hyperintensity on MRI. Group differences and associations with systemic markers of immune activation (IL6, ICAM1), cognition and neuroimaging were calculated via regression modelling.EDE complement factors within the alternative and classical pathways were found to be higher and regulatory proteins lower in subjects with WMH. EDE levels of several factors demonstrated significant associations with cognitive slowing and systolic blood pressure. The inhibitor of the membrane attack complex, CD46, showed a significant positive association with cerebral grey matter volume. Systemic inflammatory markers, IL6 and ICAM1, were positively associated with EDE levels of several factors.These findings provide the first in vivo evidence of the association of endothelial cell inflammation with white matter injury, cognition, and brain degeneration in functionally normal older individuals, and form the basis for future biomarker development in early or preclinical stages of vascular cognitive impairment and dementia.

Abstract 362: Proteomic Analysis of Low Oxygen Tension-Induced Secretome of Adipose Tissue-Derived Stem Cells

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Zeljko Bosnjak ◽  
Bassam Wakim ◽  
Yasheng Yan ◽  
Scott Canfield ◽  
Chika Kikuchi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Adipose Tissue ◽  
Oxygen Tension ◽  
Proteomic Analysis ◽  
Stem Cell Markers ◽  
Paracrine Factors ◽  
Differentiation Potential ◽  
Trophic Effect ◽  
Lower Oxygen

Growing evidence from animal studies shows that adipose tissue-derived stem cells (ASCs) improve cardiac function of infarcted hearts. It is commonly accepted that therapeutic potential of ASCs may depend more on their paracrine effects than differentiation potential. The underlying mechanisms remain unclear. However, most data regarding paracrine factors were obtained from ASCs cultured in normoxic condition (20%). The present study investigated how in vivo physiological oxygen (4%) tension influenced the secretome of ASCs. ASCs were isolated from three 8-week-old BALB/c mice. ASCs were confirmed by the expression of stem cell markers (CD44 and CD90) and their capacity to differentiate into adipocytes and osteocytes. ASCs at passage 5 were cultured in normoxic (20%) and lower oxygen (4%) incubators and conditioned for 24 h (3 cultures/group). The conditioned media (CM) from ASCs were subjected to trypsin digestion followed by analysis using automated nano-flow liquid chromatography tandem mass spectrometry. The collected LC/MS/MS data were searched against the rodent subset of the Uniprot database and the total proteomes were identified. The data were from 6 technical replicates. A total of 28 proteins were identified and 7 proteins were unique to normoxic CM. Of the 21 common proteins detected in both normoxic and lower oxygen CM, 9 were extracellular matrix proteins. The abundance of 6 of these proteins (e.g., collagen I and laminin) differed noticeably between normoxic and lower oxygen CM. In addition, a greater amount of cytokine CXCL5 and matrix metalloproteinase (MMP)-2 was detected in lower oxygen CM than in normoxic CM while tissue inhibitor of metalloproteinase (TIMP)-1 was only detected in normoxic CM. These results indicate that lower oxygen tension differentially regulates the secretome of ASCs. Extrapolating the results of this study to the in vivo setting, it would appear that injected ASCs may exert their anti-fibrotic and trophic effect by 1) directly regulating the balance of MMP/TIMP production and preventing collagen accumulation in ischemic hearts to decrease fibrosis, and 2) secreting trophic factors including CXCL5. These data suggest that proteomic analysis of CM is useful for elucidation of the paracrine effect of ASCs in vivo.

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