scholarly journals Transcription factors involved in stem cell maintenance are downstream of Slug/Snail2 and repressed by TGF-β in bronchial basal stem/progenitor cells from COPD

2020 ◽  
Author(s):  
Pierre de la Grange ◽  
Ariane Jolly ◽  
Charlotte Courageux ◽  
Chamseddine Ben Brahim ◽  
Pascale Leroy
Keyword(s):  
Stem Cell ◽  
Transcription Factors ◽  
Progenitor Cells ◽  
Cell Fate ◽  
Airway Epithelium ◽  
Normal Subjects ◽  
Differentiation Potential ◽  
Stem Cell Maintenance ◽  
Basal Progenitor ◽  
Cell Maintenance

AbstractPatients with COPD have many anomalies in their airway epithelium, and their basal stem/progenitor cells show a decrease in self-renewal and differentiation potential. The objective of this study was to identify deregulations in the genetic program of COPD bronchial basal stem/progenitor cells that could account for their exhaustion. TGF-β is found at higher levels in the lungs of COPD subjects. It has been shown to play a role in stem/progenitor cell fate and also to regulate the expression of the EMT-inducing transcription factor Slug/Snail2. In contrast to other transcription factors of the Snail family, Slug is highly expressed in basal progenitor cells, the adult stem/progenitors of human airway epithelium. We aimed at identifying genes downstream of Slug that respond to TGF-β, and whose expression is deregulated in COPD airway basal stem/progenitor cells, and could account for the decrease in count and functional ability of these cells observed in COPD. For this, we knocked down Slug in primary bronchial basal progenitor cells from COPD and normal subjects and, among the genes downstream of Slug, we selected those responding to TGF-β and differentiation. We identified 5 genes coding for transcription factors involved in stem cell maintenance that are repressed downstream of Slug and by TGF-β in COPD but not normal basal progenitor cells. Our results bring a molecular perspective to the exhaustion of airway basal stem/progenitor cells observed in COPD by revealing that stem cell maintenance genes are repressed in these cells, with TGF-β and Slug being involved in this deregulation.

scholarly journals Transcription factors involved in stem cell maintenance are downstream of Slug/Snail2 and repressed by TGF-β in bronchial epithelial progenitors from Chronic Obstructive Pulmonary Disease

2019 ◽  
Author(s):  
Pierre de la Grange ◽  
Ariane Jolly ◽  
Charlotte Courageux ◽  
Chamseddine Ben Brahim ◽  
Pascale LEROY
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Stem Cell ◽  
Transcription Factors ◽  
Pulmonary Disease ◽  
Chronic Obstructive ◽  
Mrna Levels ◽  
Differentiation Potential ◽  
Obstructive Pulmonary Disease ◽  
Stem Cell Maintenance ◽  
Cell Maintenance

Abstract Objectives: Patients with Chronic Obstructive Pulmonary Disease (COPD) have a bronchial epithelium with many anomalies and basal/progenitor cells showing a decrease of self-renewal and differentiation potential. The objective of this study was to identify deregulations in the genetic program of COPD bronchial progenitors that could account for their exhaustion. The transcription factor Slug/Snail2 is highly expressed in bronchial progenitors and we aimed at identifying genes downstream of Slug whose expression is deregulated in COPD progenitors. Results: We knocked down Slug in primary basal cells from COPD subjects and, since COPD subjects have higher levels of Transforming Growth Factor (TGF)-β Slug is regulated by TGF-β, we selected genes downstream of Slug involved in differentiation that respond to TGF-β. We identified transcription factors involved in stem cell maintenance downstream of Slug and repressed by TGF-β in COPD but not normal progenitors. We found that the effect of TGF-β on the expression of these genes is correlated to Slug knockdown effect. We also found a correlation between the mRNA levels of Slug and these genes only in presence of TGF-β. These results reveal that stem cell maintenance genes are deregulated in COPD bronchial progenitors, Slug and TGF-β being involved in that deregulation.

scholarly journals Human Cytomegalovirus IE2 Protein Disturbs Brain Development by the Dysregulation of Neural Stem Cell Maintenance and the Polarization of Migrating Neurons

2017 ◽  
Vol 91 (17) ◽  
Author(s):  
Dasol Han ◽  
Sung-Hyun Byun ◽  
Juwan Kim ◽  
Mookwang Kwon ◽  
Samuel J. Pleasure ◽  
...  
Keyword(s):  
Stem Cell ◽  
Brain Development ◽  
Progenitor Cells ◽  
Neural Stem Cell ◽  
Human Cytomegalovirus ◽  
Neural Progenitor Cells ◽  
Hcmv Infection ◽  
Stem Cell Maintenance ◽  
Cell Maintenance

ABSTRACT Despite the high incidence of severe defects in the central nervous system caused by human cytomegalovirus (HCMV) congenital infection, the mechanism of HCMV neuropathogenesis and the roles of individual viral genes have not yet been fully determined. In this study, we show that the immediate-early 2 (IE2) protein may play a key role in HCMV-caused neurodevelopmental disorders. IE2-transduced neural progenitor cells gave rise to neurospheres with a lower frequency and produced smaller neurospheres than control cells in vitro, indicating reduction of self-renewal and expansion of neural progenitors by IE2. At 2 days after in utero electroporation into the ventricle of the developing brain, a dramatically lower percentage of IE2-expressing cells was detected in the ventricular zone (VZ) and cortical plate (CP) compared to control cells, suggesting that IE2 concurrently dysregulates neural stem cell maintenance in the VZ and neuronal migration to the CP. In addition, most IE2+ cells in the lower intermediate zone either showed multipolar morphology with short neurites or possessed nonradially oriented processes, whereas control cells had long, radially oriented monopolar or bipolar neurites. IE2+ callosal axons also failed to cross the midline to form the corpus callosum. Furthermore, we provide molecular evidence that the cell cycle arrest and DNA binding activities of IE2 appear to be responsible for the increased neural stem cell exit from the VZ and cortical migrational defects, respectively. Collectively, our results demonstrate that IE2 disrupts the orderly process of brain development in a stepwise manner to further our understanding of neurodevelopmental HCMV pathogenesis. IMPORTANCE HCMV brain pathogenesis has been studied in limited experimental settings, such as in vitro HCMV infection of neural progenitor cells or in vivo murine CMV infection of the mouse brain. Here, we show that IE2 is a pivotal factor that contributes to HCMV-induced abnormalities in the context of the embryonic brain using an in utero gene transfer tool. Surprisingly, IE2, but not HCMV IE1 or murine CMV ie3, interferes pleiotropically with key neurodevelopmental processes, including neural stem cell regulation, proper positioning of migrating neurons, and the callosal axon projections important for communication between the hemispheres. Our data suggest that the wide spectrum of clinical outcomes, ranging from mental retardation to microcephaly, caused by congenital HCMV infection can be sufficiently explained in terms of IE2 action alone.

scholarly journals The Importance of Ubiquitination and Deubiquitination in Cellular Reprogramming

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Bharathi Suresh ◽  
Junwon Lee ◽  
Kye-Seong Kim ◽  
Suresh Ramakrishna
Keyword(s):  
Stem Cell ◽  
Transcription Factors ◽  
Embryonic Stem ◽  
Cellular Reprogramming ◽  
Stem Cell Maintenance ◽  
Opposite Action ◽  
Induced Pluripotent ◽  
Related Proteins ◽  
Cell Maintenance

Ubiquitination of core stem cell transcription factors can directly affect stem cell maintenance and differentiation. Ubiquitination and deubiquitination must occur in a timely and well-coordinated manner to regulate the protein turnover of several stemness related proteins, resulting in optimal embryonic stem cell maintenance and differentiation. There are two switches: an E3 ubiquitin ligase enzyme that tags ubiquitin molecules to the target proteins for proteolysis and a second enzyme, the deubiquitinating enzyme (DUBs), that performs the opposite action, thereby preventing proteolysis. In order to maintain stemness and to allow for efficient differentiation, both ubiquitination and deubiquitination molecular switches must operate properly in a balanced manner. In this review, we have summarized the importance of the ubiquitination of core stem cell transcription factors, such as Oct3/4, c-Myc, Sox2, Klf4, Nanog, and LIN28, during cellular reprogramming. Furthermore, we emphasize the role of DUBs in regulating core stem cell transcriptional factors and their function in stem cell maintenance and differentiation. We also discuss the possibility of using DUBs, along with core transcription factors, to efficiently generate induced pluripotent stem cells. Our review provides a relatively new understanding regarding the importance of ubiquitination/deubiquitination of stem cell transcription factors for efficient cellular reprogramming.

scholarly journals Sry-box (Sox) transcription factors in gastrointestinal physiology and disease

2011 ◽  
Vol 300 (4) ◽  
pp. G503-G515 ◽  
Author(s):  
A. D. Gracz ◽  
S. T. Magness
Keyword(s):  
Stem Cell ◽  
Transcription Factors ◽  
Gastrointestinal Tract ◽  
Proper Function ◽  
Valuable Insight ◽  
Gastrointestinal Physiology ◽  
Cell Fate Decisions ◽  
Stem Cell Maintenance ◽  
Organ Systems ◽  
Cell Maintenance

The genetic mechanisms underlying tissue maintenance of the gastrointestinal tract are critical for the proper function of the digestive system under normal physiological stress. The identification of transcription factors and related signal transduction pathways that regulate stem cell maintenance and lineage allocation is attractive from a clinical standpoint in that it may provide targets for novel cell- or drug-based therapies. Sox [sex-determining region Y ( Sry) box-containing] factors are a family of transcription factors that are emerging as potent regulators of stem cell maintenance and cell fate decisions in multiple organ systems and might provide valuable insight toward the understanding of these processes in endodermally derived tissues of the gastrointestinal tract. In this review, we focus on the known genetic functions of Sox factors and their roles in epithelial tissues of the esophagus, stomach, intestine, colon, pancreas, and liver. Additionally, we discuss pathological conditions in the gastrointestinal tract that are associated with a dysregulation of Sox factors. Further study of Sox factors and their role in gastrointestinal physiology and pathophysiology may lead to advances that facilitate control of tissue maintenance and development of advanced clinical therapies.

scholarly journals The RNA binding protein Swm is critical for Drosophila melanogaster intestinal progenitor cell maintenance

2022 ◽  
Author(s):  
Ishara S Ariyapala ◽  
Kasun Buddika ◽  
Heather A Hundley ◽  
Brian Calvi ◽  
Nicholas Sokol
Keyword(s):  
Stem Cell ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
Transcriptional Control ◽  
Rna Binding ◽  
Rna Binding Protein ◽  
Adult Stem Cell ◽  
Stem Cell Maintenance ◽  
And Function ◽  
Cell Maintenance

The regulation of stem cell survival, self-renewal, and differentiation is critical for the maintenance of tissue homeostasis. Although the involvement of signaling pathways and transcriptional control mechanisms in stem cell regulation have been extensively investigated, the role of post-transcriptional control is still poorly understood. Here we show that the nuclear activity of the RNA-binding protein Second Mitotic Wave Missing (Swm) is critical for Drosophila intestinal stem cells (ISCs) and their daughter cells, enteroblasts (EBs), to maintain their identity and function. Loss of swm in these intestinal progenitor cells leads ISCs and EBs to lose defined cell identities, fail to proliferate, and detach from the basement membrane, resulting in severe progenitor cell loss. swm loss further causes nuclear accumulation of poly(A)+ RNA in progenitor cells. Swm associates with transcripts involved in epithelial cell maintenance and adhesion, and the loss of swm, while not generally affecting the levels of these Swm-bound mRNAs, leads to elevated expression of proteins encoded by some of them, including the fly orthologs of Filamin and Talin. Taken together, this study indicates a role for Swm in adult stem cell maintenance, and raises the possibility that nuclear post-transcriptional gene regulation plays vital roles in controlling adult stem cell maintenance and function.

scholarly journals Coordinate control of basal epithelial cell fate and stem cell maintenance by core EMT transcription factor Zeb1

Cell Reports ◽  
2022 ◽  
Vol 38 (2) ◽  
pp. 110240
Author(s):  
Yingying Han ◽  
Alvaro Villarreal-Ponce ◽  
Guadalupe Gutierrez ◽  
Quy Nguyen ◽  
Peng Sun ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Stem Cell ◽  
Epithelial Cell ◽  
Cell Fate ◽  
Stem Cell Maintenance ◽  
Basal Epithelial Cell ◽  
Coordinate Control ◽  
Cell Maintenance

STEM-14. THE WRAD COMPLEX REPRESENTS A THERAPEUTIC TARGET FOR CANCER STEM CELLS IN GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi23-vi24
Author(s):  
Kelly Mitchell ◽  
Joseph Alvarado ◽  
Christopher Goins ◽  
Steven Martinez ◽  
Jonathan Macdonald ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Transcription Factors ◽  
Cancer Stem Cells ◽  
Molecular Mechanisms ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Self Renewal ◽  
Stem Cell Maintenance ◽  
Cell Maintenance

Abstract Glioblastoma (GBM) progression and resistance to conventional therapies is driven in part by cells within the tumor with stem cell properties including quiescence, self-renewal and drug efflux potential. It is thought that eliminating these cancer stem cells (CSCs) is a key component to successful clinical management of GBM. However, currently, few known molecular mechanisms driving CSCs can be exploited for therapeutic development. Core transcription factors such as SOX2, OLIG2, OCT4 and NANOG maintain the CSC state in GBM. Our laboratory recently uncovered a self-renewal signaling axis involving RBBP5 that is necessary and sufficient for CSC maintenance through driving expression of these core stem cell maintenance transcription factors. RBBP5 is a component of the WRAD complex, which promotes Lys4 methylation of histone H3 to positively regulate transcription. We hypothesized that targeting RBBP5 could be a means to disrupt epigenetic programs that maintain CSCs in stemness transcriptional states. We found that genetic and pharmacologic inhibition of the WRAD complex reduced CSC growth, self-renewal and tumor initiation potential. WRAD inhibitors partially dissembled the WRAD complex and reduced H3K4 trimethylation both globally and at the promoters of key stem cell maintenance transcription factors. Using a CSC reporter system, we demonstrated that WRAD complex inhibition decreased growth of SOX2/OCT4 expressing CSCs in a concentration-dependent manner as quantified by live imaging. Overall, our studies assess the function of the WRAD complex and the effect of WRAD complex inhibitors in preclinical models and specifically on the stem cell state for the first time in GBM. Studying the functions of the WRAD complex in CSCs may improve understanding of GBM pathogenesis and elucidate how CSCs survive despite aggressive chemotherapy and radiation. Our ongoing studies aim to develop brain penetrant inhibitors targeting the WRAD complex as an anti-CSC strategy that could potentially synergize with standard of care treatments.

Hematopoietic Stem Cell Maintenance and Differentiation Are Supported by Embryonic Aorta-Gonad-Mesonephros Region–Derived Endothelium

Blood ◽  
1998 ◽  
Vol 92 (3) ◽  
pp. 908-919 ◽  
Author(s):  
Osamu Ohneda ◽  
Christopher Fennie ◽  
Zhong Zheng ◽  
Christopher Donahue ◽  
Hank La ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Progenitor Cells ◽  
Fetal Liver ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Stem Cell Maintenance ◽  
Cell Maintenance

Abstract Hematopoietic stem cells are capable of extensive self-renewal and expansion, particularly during embryonic growth. Although the molecular mechanisms involved with stem cell maintenance remain mysterious, it is now clear that an intraembryonic location, the aorta-gonad-mesonephros (AGM) region, is a site of residence and, potentially, amplification of the definitive hematopoietic stem cells that eventually seed the fetal liver and adult bone marrow. Because several studies suggested that morphologically defined hematopoietic stem/progenitor cells in the AGM region appeared to be attached in clusters to the ventrally located endothelium of the dorsal aorta, we derived cell lines from this intraembryonic site using an anti-CD34 antibody to select endothelial cells. Analysis of two different AGM-derived CD34+ cell lines revealed that one, DAS 104-8, efficiently induced fetal-liver hematopoietic stem cells to differentiate down erythroid, myeloid, and B-lymphoid pathways, but it did not mediate self-renewal of these pluripotent cells. In contrast, a second cell line, DAS 104-4, was relatively inefficient at the induction of hematopoietic differentiation. Instead, this line provoked the expansion of early hematopoietic progenitor cells of the lin−CD34+Sca-1+c-Kit+phenotype and was proficient at maintaining fetal liver–derived hematopoietic stem cells able to competitively repopulate the bone marrow of lethally irradiated mice. These data bolster the hypothesis that the endothelium of the AGM region acts to mediate the support and differentiation of hematopoietic stem cells in vivo. © 1998 by The American Society of Hematology.

scholarly journals Cytokine and integrin stimulation synergize to promote higher levels of GATA-2, c-myb, and CD34 protein in primary human hematopoietic progenitors from bone marrow

Blood ◽  
2006 ◽  
Vol 109 (6) ◽  
pp. 2373-2379 ◽  
Author(s):  
Mo A. Dao ◽  
Jan A. Nolta
Keyword(s):  
Stem Cell ◽  
Transcription Factors ◽  
Myeloid Differentiation ◽  
Immunodeficient Mice ◽  
Factors Associated ◽  
Stem Cell Maintenance ◽  
Fibronectin Fragment ◽  
Cell Maintenance ◽  
Cells Cultured ◽  
In Cells

Abstract We have previously shown that engagement of the integrins VLA-4 and VLA-5 to the fibronectin fragment CH-296 in combination with cytokines sustained the capacity of cultured human CD34+ cells to undergo hematopoiesis in immunodeficient mice for 7 to 12 months, whereas this capacity was rapidly lost in cells cultured in suspension with the same cytokines. In the current study, we assessed the molecular pathways that might explain the loss of long-term engraftment capacity in cells cultured in suspension. Although the cell cycle profile was similar between cells cultured in suspension versus on fibronectin, levels of cell death were higher in the suspended cultures. While the CDK inhibitors p27Kip1 and p57Kip2 were present at equal levels in cells from both cultures, low levels of p21Cip1 were detectable only in the cytoplasmic compartment of cells cultured in suspension. Cytoplasmic location of p21Cip1 has been linked to monocytic differentiation. The levels of c-myb and GATA-2, transcription factors associated with stem cell maintenance, were higher in cells cultured on fibronectin as compared with suspension. In contrast, the levels of PU.1, which is induced during myeloid differentiation, were higher in cells cultured in suspension. There were no significant differences in surface expression of CD34 on the cells after culture, but total CD34 protein, assessed by immunoblotting, was significantly higher in cells cultured on fibronectin. Our data suggest that, in the presence of cytokines, the engagement of VLA-4 and VLA-5 integrins to the fibronectin fragment CH-296 preserves the expression of specific transcription factors associated with primitive stem cell maintenance. In contrast, a lack of integrin engagement leads to the induction of cellular markers associated with myeloid differentiation.

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