scholarly journals PPARγ2 Regulates a Molecular Signature of Marrow Mesenchymal Stem Cells

PPAR Research ◽  
2007 ◽  
Vol 2007 ◽  
pp. 1-13 ◽  
Author(s):  
K. R. Shockley ◽  
C. J. Rosen ◽  
G. A. Churchill ◽  
B. Lecka-Czernik
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Biology ◽  
Molecular Signature ◽  
Cell Phenotype ◽  
Differentiation Potential ◽  
Gene Markers ◽  
Therapeutic Consequences ◽  
Expression Of Genes ◽  
Stem Cell Phenotype

Bone formation and hematopoiesis are anatomically juxtaposed and share common regulatory mechanisms. Bone marrow mesenchymal stromal/stem cells (MSC) contain a compartment that provides progeny with bone forming osteoblasts and fat laden adipocytes as well as fibroblasts, chondrocytes, and muscle cells. In addition, marrow MSC provide an environment for support of hematopoiesis, including the development of bone resorbing osteoclasts. The PPARγ2 nuclear receptor is an adipocyte-specific transcription factor that controls marrow MSC lineage allocation toward adipocytes and osteoblasts. Increased expression of PPARγ2 with aging correlates with changes in the MSC status in respect to both their intrinsic differentiation potential and production of signaling molecules that contribute to the formation of a specific marrow microenvironment. Here, we investigated the effect of PPARγ2 on MSC molecular signature in respect to the expression of gene markers associated exclusively with stem cell phenotype, as well as genes involved in the formation of a stem cell supporting marrow environment. We found that PPARγ2 is a powerful modulator of stem cell-related gene expression. In general, PPARγ2 affects the expression of genes specific for the maintenance of stem cell phenotype, including LIF, LIF receptor, Kit ligand, SDF-1, Rex-1/Zfp42, and Oct-4. Moreover, the antidiabetic PPARγagonist TZD rosiglitazone specifically affects the expression of “stemness” genes, including ABCG2, Egfr, and CD44. Our data indicate that aging and antidiabetic TZD therapy may affect mesenchymal stem cell phenotype through modulation of PPARγ2 activity. These observations may have important therapeutic consequences and indicate a need for more detailed studies of PPARγ2 role in stem cell biology.

scholarly journals Circular RNAs in Stem Cells: from Basic Research to Clinical Implications

2021 ◽  
Author(s):  
Hui-Juan Lu ◽  
Juan Li ◽  
Guodong Yang ◽  
Cun-Jian Yi ◽  
Daping Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Biology ◽  
Basic Research ◽  
Cell Types ◽  
Circular Rnas ◽  
Diagnostic Significance ◽  
Differentiation Potential ◽  
Self Renewal ◽  
Cell Based Therapy

Circular RNAs (circRNAs) are a special class of endogenous RNAs with a wide variety of pathophysiological functions via diverse mechanisms, including transcription, miRNA sponge, protein sponge/decoy, and translation. Stem cells are pluripotent cells with unique properties of self-renewal and differentiation. Dysregulated circRNAs identified in various stem cell types can affect stem cell self-renewal and differentiation potential by manipulating stemness. However, the emerging roles of circRNAs in stem cells remain largely unknown. This review summarizes the major functions and mechanisms of action of circRNAs in stem cell biology and disease progression. We also highlight circRNAs-mediated common pathways in diverse stem cell types and discuss their diagnostic significance with respect to stem cell-based therapy.

scholarly journals The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype

Cell Cycle ◽  
2009 ◽  
Vol 8 (20) ◽  
pp. 3274-3284 ◽  
Author(s):  
John M. Heddleston ◽  
Zhizhong Li ◽  
Roger E. McLendon ◽  
Anita B. Hjelmeland ◽  
Jeremy N. Rich
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Cell Phenotype ◽  
Glioblastoma Stem Cells ◽  
Cancer Stem Cell Phenotype ◽  
Stem Cell Phenotype

Characterizing the clinical relevance of an embryonic stem cell phenotype in lung adenocarcinoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 11001-11001
Author(s):  
M. M. Stevenson ◽  
W. Mostertz ◽  
C. Acharya ◽  
K. Walters ◽  
W. Barry ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Lung Adenocarcinoma ◽  
Gene Expression Data ◽  
Embryonic Stem ◽  
Cell Phenotype ◽  
Expression Data ◽  
Stem Cell Phenotype

11001 Background: Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear whether these phenotypic similarities between normal/embryonic stem cells and mature tumor cells, specific to lung cancer, are a result of underlying biologic processes, such as specific molecular pathways and regulatory networks. Methods: Using a large cohort of lung cancer cell lines with associated gene expression data, genes associated with an embryonic stem cell identity were used to develop a ‘signature’ representative of embryonic stemness (ES) activity specific to lung adenocarcinoma. Differential biology was evaluated using Gene Set Enrichment Analysis (GSEA) and signatures of oncogenic pathway deregulation. The ES signature was applied to three independent early (stage I - IIIa) lung adenocarcinoma data sets (N = 634) with clinically annotated gene expression data. The relationship between the ES phenotype and cisplatin sensitivity was also evaluated. Results: Using Bayesian regression analysis, a 100 gene signature representative of ES activity in lung adenocarcinoma was developed and validated in a leave-one-out-analysis. GSEA identified gene sets significantly represented in the ES signature: signature of neoplastic transformation, signature of undifferentiated cancer, BRCA pathway, and fibroblast serum response pathway, all associated with cancer invasiveness. Adenocarcinomas with ES demonstrated increased activation of RAS (p = 0.0002), MYC (p = 0.0057), wound healing (angiogenesis) (p < 0.0001), chromosomal instability (p < 0.0001), and invasiveness (p < 0.0001) gene signatures. Adenocarcinomas (N= 634) with ES had a decreased survival (p<0.04). The ES signature was not prognostic in prostate, ovarian, or breast adenocarcinomas. Lung tumors (N=634) and adenocarcinoma cell lines (N=31) with ES were more resistant to cisplatin (p<0.0001 and p=0.0063, respectively). Conclusions: Lung adenocarcinomas that share a common gene expression pattern with normal stem cells were associated with decreased survival and increased likelihood of resistance to cisplatin, indicating the aggressiveness of lung tumors with a stem cell phenotype. No significant financial relationships to disclose.

scholarly journals miRNA function and modulation in stem cells and cancer stem cells

2014 ◽  
Vol 1 (1) ◽  
Author(s):  
Andrew J. DeCastro ◽  
James DiRenzo
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cell Phenotype ◽  
Pluripotent State ◽  
Differentiated Cells ◽  
Non Coding Rnas ◽  
Multicellular Organisms ◽  
Stem Cell Phenotype

AbstractStem cells belong to a unique class of cells that is collectively responsible for the development and subsequent maintenance of all tissues comprising multicellular organisms. These cells possess unique characteristics that allow them to remain in a pluripotent state, while also continuing to generate differentiated cells. microRNAs, a specialized class of non-coding RNAs, are integral components of the network of pathways that modulates this combination of abilities. This review highlights recent discoveries about the roles miRNAs play in governing stem cell phenotype, and discusses the potential therapeutic utility that miRNAs may have in the treatment of multiple diseases. Additionally, it addresses a novel mode of regulation of stem cell phenotype through lincRNA-mediated modulation of select miRNAs, and the role of secreted, stem cell-derived miRNAs in exerting a paracrine influence on surrounding non-stem cells.

scholarly journals Multi-differentiation potential is necessary for optimal tenogenesis of tendon stem cells

2019 ◽  
Author(s):  
Ibtesam Rajpar ◽  
Jennifer G. Barrett
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Lines ◽  
Cell Phenotype ◽  
Differentiation Potential ◽  
Therapeutic Benefits ◽  
Tendon Stem Cells ◽  
Stem Cell Lines ◽  
Population Doublings ◽  
Cell Phenotypes

ABSTRACTBackgroundTendon injury is a significant clinical problem, and regenerative treatments are limited by our understanding of endogenous tendon stem cells. Recent evidence suggests that tendon stem cells are diverse in phenotypic character, and may in fact exist on a spectrum of differentiation capacities. However, the functional significance of each differentiation phenotype is poorly understood. Toward this end, we performed a comprehensive assessment of differentiation capacity toward four connective tissue lineages (adipose, bone, cartilage and tendon) with clonal tendon stem cell lines to: 1) evaluate the differences, if any, in tenogenic potential, and 2) identify the relationships in differentiation phenotype and proliferation capacity.MethodsTendon stem cells were derived from whole equine flexor tendons for this study (N=3). Clonal tendon stem lines were generated by low-density cell plating, and subjected to standard assays of tri-lineage differentiation and population doublings. For tenogenesis, a previously engineered three-dimensional hydrogel construct was incorporated. Differentiation was quantified by the relative gene expression of lineage-specific markers, and confirmed with lineage-specific cell staining. Tenogenesis was further analyzed by hydrogel contraction and histomorphometry. Statistical significance was determined using analysis of variance and post-hoc Tukey’s tests.ResultsThree distinct tendon stem cell phenotypes were identified, namely differentiation toward: 1) adipose, bone, cartilage and tendon, 2) bone, cartilage and tendon, or 3) adipose, cartilage and tendon. Further, a positive correlation was found in the ability to differentiate toward all four lineages and the generation of a robust, composite tendon-like construct upon tenogenesis, manifested by the strongest expressions of scleraxis and mohawk, and parallel alignment of tenocyte-like cells with elongated cell morphologies. Significantly increased numbers of cumulative cell population doublings were seen in the absence of adipogenic potential in clonal tendon stem cell lines.ConclusionsOur study strengthens reports on the heterogeneous character of tendon stem cells and identifies key differences in their differentiation and proliferative potentials. Isolation of potent tendon stem cell populations from tendon stromal fractions may yield improved therapeutic benefits in clinical models of repair and promote a native, regenerative phenotype in engineered tendons. Future studies may be targeted to understanding the functional contributions of each tendon stem cell phenotype in vivo, and identifying additional cell phenotypes.

scholarly journals Empty spiracles homeobox genes EMX1 and EMX2 regulate WNT pathway activation in sarcomagenesis

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Manuel Pedro Jimenez-García ◽  
Antonio Lucena-Cacace ◽  
Daniel Otero-Albiol ◽  
Amancio Carnero
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Transcription Factors ◽  
Cell Biology ◽  
Wnt Pathway ◽  
Ectopic Expression ◽  
Homeobox Genes ◽  
Cell Phenotype

Abstract Background Sarcomas are a very heterogeneous group of tumors with intrinsic developmental programs derived from the cell of origin. This implies a functional hierarchy inside tumors governed by sarcoma stem cells. Therefore, genetic and/or epigenetic changes profoundly affect the biology of sarcoma tumor stem cells. EMX genes are proposed to be transcription factors that are involved in the sarcomagenesis process, regardless of the neural or mesodermal embryological sarcoma origin. It has been shown that EMX1 or EMX2 overexpression reduces tumorigenic properties, while reducing the levels of these genes enhances these properties. Furthermore, it has been shown that EMX genes decrease the expression of stem cell regulatory genes and the stem cell phenotype. Taken together, these results indicate that the EMX1 and EMX2 genes negatively regulate these tumor-remodeling populations or sarcoma stem cells, acting as tumor suppressors in sarcoma. Methods Bioinformatic analysis, quantitative mRNA and protein expression analysis, cell models of sarcoma by ectopic expression of EMX genes. By cell biology methods we measured tumorigenesis and populations enriched on stem cell phenotypes, either in vitro or in vivo. Results In this work, we showed that the canonical Wnt pathway is one of the mechanisms that explains the relationships of EMX1/EMX2 and stem cell genes in sarcoma. The Wnt-EMX1/EMX2 relationship was validated in silico with sarcoma patient datasets, in vitro in primary derived sarcoma cell lines, and in vivo. EMX expression was found to negatively regulate the Wnt pathway. In addition, the constitutive activation of the Wnt pathway revers to a more aggressive phenotype with stem cell properties, and stemness gene transcription increased even in the presence of EMX1 and/or EMX2 overexpression, establishing the relationship among the Wnt pathway, stem cell genes and the EMX transcription factors. Conclusions Our data showed that Empty Spiracles Homeobox Genes EMX1 and EMX2 represses WNT signalling and activation of WNT pathway bypass EMX-dependent stemness repression and induces sarcomagenesis. These results also suggest the relevance of the Wnt/b-catenin/stemness axis as a therapeutic target in sarcoma.

Identification of a novel class of human adherent CD34− stem cells that give rise to SCID-repopulating cells

Blood ◽  
2003 ◽  
Vol 101 (3) ◽  
pp. 869-876 ◽  
Author(s):  
Selim Kuçi ◽  
Johannes T. Wessels ◽  
Hans-Jörg Bühring ◽  
Karin Schilbach ◽  
Michael Schumm ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Killer Cell ◽  
Cell Subset ◽  
Cell Phenotype ◽  
Adherent Cells ◽  
Differentiation Potential ◽  
Hematopoietic Stem ◽  
Cd34 Cells

Abstract Here we describe the in vitro generation of a novel adherent cell fraction derived from highly enriched, mobilized CD133+ peripheral blood cells after their culture with Flt3/Flk2 ligand and interleukin-6 for 3 to 5 weeks. These cells lack markers of hematopoietic stem cells, endothelial cells, mesenchymal cells, dendritic cells, and stromal fibroblasts. However, all adherent cells expressed the adhesion molecules VE-cadherin, CD54, and CD44. They were also positive for CD164 and CD172a (signal regulatory protein-α) and for a stem cell antigen defined by the recently described antibody W7C5. Adherent cells can either spontaneously or upon stimulation with stem cell factor give rise to a transplantable, nonadherent CD133+CD34−stem cell subset. These cells do not generate in vitro hematopoietic colonies. However, their transplantation into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice induced substantially higher long-term multilineage engraftment compared with that of freshly isolated CD34+ cells, suggesting that these cells are highly enriched in SCID-repopulating cells. In addition to cells of the myeloid lineage, nonadherent CD34− cells were able to give rise to human cells with B-, T-, and natural killer–cell phenotype. Hence, these cells possess a distinct in vivo differentiation potential compared with that of CD34+ stem cells and may therefore provide an alternative to CD34+ progenitor cells for transplantation.

Hemangioblastoma Stromal Cells Show Committed Stem Cell Phenotype

2012 ◽  
Vol 39 (6) ◽  
pp. 821-827 ◽  
Author(s):  
Cassandra M. Welten ◽  
Emily C. Keats ◽  
Lee-Cyn Ang ◽  
Zia A. Khan
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Stem Cell ◽  
Stromal Cells ◽  
Vascular Endothelial Cells ◽  
Cell Types ◽  
Vascular Tumors ◽  
Cell Phenotype ◽  
Vascular Endothelial ◽  
Stem Cell Phenotype

Background:Hemangioblastomas are benign vascular tumors of the central nervous system that occur sporadically or in association with von Hippel-Lindau disease. These tumors are characteristically composed of a dense capillary network with intervening stromal/interstitial cells. To date, the histogenesis of hemangioblastoma remains unclear. We hypothesize that hemangioblastomas arise from a defective mesodermal stem cell, which gives rise to the atypical vasculature.Methods:To test our hypothesis, we have characterized the cellular composition of hemangioblastomas by immunophenotyping pluripotent and committed stem cells and vascular endothelial cells.Results:Our findings show that hemangioblastoma endothelial cells are positive for CD133, a stem and progenitor cell marker. Vascular endothelial cells also expressed nuclear Oct4. In addition to the endothelium, both CD133 and Oct4 were present in stromal and perivascular cells. Interestingly, neither the endothelium nor the stromal cells expressed Sox2 or Nanog suggesting a committed stem cell phenotype.Conclusions:From these findings, we believe that hemangioblastoma stromal cells are committed stem cells producing both vascular cell types. The findings also show an unusual CD133-positive endothelial phenotype in hemangioblastoma.

scholarly journals Transcriptome Response and Spatial Pattern of Gene Expression in the Primate Subventricular Zone Neurogenic Niche After Cerebral Ischemia

2020 ◽  
Vol 8 ◽  
Author(s):  
Monika C. Chongtham ◽  
Haifang Wang ◽  
Christina Thaller ◽  
Nai-Hua Hsiao ◽  
Ivan H. Vachkov ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cerebral Ischemia ◽  
Subventricular Zone ◽  
Cell Biology ◽  
Global Cerebral Ischemia ◽  
Mammalian Brain ◽  
Gene Markers ◽  
Ependymal Layer ◽  
Upregulated Genes

The main stem cell niche for neurogenesis in the adult mammalian brain is the subventricular zone (SVZ) that extends along the cerebral lateral ventricles. We aimed at characterizing the initial molecular responses of the macaque monkey SVZ to transient, global cerebral ischemia. We microdissected tissue lining the anterior horn of the lateral ventricle (SVZa) from 7 day post-ischemic and sham-operated monkeys. Transcriptomics shows that in ischemic SVZa, 541 genes were upregulated and 488 genes were down-regulated. The transcription data encompassing the upregulated genes revealed a profile typical for quiescent stem cells and astrocytes. In the primate brain the SVZ is morphologically subdivided in distinct and separate ependymal and subependymal regions. The subependymal contains predominantly neural stem cells (NSC) and differentiated progenitors. To determine in which SVZa region ischemia had evoked transcriptional upregulation, sections through control and ischemic SVZa were analyzed by high-throughput in situ hybridization for a total of 150 upregulated genes shown in the www.monkey-niche.org image database. The majority of the differentially expressed genes mapped to the subependymal layers on the striatal or callosal aspect of the SVZa. Moreover, a substantial number of upregulated genes was expressed in the ependymal layer, implicating a contribution of the ependyma to stem cell biology. The transcriptome analysis yielded several novel gene markers for primate SVZa including the apelin receptor that is strongly expressed in the primate SVZa niche upon ischemic insult.

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