Axial progenitors with extensive potency are localised to the mouse chordoneural hinge

Development ◽  
2002 ◽  
Vol 129 (20) ◽  
pp. 4855-4866 ◽  
Author(s):  
Noemí Cambray ◽  
Valerie Wilson
Keyword(s):  
Stem Cells ◽  
Cell Model ◽  
Primitive Streak ◽  
Serial Passage ◽  
Small Population ◽  
Lineage Tracing ◽  
Tail Bud ◽  
Apparent Loss ◽  
Stem Cell Model ◽  
Successive Generations

Elongation of the mouse anteroposterior axis depends on a small population of progenitors initially located in the primitive streak and later in the tail bud. Gene expression and lineage tracing have shown that there are many features common to these progenitor tissues throughout axial elongation. However, the identity and location of the progenitors is unclear. We show by lineage tracing that the descendants of 8.5 d.p.c. node and anterior primitive streak which remain in the tail bud are located in distinct territories: (1) ventral node descendants are located in the widened posterior end of the notochord; and (2) descendants of anterior streak are located in both the tail bud mesoderm, and in the posterior end of the neurectoderm. We show that cells from the posterior neurectoderm are fated to give rise to mesoderm even after posterior neuropore closure. The posterior end of the notochord, together with the ventral neurectoderm above it, is thus topologically equivalent to the chordoneural hinge region defined in Xenopus and chick. A stem cell model has been proposed for progenitors of two of the axial tissues, the myotome and spinal cord. Because it was possible that labelled cells in the tail bud represented stem cells, tail bud mesoderm and chordoneural hinge were grafted to 8.5 d.p.c. primitive streak to compare their developmental potency. This revealed that cells from the bulk of the tail bud mesoderm are disadvantaged in such heterochronic grafts from incorporating into the axis and even when they do so, they tend to contribute to short stretches of somites suggesting that tail bud mesoderm is restricted in potency. By contrast, cells from the chordoneural hinge of up to 12.5 d.p.c. embryos contribute efficiently to regions of the axis formed after grafting to 8.5 d.p.c. embryos, and also repopulate the tail bud. These cells were additionally capable of serial passage through three successive generations of embryos in culture without apparent loss of potency. This potential for self-renewal in chordoneural hinge cells strongly suggests that stem cells are located in this region.

scholarly journals Maintenance of active chromatin states by HMGN2 is required for stem cell identity in a pluripotent stem cell model

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Sylvia Garza-Manero ◽  
Abdulmajeed Abdulghani A. Sindi ◽  
Gokula Mohan ◽  
Ohoud Rehbini ◽  
Valentine H. M. Jeantet ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neuronal Differentiation ◽  
Embryonal Carcinoma ◽  
Cell Model ◽  
Carcinoma Cells ◽  
Adult Brain ◽  
Embryonal Carcinoma Cells ◽  
Stem Cell Model ◽  
Neural Stem Progenitor Cells

Abstract Background Members of the HMGN protein family modulate chromatin structure and influence epigenetic modifications. HMGN1 and HMGN2 are highly expressed during early development and in the neural stem/progenitor cells of the developing and adult brain. Here, we investigate whether HMGN proteins contribute to the chromatin plasticity and epigenetic regulation that is essential for maintaining pluripotency in stem cells. Results We show that loss of Hmgn1 or Hmgn2 in pluripotent embryonal carcinoma cells leads to increased levels of spontaneous neuronal differentiation. This is accompanied by the loss of pluripotency markers Nanog and Ssea1, and increased expression of the pro-neural transcription factors Neurog1 and Ascl1. Neural stem cells derived from these Hmgn-knockout lines also show increased spontaneous neuronal differentiation and Neurog1 expression. The loss of HMGN2 leads to a global reduction in H3K9 acetylation, and disrupts the profile of H3K4me3, H3K9ac, H3K27ac and H3K122ac at the Nanog and Oct4 loci. At endodermal/mesodermal genes, Hmgn2-knockout cells show a switch from a bivalent to a repressive chromatin configuration. However, at neuronal lineage genes whose expression is increased, no epigenetic changes are observed and their bivalent states are retained following the loss of HMGN2. Conclusions We conclude that HMGN1 and HMGN2 maintain the identity of pluripotent embryonal carcinoma cells by optimising the pluripotency transcription factor network and protecting the cells from precocious differentiation. Our evidence suggests that HMGN2 regulates active and bivalent genes by promoting an epigenetic landscape of active histone modifications at promoters and enhancers.

In Acute Lymphoblastic Leukaemia, Stemness Is Frequent and Ubiquitous

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 92-92
Author(s):  
Klaus Rehe ◽  
Kerrie Wilson ◽  
Simon Bomken ◽  
Hesta McNeill ◽  
Martin Stanulla ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Cord Blood ◽  
Cell Model ◽  
Cell Activity ◽  
Self Renewal ◽  
Nsg Mice ◽  
Stem Cell Activity ◽  
Stem Cell Model

Abstract Abstract 92 Research on cancer stem cells, cells that self-renew and reconstitute the full phenotype of the original malignancy, has yielded controversial results regarding their frequency and identity for many cancers. The hierarchical stem cell model has been well established in some malignancies such as acute myeloid leukemia and states that only rare, immunophenotypically immature blasts harbor stem cell activity, resembling a normal physiological hierarchy. The opposing stochastic model proposes that stemness in cancer cells is supported by extrinsic stimuli and that a substantial fraction of malignant cells have this potential. Continued optimization of in vivo xenotransplantation modeling recently caused a paradigm shift for some cancers, for example in malignant melanoma where stem cell activity was found in as many as 1 in 4 cells. For acute lymphoblastic leukemia (ALL) we and others previously challenged the hierarchical model by demonstrating that both immature and more mature leukemic blasts contain self-renewal properties (Cancer Cell 2008, 14(1), p47-58). In this study we address the frequency of leukemic stem cells in the bulk leukemia and also, more specifically, in subpopulations of different blast maturity by using unsorted and highly purified flow sorted cell fractions. Primary patient material as well as leukemic blasts harvested from engrafted mouse bone marrow (secondary and tertiary material) were sorted for their CD10, CD20 or CD34 expression followed by orthotopic intrafemoral transplantation into severely immunocompromised NOD/scid IL2Rγnull (NSG) mice. Engraftment of transplanted CD19+CD10low and CD19+CD10high, CD19+CD20low and CD19+CD20high and CD19+CD34low and CD19+CD34high blast populations was monitored by 5 color flow cytometry using material from consecutive bone marrow punctures, final bone marrow harvests and/or single cell suspensions from spleens. Primary ALL samples from 15 high risk (BCR/ABL positive (n=8), BCR/ABL like ALL (n=2), high hyperdiploid/MRD positive (n=2), MRD positive (n=1), MLL/AF4 (n=2)), 3 intermediate risk (high WBC/MRD negative (n=2), age >10 years (n=1)) and 3 standard risk (n=3) patients were included. Cells sorted into CD19+CD10low and CD19+CD10high fractions were transplanted from primary patient material (n=4, HR; n=1, SR) and from secondary samples (n=4, HR; n=1; IR) with cells from one HR patient used at limiting dilutions. As few as 100 sorted cells of either fraction were sufficient to repopulate the leukemia. CD19+CD20high and CD19+CD20 low fractions from primary (n=7, HR; n=1, IR), secondary (n=5, HR; n=1, IR) and tertiary material (n=2, HR; n=1, IR) engrafted NSG mice. Limiting dilutions were performed on secondary (n=4, HR) and tertiary material (n=2, HR). Cell numbers required for engraftment varied between leukemias with as few as 100 cells being sufficient to cause engraftment. Limiting dilution experiments using CD19+CD34high and CD19+CD34low fractions from secondary (n=1, HR) and tertiary (n=1, HR) material yielded engraftment with as few as 10 CD19+CD34high and 100 CD19+CD34low cells. Similarly, unsorted primary (n=11, HR; n=2, IR), secondary (n=2, HR) and tertiary material (n=1, HR) required as few as 10 cells for leukemic reconstitution. Taken together, both unsorted and sorted blasts of all immunophenotypes and transplanted with low numbers were able to reconstitute the complete original phenotype of the patient leukemia. All limiting dilutions were transplanted down to 10 cells per mouse and those mice not engrafted yet are still under observation. Furthermore, the ability to self-renew was demonstrated by serial transplantation. Finally, we compared expression of self-renewal associated genes (BMI1, EZH2, HMGA2, MEIS1, TERT) in CD19+CD34low and CD19+CD34high fractions of 5 HR and 1 SR samples with that in cord blood. Interestingly, expression of these genes was not dependent on the CD34 status of the leukemic cells, whereas HMGA2, MEIS1 and TERT were upregulated in CD34+ cord blood cells. In summary we provide strong evidence for the stochastic cancer stem cell model in B precursor ALL by demonstrating that (i) a broad spectrum of blast immunophenotypes exhibit stem cell characteristics and (ii) that this stemness is highly frequent among ALL cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals C. elegans germ cells divide and differentiate along a folded epithelium

2018 ◽  
Author(s):  
Hannah S. Seidel ◽  
Tilmira A. Smith ◽  
Jessica K. Evans ◽  
Jarred Q. Stamper ◽  
Thomas G. Mast ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Germ Cells ◽  
Cell Model ◽  
Three Dimensional ◽  
3D Models ◽  
Germline Stem Cells ◽  
C Elegans ◽  
Stem Cell Regulation ◽  
Stem Cell Model

AbstractKnowing how stem cells and their progeny are positioned within their tissues is essential for understanding their regulation. One paradigm for stem cell regulation is the C. elegans germline, which is maintained by a pool of germline stem cells in the distal gonad, in a region known as the ‘progenitor zone’. The C. elegans germline is widely used as a stem cell model, but the cellular architecture of the progenitor zone has been unclear. Here we characterize this architecture by creating virtual 3D models of the progenitor zone in both sexes. We show that the progenitor zone in adult hermaphrodites is essentially a folded epithelium. The progenitor zone in males is not folded. Analysis of germ cell division shows that daughter cells are born side-by-side along the surface of the epithelium. Analysis of a key regulator driving differentiation, GLD-1, shows that germ cells in hermaphrodites differentiate along the path of the folded epithelium, with previously described “steps” in GLD-1 expression corresponding to germline folds. Our study provides a three-dimensional view of how C. elegans germ cells progress from stem cell to overt differentiation, with critical implications for regulators driving this transition.

Invincible, but Not Invisible: Imaging Approaches Toward In Vivo Detection of Cancer Stem Cells

2008 ◽  
Vol 26 (17) ◽  
pp. 2901-2910 ◽  
Author(s):  
Lori S. Hart ◽  
Wafik S. El-Deiry
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cancer Stem Cell ◽  
Natural Environment ◽  
Cell Model ◽  
Advanced Imaging ◽  
Stem Cell Model ◽  
Cancer Stem Cell Model

With evidence emerging in support of a cancer stem-cell model of carcinogenesis, it is of paramount importance to identify and image these elusive cells in their natural environment. The cancer stem-cell hypothesis has the potential to explain unresolved questions of tumorigenesis, tumor heterogeneity, chemotherapeutic and radiation resistance, and even the metastatic phenotype. Intravital imaging of cancer stem cells could be of great value for determining prognosis, as well as monitoring therapeutic efficacy and influencing therapeutic protocols. Cancer stem cells represent a rare population of cells, as low as 0.1% of cells within a human tumor, and the phenotype of isolated cancer stem cells is easily altered when placed under in vitro conditions. This represents a challenge in studying cancer stem cells without manipulation or extraction from their natural environment. Advanced imaging techniques allow for the in vivo observation of physiological events at cellular resolution. Cancer stem-cell studies must take advantage of such technology to promote a better understanding of the cancer stem-cell model in relation to tumor growth and metastasis, as well as to potentially improve on the principles by which cancers are treated. This review examines the opportunities for in vivo imaging of putative cancer stem cells with regard to currently accepted cancer stem-cell characteristics and advanced imaging technologies.

Aberrant Regulation of Wnt/Beta-Catenin Pathway Mediators in Chronic Myelogenous Leukemia Stem Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2135-2135
Author(s):  
Annelie Abrahamsson ◽  
Ifat Geron ◽  
Jason Gotlib ◽  
Jeffrey Durocher ◽  
Remi Creusot ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Model ◽  
Blast Crisis ◽  
Wnt Signaling Pathway ◽  
Myelogenous Leukemia ◽  
Beta Catenin ◽  
Rt Pcr ◽  
Facs Analysis ◽  
Advanced Phase ◽  
Stem Cell Model

Abstract Background Recent research suggests that self-renewing leukemia stem cells (LSC) with increased beta-catenin expression are involved in chronic myelogenous leukemia (CML) progression. We investigated whether aberrant regulation of beta-catenin destruction complex genes contributed to the enhanced self-renewal potential of CML LSC. Methods FACS Aria purified normal and CML hematopoietic stem cells (HSC), granulocyte-macrophage progenitors (GMP) and lineage positive cells were transduced for 48 hours with lentiviral luciferase GFP and transplanted intrahepatically into newborn RAG2−/−gama−/− mice. At 8 to 12 weeks human CD45+ cells were FACS-purified and transplanted into secondary recipients to establish a bioluminescent CML LSC model. RT-PCR for BCR-ABL was used to confirm CML engraftment. Wnt mediator mutation analysis was performed on cDNA via fluorescent denaturing high performance liquid chromatography (DHPLC) technology and SURVEYOR mismatch cleavage analysis both with the WAVE-HS System (Transgenomic, Gaithersberg, MD). Aliquots of PCR product (3-15 ul) from all samples were scanned for mutations by DHPLC and confirmed by Surveyor mismatch cleavage, and identified with bidirectional sequence analysis on an ABI 3100 sequencer using BigDye V3.1 terminator chemistry. Quantitative RT-PCR was also performed on CML progenitors using destruction complex gene specific primers. FACS analysis was performed with the aid of a FACS Aria to analyze changes in Wnt signaling pathway mediators. Results Advanced phase CML was typified by expansion of a GMP population with aberrantly activated beta-catenin expression, enhanced in vitro replating capacity as well as serial transplantation potential in a CML LSC bioluminescent imaging model suggesting that the GMP population was enriched for LSC (Figure 1). A targeted Wnt mutation analysis revealed a mutation in a key component of the beta-catenin destruction complex - glycogen synthase kinase 3beta (GSK) in progenitors from three of six blast crisis CML samples analyzed. Decreased GSK expression was confirmed via FACS analysis using a GSK specific antibody in three separate experiments with CML blast crisis progenitors (Figure 2). Some CML blast crisis progenitors also demonstrated a decrease in axin 2 by quantitative RT-PCR. Conclusions Altered expression of Wnt signaling pathway regulators, such as GSK3, may result in increased LSC self-renewal capacity and may represent novel therapeutic targets for advanced phase CML. Figure 1. Bioluminescent Chronic Myeloneous Leukemis stem cell Model Figure 1. Bioluminescent Chronic Myeloneous Leukemis stem cell Model Figure 2. GSK FACS Analysis. Figure 2. GSK FACS Analysis.

Mesenchymal stem cells from the outer ear: a novel adult stem cell model system for the study of adipogenesis

2005 ◽  
Vol 19 (9) ◽  
pp. 1205-1207 ◽  
Author(s):  
Jong‐Seop Rim ◽  
Randall L. Mynatt ◽  
Barbara Gawronska‐Kozak
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Cell Model ◽  
Adult Stem Cell ◽  
Model System ◽  
Stem Cell Model ◽  
Cell Model System

scholarly journals The role of cancer stem cells in glioblastoma

2014 ◽  
Vol 37 (6) ◽  
pp. E6 ◽  
Author(s):  
Swetha J. Sundar ◽  
Jason K. Hsieh ◽  
Sunil Manjila ◽  
Justin D. Lathia ◽  
Andrew Sloan
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cell Model ◽  
Critical Role ◽  
Treatment Resistance ◽  
Molecular Heterogeneity ◽  
Clinical Investigations ◽  
Stem Cell Model ◽  
Cancer Stem Cell Model

Recurrence in glioblastoma is nearly universal, and its prognosis remains dismal despite significant advances in treatment over the past decade. Glioblastoma demonstrates considerable intratumoral phenotypic and molecular heterogeneity and contains a population of cancer stem cells that contributes to tumor propagation, maintenance, and treatment resistance. Cancer stem cells are functionally defined by their ability to self-renew and to differentiate, and they constitute the diverse hierarchy of cells composing a tumor. When xenografted into an appropriate host, they are capable of tumorigenesis. Given the critical role of cancer stem cells in the pathogenesis of glioblastoma, research into their molecular and phenotypic characteristics is a therapeutic priority. In this review, the authors discuss the evolution of the cancer stem cell model of tumorigenesis and describe the specific role of cancer stem cells in the pathogenesis of glioblastoma and their molecular and microenvironmental characteristics. They also discuss recent clinical investigations into targeted therapies against cancer stem cells in the treatment of glioblastoma.

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