scholarly journals An ancient Pygo-dependent Wnt enhanceosome integrated by Chip/LDB-SSDP

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Marc Fiedler ◽  
Michael Graeb ◽  
Juliusz Mieszczanek ◽  
Trevor J Rutherford ◽  
Christopher M Johnson ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Development ◽  
Wnt Signaling ◽  
Binding Proteins ◽  
Adult Stem Cell ◽  
Previous Evidence ◽  
Cell Compartments ◽  
Nuclear Factors ◽  
Proteomics Approach

TCF/LEF factors are ancient context-dependent enhancer-binding proteins that are activated by β-catenin following Wnt signaling. They control embryonic development and adult stem cell compartments, and their dysregulation often causes cancer. β-catenin-dependent transcription relies on the NPF motif of Pygo proteins. Here, we use a proteomics approach to discover the Chip/LDB-SSDP (ChiLS) complex as the ligand specifically binding to NPF. ChiLS also recognizes NPF motifs in other nuclear factors including Runt/RUNX2 and Drosophila ARID1, and binds to Groucho/TLE. Studies of Wnt-responsive dTCF enhancers in the Drosophila embryonic midgut indicate how these factors interact to form the Wnt enhanceosome, primed for Wnt responses by Pygo. Together with previous evidence, our study indicates that ChiLS confers context-dependence on TCF/LEF by integrating multiple inputs from lineage and signal-responsive factors, including enhanceosome switch-off by Notch. Its pivotal function in embryos and stem cells explain why its integrity is crucial in the avoidance of cancer.

scholarly journals Wnt regulation: exploring Axin-Disheveled interactions and defining mechanisms by which the SCF E3 ubiquitin ligase is recruited to the destruction complex

2020 ◽  
Vol 31 (10) ◽  
pp. 992-1014 ◽  
Author(s):  
Kristina N. Schaefer ◽  
Mira I. Pronobis ◽  
Clara E. Williams ◽  
Shiping Zhang ◽  
Lauren Bauer ◽  
...  
Keyword(s):  
Stem Cell ◽  
Embryonic Development ◽  
Wnt Signaling ◽  
Ubiquitin Ligase ◽  
Human Cancer ◽  
E3 Ubiquitin Ligase ◽  
E3 Ligase ◽  
Adult Stem Cell ◽  
Cell Homeostasis ◽  
Test Models

Wnt signaling plays key roles in embryonic development and adult stem cell homeostasis and is altered in human cancer. We explore β-catenin transfer from the destruction complex to the E3 ligase, and test models suggesting Dishevelled and APC2 compete for association with Axin.

scholarly journals WNT inhibition creates a BRCA-like state in Wnt-addicted cancer

2020 ◽  
Author(s):  
Amanpreet Kaur ◽  
Sugunavathi Sepramaniam ◽  
Jun Yi Stanley Lim ◽  
Siddhi Patnaik ◽  
Nathan Harmston ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Repair ◽  
Wnt Signaling ◽  
Fanconi Anemia ◽  
Parp Inhibitor ◽  
Chemotherapy Resistance ◽  
Adult Stem Cell ◽  
Cell Compartments ◽  
Dna Damaging Agents ◽  
Cancer Models

ABSTRACTWnt signaling maintains diverse adult stem cell compartments and is implicated in chemotherapy resistance in cancer. PORCN inhibitors that block Wnt secretion have proven effective in Wnt-addicted preclinical cancer models and are in clinical trials. In a survey for potential combination therapies, we found that Wnt inhibition synergizes with the PARP inhibitor olaparib in Wnt-addicted cancers. Mechanistically, we find that multiple genes in the homologous recombination and Fanconi anemia repair pathways, including BRCA1, FANCD2, and RAD51 are dependent on Wnt/β-catenin signaling in Wnt-high cancers, and treatment with a PORCN inhibitor creates a BRCA-like state. This coherent regulation of DNA repair genes occurs via a Wnt/β-catenin/MYBL2 axis. Importantly, this pathway also functions in intestinal crypts, where high expression of BRCA and Fanconi anemia genes is seen in intestinal stem cells, with further upregulation in Wnt high APCmin mutant polyps. Our findings suggest a general paradigm that Wnt/β-catenin signaling enhances DNA repair in stem cells and cancers to maintain genomic integrity. Conversely, interventions that block Wnt signaling may sensitize cancers to radiation and other DNA damaging agents.

scholarly journals Gradual segregation of Adult Stem Cells and Niche cells during development from common precursors under the guidance of graded extracellular signals

2020 ◽  
Author(s):  
Amy Reilein ◽  
Helen V. Kogan ◽  
Rachel Misner ◽  
Karen Sophia Park ◽  
Daniel Kalderon
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Wnt Signaling ◽  
Cell Function ◽  
Adult Stem Cell ◽  
Follicle Cells ◽  
Pupal Development ◽  
Pathway Activity ◽  
Extracellular Signals ◽  
Egg Chambers

SummaryAdult stem cell function relies on the prior specification and organization of appropriate numbers of stem cells and supportive niche cells during development. Insights into those developmental processes could facilitate the synthesis of organoid mimics. Drosophila Follicle Stem Cells (FSCs) present an amenable paradigm with many similarities to mammalian gut stem cells. In an adult germarium a central domain of about 16 FSCs produces a posterior stream of transit-amplifying Follicle Cells (FCs), which encapsulate mature germline cysts to support egg development and, from their anterior face, quiescent Escort Cells (EC), which support the maturation of germline cysts. The behavior of FSCs is guided in part by niche signals produced by ECs and by a specialized polar cell FC derivative. Thus, ECs and FCs are both adult stem cell products and niche cells. Here we show by lineage analyses that adult ECs, FSCs and FCs derive from common precursors during pupal development. We infer that disparities in initial anterior-posterior (AP) precursor location followed by limited dispersal of progeny leads to a gradual acquisition of distinct fates determined by final AP location, with progeny of a single precursor commonly straddling EC and FSC, FSC and FC, or all three territories through most of pupal development. Direct visualization of pupal ovaries, including live imaging revealed a transient population of FC precursors posterior to the developing germarium awaiting emergence of the most mature germline cyst. The consequent budding process was quite different from the budding of egg chambers in adults. An anterior to posterior gradient of Wnt signaling develops shortly after pupariation. Loss of pathway activity cell autonomously resulted in more posterior adult progeny fates, while increased pathway activity elicited the opposite response, suggesting that stronger Wnt signaling favors anterior migration. Clearly detectable JAK-STAT pathway activity emerges only halfway through pupation after polar cells form, and spreads from posterior to anterior. Loss of JAK-STAT activity had similar consequences to increased Wnt pathway activity, drastically reducing FSC and FC production cell autonomously, while increased JAK-STAT activity promoted excessive precursor proliferation. We conclude that FSCs develop in co-ordination with their niche and product cells, that specification of stem cell identity is gradual, subject to stochastic influences and guided by graded extracellular signals, presaging similar regulation of adult stem cell behavior by the same pathways.

scholarly journals GSK3β, a Master Kinase in the Regulation of Adult Stem Cell Behavior

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 225
Author(s):  
Claire Racaud-Sultan ◽  
Nathalie Vergnolle
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Adult Stem Cells ◽  
Glycogen Synthase ◽  
Inflammatory Diseases ◽  
Adult Stem Cell ◽  
Leukemic Cells ◽  
Cell Phenotype ◽  
Epithelial Regeneration ◽  
Cell Functions

In adult stem cells, Glycogen Synthase Kinase 3β (GSK3β) is at the crossroad of signaling pathways controlling survival, proliferation, adhesion and differentiation. The microenvironment plays a key role in the regulation of these cell functions and we have demonstrated that the GSK3β activity is strongly dependent on the engagement of integrins and protease-activated receptors (PARs). Downstream of the integrin α5β1 or PAR2 activation, a molecular complex is organized around the scaffolding proteins RACK1 and β-arrestin-2 respectively, containing the phosphatase PP2A responsible for GSK3β activation. As a consequence, a quiescent stem cell phenotype is established with high capacities to face apoptotic and metabolic stresses. A protective role of GSK3β has been found for hematopoietic and intestinal stem cells. Latters survived to de-adhesion through PAR2 activation, whereas formers were protected from cytotoxicity through α5β1 engagement. However, a prolonged activation of GSK3β promoted a defect in epithelial regeneration and a resistance to chemotherapy of leukemic cells, paving the way to chronic inflammatory diseases and to cancer resurgence, respectively. In both cases, a sexual dimorphism was measured in GSK3β-dependent cellular functions. GSK3β activity is a key marker for inflammatory and cancer diseases allowing adjusted therapy to sex, age and metabolic status of patients.

Article Commentary: Stem Cell Research in Cell Transplantation: An Analysis of Geopolitical Influence by Publications

2007 ◽  
Vol 16 (8) ◽  
pp. 867-873 ◽  
Author(s):  
David J. Eve ◽  
Paul R. Sanberg
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Transplantation ◽  
Adult Stem Cells ◽  
Adult Stem Cell ◽  
Therapeutic Area ◽  
Fetal Stem Cells ◽  
Major Player ◽  
The Us ◽  
Restricted Use

One of the fastest growing fields in researching treatments for neurodegenerative and other disorders is the use of stem cells. These cells are naturally occurring and can be obtained from three different stages of an organism's life: embryonic, fetal, and adult. In the US, political doctrine has restricted use of federal funds for stem cells, enhancing research towards an adult source. In order to determine how this legislation may be represented by the stem cell field, a retrospective analysis of stem cell articles published in the journal Cell Transplantation over a 2-year period was performed. Cell Transplantation is considered a translational journal from preclinical to clinical, so it was of interest to determine the publication outcome of stem cell articles 6 years after the US regulations. The distribution of the source of stem cells was found to be biased towards the adult stage, but relatively similar over the embryonic and fetal stages. The fetal stem cell reports were primarily neural in origin, whereas the adult stem cell ones were predominantly mesenchymal and used mainly in neural studies. The majority of stem cell studies published in Cell Transplantation were found to fall under the umbrella of neuroscience research. American scientists published the most articles using stem cells with a bias towards adult stem cells, supporting the effect of the legislation, whereas Europe was the leading continent with a bias towards embryonic and fetal stem cells, where research is “controlled” but not restricted. Japan was also a major player in the use of stem cells. Allogeneic transplants (where donor and recipient are the same species) were the most common transplants recorded, although the transplantation of human-derived stem cells into rodents was the most common specific transplantation performed. This demonstrates that the use of stem cells is an increasingly important field (with a doubling of papers between 2005 and 2006), which is likely to develop into a major therapeutic area over the next few decades and that funding restrictions can affect the type of research being performed.

scholarly journals Comparative characterization and osteogenic / adipogenic differentiation of mesenchymal stem cells derived from male rat hair follicles and bone marrow

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Abdel Kader A. Zaki ◽  
Tariq I. Almundarij ◽  
Faten A. M. Abo-Aziza
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Adipogenic Differentiation ◽  
Adult Stem Cell ◽  
Cell Counting ◽  
Population Doubling ◽  
Male Rat ◽  
Cell Source

AbstractClinical applications of cell therapy and tissue regeneration under different conditions need a multiplicity of adult stem cell sources. Up to date, little is available on the comparative isolation, characterization, proliferation, rapid amplification, and osteogenic/adipogenic differentiation of rat mesenchymal stem cells (MSCs) isolated from living bulge cells of the hair follicle (HF) and bone marrow (BM) from the same animal. This work hopes to use HF-MSCs as an additional adult stem cell source for research and application. After reaching 80% confluence, the cell counting, viability %, and yields of HF-MSCs and BM-MSCs were nearly similar. The viability % was 91.41 ± 2.98 and 93.11 ± 3.06 while the cells yield of initial seeding was 33.15 ± 2.76 and 34.22 ± 3.99 and of second passage was 28.76 ± 1.01 and 29.56 ± 3.11 for HF-MSCs and BM-MSCs respectively. Clusters of differentiation (CDs) analysis revealed that HF-MSCs were positively expressed CD34, CD73 and CD200 and negatively expressed CD45. BM-MSCs were positively expressed CD73 and CD200 and negatively expressed of CD34 and CD45. The proliferation of HF-MSCs and BM-MSCs was determined by means of incorporation of Brd-U, population doubling time (PDT) assays and the quantity of formazan release. The percentage of Brd-U positive cells and PDT were relatively similar in both types of cells. The proliferation, as expressed by the quantity of formazan assay in confluent cells, revealed that the quantity of release by BM-MSCs was slightly higher than HF-MSCs. Adipogenic differentiated BM-MSCs showed moderate accumulation of oil red-O stained lipid droplets when compared to that of HF-MSCs which exhibited high stain. The total lipid concentration was significantly higher in adipogenic differentiated HF-MSCs than BM-MSCs (P < 0.05). It was found that activity of bone alkaline phosphatase and calcium concentration were significantly higher (P < 0.01 and P < 0.05 respectively) in osteogenic differentiated BM-MSCs than that of HF-MSCs. The present findings demonstrate that the HF-MSCs are very similar in most tested characteristics to BM-MSCs with the exception of differentiation. Additionally; no issues have been reported during the collection of HF-MSCs. Therefore, the HF may represent a suitable and accessible source for adult stem cells and can be considered an ideal cell source for adipogenesis research.

scholarly journals Silencing of long noncoding RNA HOXA11-AS inhibits the Wnt signaling pathway via the upregulation of HOXA11 and thereby inhibits the proliferation, invasion, and self-renewal of hepatocellular carcinoma stem cells

2019 ◽  
Vol 51 (11) ◽  
pp. 1-20 ◽  
Author(s):  
Jun-Cheng Guo ◽  
Yi-Jun Yang ◽  
Jin-Fang Zheng ◽  
Jian-Quan Zhang ◽  
Min Guo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Stem Cells ◽  
Stem Cell ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Methylation Level ◽  
Wnt Signaling Pathway ◽  
The Self ◽  
Self Renewal

AbstractHepatocellular carcinoma (HCC) is a major cause of cancer-related deaths, but its molecular mechanisms are not yet well characterized. Long noncoding RNAs (lncRNAs) play crucial roles in tumorigenesis, including that of HCC. However, the role of homeobox A11 antisense (HOXA11-AS) in determining HCC stem cell characteristics remains to be explained; hence, this study aimed to investigate the effects of HOXA11-AS on HCC stem cell characteristics. Initially, the expression patterns of HOXA11-AS and HOXA11 in HCC tissues, cells, and stem cells were determined. HCC stem cells, successfully sorted from Hep3B and Huh7 cells, were transfected with short hairpin or overexpression plasmids for HOXA11-AS or HOXA11 overexpression and depletion, with an aim to study the influences of these mediators on the self-renewal, proliferation, migration, and tumorigenicity of HCC stem cells in vivo. Additionally, the potential relationship and the regulatory mechanisms that link HOXA11-AS, HOXA11, and the Wnt signaling pathway were explored through treatment with Dickkopf-1 (a Wnt signaling pathway inhibitor). HCC stem cells showed high expression of HOXA11-AS and low expression of HOXA11. Both HOXA11-AS silencing and HOXA11 overexpression suppressed the self-renewal, proliferation, migration, and tumorigenicity of HCC stem cells in vivo, as evidenced by the decreased expression of cancer stem cell surface markers (CD133 and CD44) and stemness-related transcription factors (Nanog, Sox2, and Oct4). Moreover, silencing HOXA11-AS inactivated the Wnt signaling pathway by decreasing the methylation level of the HOXA11 promoter, thereby inhibiting HCC stem cell characteristics. Collectively, this study suggested that HOXA11-AS silencing exerts an antitumor effect, suppressing HCC development via Wnt signaling pathway inactivation by decreasing the methylation level of the HOXA11 promoter.

scholarly journals Loss of foxo rescues stem cell aging in Drosophila germ line

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Filippo Artoni ◽  
Rebecca E Kreipke ◽  
Ondina Palmeira ◽  
Connor Dixon ◽  
Zachary Goldberg ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Ionizing Radiation ◽  
Cell Injury ◽  
Germ Line ◽  
Adult Stem Cell ◽  
Cell Aging ◽  
Germline Stem Cells ◽  
Cell Cycle Reentry

Aging stem cells lose the capacity to properly respond to injury and regenerate their residing tissues. Here, we utilized the ability of Drosophila melanogaster germline stem cells (GSCs) to survive exposure to low doses of ionizing radiation (IR) as a model of adult stem cell injury and identified a regeneration defect in aging GSCs: while aging GSCs survive exposure to IR, they fail to reenter the cell cycle and regenerate the germline in a timely manner. Mechanistically, we identify foxo and mTOR homologue, Tor as important regulators of GSC quiescence following exposure to ionizing radiation. foxo is required for entry in quiescence, while Tor is essential for cell cycle reentry. Importantly, we further show that the lack of regeneration in aging germ line stem cells after IR can be rescued by loss of foxo.

scholarly journals Strategic Tools in Regenerative and Translational Dentistry

2019 ◽  
Vol 20 (8) ◽  
pp. 1879 ◽  
Author(s):  
Marco Tatullo ◽  
Bruna Codispoti ◽  
Francesco Paduano ◽  
Manuel Nuzzolese ◽  
Irina Makeeva
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
State Of The Art ◽  
Adult Stem Cell ◽  
Point Of View ◽  
Local Inflammation ◽  
Differentiation Potential ◽  
Clear Point ◽  
Regenerative Ability ◽  
Stem Cell Populations

Human oral-derived stem cells can be easily obtained from several oral tissues, such as dental pulp, periodontal ligament, from gingiva, or periapical cysts. Due to their differentiation potential, oral-derived mesenchymal stem cells are promising for tissue engineering and regenerative medicine. The regenerative ability showed by some oral tissues strongly depends on their sleeping adult stem cell populations that are able to repair small defects and to manage local inflammation. To date, researchers are working on effective and efficient methods to ensure safe and predictable protocols to translate stem cell research into human models. In the last decades, the challenge has been to finally use oral-derived stem cells together with biomaterials or scaffold-free techniques, to obtain strategic tools for regenerative and translational dentistry. This paper aims to give a clear point of view on state of the art developments, with some exciting insights into future strategies.

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