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Self-renewal
Kinds of Self-renewal Terms modified by Self-renewal Selected AbstractsThe expression patterns of Pax7 in satellite cells during overload-induced rat adult skeletal muscle hypertrophyACTA PHYSIOLOGICA, Issue 4 2009M. Ishido Abstract Aim:, Activated satellite cells (SCs) have the ability to reacquire a quiescent, undifferentiated state. Pax7 plays a crucial role in allowing activated SCs to undergo self-renewal. Because the increase in the SC population is induced during overload-induced skeletal muscle hypertrophy, it is possible that Pax7-regulated SC self-renewal is involved in the modulation of the SC population during the functional overload of skeletal muscles. However, the characteristics of the expression patterns of Pax7 in SCs during the functional overload of adult skeletal muscles are poorly understood. Methods:, Using immunohistochemical approaches, we examined the temporal and spatial expression patterns of Pax7 expressed in SCs during the functional overloading of rat skeletal muscles. Results:, The time course of Pax7 expression in SCs was similar to that of the expression of the differentiation regulatory factor myogenin during the early stage of functional overload. However, the percentage of SCs that expressed Pax7 was markedly higher than that of the SCs that expressed myogenin. Coexpression of Pax7 and myogenin was not detected in SCs. In addition, the expression of cyclin-dependent kinase inhibitor p21, which regulates cell cycle arrest and differentiation, was not detected in Pax7-positive SCs. Conclusion:, These results suggest that Pax7-regulated self-renewal of SCs may be induced during the early stage of functional overload and may contribute to modulating the SC population in hypertrophied muscles. Furthermore, it was suggested that the numbers of SCs which underwent self-renewal may be higher than that of SCs which were provided as the additional myonuclei for hypertrophying myofibres. [source] Identification and characterization of nucleoplasmin 3 as a histone-binding protein in embryonic stem cellsDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 5 2008Natsuki Motoi Embryonic stem (ES) cells are thought to have unique chromatin structures responsible for their capacity for self-renewal and pluripotency. To examine this possibility, we sought nuclear proteins in mouse ES cells that specifically bind to histones using a pull-down assay with synthetic peptides of histone H3 and H4 tail domain as baits. Nuclear proteins preferentially bound to the latter. We identified 45 proteins associated with the histone H4 tail and grouped them into four categories: 10 chromatin remodeling proteins, five histone chaperones, two histone modification-related proteins, and 28 other proteins. mRNA expression levels of 20 proteins selected from these 45 proteins were compared between undifferentiated and retinoic acid (RA)-induced differentiated ES cells. All of the genes were similarly expressed in both states of ES cells, except nucleoplasmin 3 (NPM3) that was expressed at a higher level in the undifferentiated cells. NPM3 proteins were localized in the nucleoli and nuclei of the cells and expression was decreased during RA-induced differentiation. When transfected with NPM3 gene, ES cells significantly increased their proliferation compared with control cells. The present study strongly suggests that NPM3 is a chromatin remodeling protein responsible for the unique chromatin structure and replicative capacity of ES cells. [source] C-myc as a modulator of renal stem/progenitor cell populationDEVELOPMENTAL DYNAMICS, Issue 2 2009Martin Couillard Abstract The role of c - myc has been well-studied in gene regulation and oncogenesis but remains elusive in murine development from midgestation. We determined c - myc function during kidney development, organogenesis, and homeostasis by conditional loss of c - myc induced at two distinct phases of nephrogenesis, embryonic day (e) 11.5 and e17.5. Deletion of c - myc in early metanephric mesenchyme (e11.5) led to renal hypoplasia from e15.5 to e17.5 that was sustained until adulthood (range, 20,25%) and, hence, reproduced the human pathologic condition of renal hypoplasia. This phenotype resulted from depletion of c - myc,positive cells in cap mesenchyme, causing a ,35% marked decrease of Six2- and Cited1-stem/progenitor population and of proliferation that likely impaired self-renewal. By contrast, c - myc loss from e17.5 onward had no impact on late renal differentiation/maturation and/or homeostasis, providing evidence that c - myc is dispensable during these phases. This study identified c - myc as a modulator of renal organogenesis through regulation of stem/progenitor cell population. Developmental Dynamics 238:405,414, 2009. © 2009 Wiley-Liss, Inc. [source] gfap and nestin reporter lines reveal characteristics of neural progenitors in the adult zebrafish brainDEVELOPMENTAL DYNAMICS, Issue 2 2009Chen Sok Lam Abstract Adult neurogenesis arises from niches that harbor neural stem cells (NSC). Although holding great promise for regenerative medicine, the identity of NSC remains elusive. In mammals, a key attribute of NSC is the expression of the filamentous proteins glial fibrillary acidic protein (GFAP) and NESTIN. To assess whether these two markers are relevant in the fish model, two transgenic zebrafish lines for gfap and nestin were generated. Analysis of adult brains showed that the fusion GFAP,green fluorescent protein closely mimics endogenous GFAP, while the nestin transgene recapitulates nestin at the ventricular zones. Cells expressing the two reporters display radial glial morphology, colocalize with the NSC marker Sox2, undergo proliferation, and are capable of self-renewal within the matrix of distinct thickness in the telencephalon. Together, these two transgenic lines reveal a conserved feature of putative NSC in the adult zebrafish brain and provide a means for the identification and manipulation of these cells in vivo. Developmental Dynamics 238:475,486, 2009. © 2009 Wiley-Liss, Inc. [source] Analysis of human muscle stem cells reveals a differentiation-resistant progenitor cell population expressing Pax7 capable of self-renewalDEVELOPMENTAL DYNAMICS, Issue 1 2009Bradley Pawlikowski Abstract Studies using mouse models have established a critical role for resident satellite stem cells in skeletal muscle development and regeneration, but little is known about this paradigm in human muscle. Here, using human muscle stem cells, we address their lineage progression, differentiation, migration, and self-renewal. Isolated human satellite cells expressed ,7-integrin and other definitive muscle markers, were highly motile on laminin substrates and could undergo efficient myotube differentiation and myofibrillogenesis. However, only a subpopulation of the myoblasts expressed Pax7 and displayed a variable lineage progression as measured by desmin and MyoD expression. Analysis identified a differentiation-resistant progenitor cell population that was Pax7+/desmin, and capable of self-renewal. This study extends our understanding of the role of Pax7 in regulating human satellite stem cell differentiation and self-renewal. Developmental Dynamics 238:138,149, 2009. © 2008 Wiley-Liss, Inc. [source] Muscle stem cells and model systems for their investigationDEVELOPMENTAL DYNAMICS, Issue 12 2007Nicolas Figeac Abstract Stem cells are characterized by their clonal ability both to generate differentiated progeny and to undergo self-renewal. Studies of adult mammalian organs have revealed stem cells in practically every tissue. In the adult skeletal muscle, satellite cells are the primary muscle stem cells, responsible for postnatal muscle growth, hypertrophy, and regeneration. In the past decade, several molecular markers have been found that identify satellite cells in quiescent and activated states. However, despite their prime importance, surprisingly little is known about the biology of satellite cells, as their analysis was for a long time hampered by a lack of genetically amenable experimental models where their properties can be dissected. Here, we review how the embryonic origin of satellite cells was discovered using chick and mouse model systems and discuss how cells from other sources can contribute to muscle regeneration. We present evidence for evolutionarily conserved properties of muscle stem cells and their identification in lower vertebrates and in the fruit fly. In Drosophila, muscle stem cells called adult muscle precursors (AMP) can be identified in embryos and in larvae by persistent expression of a myogenic basic helix,loop,helix factor Twist. AMP cells play a crucial role in the Drosophila life cycle, allowing de novo formation and regeneration of adult musculature during metamorphosis. Based on the premise that AMPs represent satellite-like cells of the fruit fly, important insight into the biology of vertebrate muscle stem cells can be gained from genetic analysis in Drosophila. Developmental Dynamics 236:3332,3342, 2007. © 2007 Wiley-Liss, Inc. [source] Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansionEMBO MOLECULAR MEDICINE, Issue 6-7 2009Frédéric Varnat Abstract Human colon cancers often start as benign adenomas through loss of APC, leading to enhanced ,CATENIN (,CAT)/TCF function. These early lesions are efficiently managed but often progress to invasive carcinomas and incurable metastases through additional changes, the nature of which is unclear. We find that epithelial cells of human colon carcinomas (CCs) and their stem cells of all stages harbour an active HH-GLI pathway. Unexpectedly, they acquire a high HEDGEHOG-GLI (HH-GLI) signature coincident with the development of metastases. We show that the growth of CC xenografts, their recurrence and metastases require HH-GLI function, which induces a robust epithelial-to-mesenchymal transition (EMT). Moreover, using a novel tumour cell competition assay we show that the self-renewal of CC stem cells in vivo relies on HH-GLI activity. Our results indicate a key and essential role of the HH-GLI1 pathway in promoting CC growth, stem cell self-renewal and metastatic behavior in advanced cancers. Targeting HH-GLI1, directly or indirectly, is thus predicted to decrease tumour bulk and eradicate CC stem cells and metastases. [source] Isolation and characterization of neural precursor cells from the Sox1,GFP reporter mouseEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2005Perrine Barraud Abstract We have made use of a reporter mouse line in which enhanced green fluorescence protein (GFP) is inserted into the Sox1 locus. We show that the GFP reporter is coexpressed with the Sox1 protein as well as with other known markers for neural stem and progenitor cells, and can be used to identify and isolate these cells by fluorescence-activated cell sorting (FACS) from the developing or adult brain and from neurosphere cultures. All neurosphere-forming cells with the capacity for multipotency and self-renewal reside in the Sox1,GFP-expressing population. Thus, the Sox1,GFP reporter system is highly useful for identification, isolation and characterization of neural stem and progenitor cells, as well as for the validation of alternative means for isolating neural stem and progenitor cells. Further, transplantation experiments show that Sox1,GFP cells isolated from the foetal brain give rise to neurons and glia in vivo, and that many of the neurons display phenotypic characteristics appropriate for the developing brain region from which the Sox1,GFP precursors were derived. On the other hand, Sox1,GFP cells isolated from the adult subventricular zone or expanded neurosphere cultures gave rise almost exclusively to glial cells following transplantation. Thus, not all Sox1,GFP cells possess the same capacity for neuronal differentiation in vivo. [source] Platypus Pou5f1 reveals the first steps in the evolution of trophectoderm differentiation and pluripotency in mammalsEVOLUTION AND DEVELOPMENT, Issue 6 2008Hitoshi Niwa SUMMARY Uterine nourishment of embryos by the placenta is a key feature of mammals. Although a variety of placenta types exist, they are all derived from the trophectoderm (TE) cell layer of the developing embryo. Egg-laying mammals (platypus and echidnas) are distinguished by a very short intrauterine embryo development, in which a simple placenta forms from TE-like cells. The Pou5f1 gene encodes a class V POU family transcription factor Oct3/4. In mice, Oct3/4 together with the highly conserved caudal -related homeobox transcription factor Cdx2, determines TE fate in pre-implantation development. In contrast to Cdx2, Pou5f1 has only been identified in eutherian mammals and marsupials, whereas, in other vertebrates, pou2 is considered to be the Pou5f1 ortholog. Here, we show that platypus and opossum genomes contain a Pou5f1 and pou2 homolog, pou2-related, indicating that these two genes are paralogues and arose by gene duplication in early mammalian evolution. In a complementation assay, we found that platypus or human Pou5f1, but not opossum or zebrafish pou2, restores self-renewal in Pou5f1 -null mouse ES cells, showing that platypus possess a fully functional Pou5f1 gene. Interestingly, we discovered that parts of one of the conserved regions (CR4) is missing from the platypus Pou5f1 promoter, suggesting that the autoregulation and reciprocal inhibition between Pou5f1 and Cdx2 evolved after the divergence of monotremes and may be linked to the development of more elaborate placental types in marsupial and eutherian mammals. [source] NANOG maintains self-renewal of primate ES cells in the absence of a feeder layerGENES TO CELLS, Issue 9 2006Shin-ya Yasuda Nanog is a homeodomain transcription factor that is expressed specifically in undifferentiated embryonic stem (ES) cells and has been shown to be essential in the maintenance of pluripotency in mouse ES cells. To examine the function of NANOG in primate ES cells, we generated transgenic monkey ES cell lines expressing three- to seven-fold higher levels of NANOG protein compared to wild-type ES cells. These NANOG over-expressing cell lines retained their undifferentiated state in the absence of a feeder layer, as shown by expression of undifferentiated ES cell markers such as alkaline phosphatase (ALP) and OCT-4. We also demonstrated that in vitro differentiation of transgenic cell lines was mostly restricted to the ectodermal lineage, as examined by reverse transcriptase-polymerase chain reaction (RT-PCR). Knockdown experiments using NANOG small interfering (si) RNA resulted in induction of differentiation markers such as AFP, GATA4 and GATA6 for the endoderm and CDX2 for the trophectoderm. These results suggest that NANOG plays a crucial role in maintaining the pluripotent state of primate ES cells. [source] New mechanism of transforming growth factor-, signaling in hepatoma: Dramatic up-regulation of tumor initiating cells and epidermal growth factor receptor expressionHEPATOLOGY RESEARCH, Issue 5 2009Takeshi Nishimura Aim:, Transforming growth factor-, (TGF-,) has dual activity in tumor cells. We studied the effect of TGF-, on tumor-initiating cells (TICs), which are similar in self-renewal and differentiation features to normal adult stem cells. Methods:, We used side population (SP) cells that exclude DNA binding dye Hoechst 33342 to obtain TICs, studied the differences in the kinetics of the SP cell response to TGF-, treatment between hepatic tumor cell lines, and performed gene analysis. Results:, SP cells from all cell lines have higher proliferative ability compared to non-SP cells and they are drug resistant. TGF-, treatment increased the percentage of SP cells (%SP) and the survival rate; chemotherapeutic drug resistance developed only in K-251 SP cells. Gene analysis showed that TGF-, up-regulated epidermal growth factor receptor (EGFR) only in K-251 cells. There were no EGFR mutations in K-251, which had been reported in lung cancer. Knockdown of Smad4 using the small-interfering RNA technique in K-251 cells inhibited EGFR overexpression and significantly decreased the %SP. In contrast, the JNK inhibitor had little effect on EGFR expression or the %SP. Conclusion:, TGF-, treatment of K-251 cells causes tumor progression and the anti-cancer drug resistant phenotype by increasing SP. [source] Promoting organizational learning and self-renewal in Taiwanese companies: The role of HRMHUMAN RESOURCE MANAGEMENT, Issue 3 2003Bih-Shiaw Jaw This study identifies key characteristics of human resource management (HRM) practices that contribute to promoting positive learning attitudes and creating a self-renewal organizational climate. We use a behavioral perspective to develop a framework to show the relationships among learning-oriented HRM, positive learning attitudes, and a self-renewal organizational climate. Structural equation analysis is applied to empirically test the relationships and the path model suggests that a learning-oriented HRM plays an important role in either directly creating a self-renewal organizational climate or indirectly facilitating positive learning attitudes that foster organizational self-renewal. © 2004 Wiley Periodicals, Inc. [source] Integrin signaling through FAK in the regulation of mammary stem cells and breast cancerIUBMB LIFE, Issue 4 2010Jun-Lin Guan Abstract Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase identified as a key mediator of intracellular signaling by integrins, a major family of cell surface receptors for extracellular matrix, in the regulation of different cellular functions in a variety of cells. Upon activation by integrins through disruption of an autoinhibitory mechanism, FAK undergoes autophosphorylation and forms a complex with Src and other cellular proteins to trigger downstream signaling through its kinase activity or scaffolding function. A number of integrins are identified as surface markers for mammary stem cells (MaSCs), and both integrins and FAK are found to play crucial roles in the maintenance of MaSCs in studies using mouse models, suggesting that integrin signaling through FAK may serve as a functional marker for MaSCs. Consistent with previous studies linking increased expression and activation of FAK to human breast cancer, these findings suggest a novel cellular mechanism of FAK promotion of mammary tumorigenesis by maintaining the pools of MaSCs as targets of oncogenic transformation. Furthermore, FAK inactivation in mouse models of breast cancer also reduced the pool of mammary cancer stem cells (MaCSCs), decreased their self-renewal in vitro, and compromised their tumorigenicity and maintenance in vivo, suggesting a potential role of integrin signaling through FAK in breast cancer growth and progression through its functions in MaCSCs. This review discusses these recent advances and future studies into the mechanism of integrin signaling through FAK in breast cancer through regulation of MaCSCs that may lead to development of novel therapies for this deadly disease. © 2010 IUBMB IUBMB Life, 62(4): 268,276, 2010 [source] Melanoma stem cells: targets for successful therapy?JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, Issue 7 2008Roland Houben Summary Increasing evidence suggests that cancer is a disease in which the persistence of the tumor relies on a small population of tumor-initiating cells, the so called tumor stem cells (TSC). Only these cells are capable of self-renewal and thereby possess the ability for unlimited proliferation. One reason for the inability of conventional tumor treatments to achieve long-term cures seems to be that TSC are resistant to many therapeutic approaches. A detailed characterization of TSC should have a substantial impact on the optimization of therapeutic protocols. While TSC in hematopoietic malignancies have been most intensively studied, subpopulations with stem cell properties have been identified in some solid tumors including breast carcinomas, gliomas and melanomas. In case of melanoma, however, a clear-cut molecular characterization is still pending. Considerable research is needed to establish standard procedures for the isolation of melanoma stem cells to facilitate determining how these cells, critical for tumor persistence and progression, can be effectively eliminated. A pressing question is if melanoma stem cells are in principle sensitive to immunotherapy. [source] Wnt signaling in hematopoiesis: Crucial factors for self-renewal, proliferation, and cell fate decisionsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 5 2010Frank J.T. Staal Abstract A large number of studies from many different laboratories have implicated the Wnt signaling pathway in regulation of hematopoiesis. However, different inducible gain- and loss-of-function approaches yielded controversial and some times contradictory results. In this prospect we will review the current ideas on Wnt signaling in hematopoiesis and early lymphopoiesis. Reviewing this large body of knowledge let us to hypothesize that different levels of activation of the pathway, dosages of Wnt signaling required and the interference by other signals in the context of Wnt activation collectively explain these controversies. Besides differences in dosage, differences in biological function of Wnt proteins in various blood cell types also is a major factor to take into account. Our own work has shown that while in the thymus Wnt signaling provides cytokine-like, proliferative stimuli to developing thymocytes, canonical Wnt signaling in HSC regulates cell fate decisions, in particular self-renewal versus differentiation. J. Cell. Biochem. 109: 844,849, 2010. © 2010 Wiley-Liss, Inc. [source] Transplantation of human embryonic stem cell-derived endothelial cells for vascular diseasesJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2009Zongjin Li Abstract Using endothelial cells for therapeutic angiogenesis/vasculogenesis of ischemia diseases has led to exploring human embryonic stem cells (hESCs) as a potentially unlimited source for endothelial progenitor cells. With their capacity for self-renewal and pluripotency, hESCs and their derived endothelial cells (hESC-ECs) may be more advantageous than other endothelial cells obtained from diseased populations. However, hESC-ECs' poor differentiation efficiency and poorly characterized in vivo function after transplantation present significant challenges for their future clinical application. This review will focus on the differentiation pathways of hESCs and their therapeutic potential for vascular diseases, as well as the monitoring of transplanted cells' fate via molecular imaging. Finally, cell enhancement strategies to improve the engraftment efficiency of hESC-ECs will be discussed. J. Cell. Biochem. 106: 194,199, 2009. © 2008 Wiley-Liss, Inc. [source] Identification of genes regulated by nanog which is involved in ES cells pluripotency and early differentiationJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2008Na Liu Abstract Nanog plays an important role in embryonic stem (ES) cells pluripotency and self-renewal, yet the precise mechanism through which Nanog accomplishes this important function remains unclear. To understand comprehensive molecular mechanism by which Nanog mediates, we identified genome-wide molecular changes upon silencing Nanog in ES cells by using microarray technology. In order to downregulate Nanog expression efficiently, four siRNAs were designed on the basis of the conserved Nanog sequence and their effects on the Nanog expression were tested. Among these four siRNAs, Nanog-siRNA-P1 was found to be most effective. Once Nanog was downregulated, ES cells underwent differentiation by showing morphological change and decreased proliferation rate. Microarray analysis was then used to identify the altered gene expression after Nanog was silenced. A series of differentially expressed genes due to reduced expression of Nanog was identified as Nanog-related genes. These genes identified here could provide insights into the roles of Nanog in ES cells self-renewal and early differentiation. J. Cell. Biochem. 104: 2348,2362, 2008. © 2008 Wiley-Liss, Inc. [source] ,-Catenin signaling in biological control and cancerJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2007Nancy Gavert Abstract A coordinated integration of cell,cell adhesion and the control of gene expression is essential for the development of multicellular, differentiated organisms. ,-Catenin fulfils important regulatory functions in both cell,cell adhesion by linking cadherin adhesion receptors to the cytoskeleton, and also as a key element in the Wnt signaling pathway where it acts as cotranscriptional activator of target genes in the cell nucleus. Wnt signaling is involved in numerous aspects of embryonic development and in the control of tissue self-renewal in a variety of adult tissues. Hyperactivation of Wnt signaling, mostly by affecting ,-catenin functions, is a hallmark of colon cancer and of many other human cancers. In this prospect, we discuss studies pointing to the molecular mechanisms that govern the integration between cell,cell adhesion and gene expression, as reflected in the switches between these two functions of ,-catenin in colon cancer cells. J. Cell. Biochem. 102: 820,828, 2007. © 2007 Wiley-Liss, Inc. [source] Building a consensus regarding the nature and origin of mesenchymal stem cellsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue S38 2002Donald G. PhinneyArticle first published online: 23 APR 200 Abstract Mesenchymal stem cells (MSCs) are believed to be the common precursors to differentiated cell lineages found in bone and bone marrow, including adipocytes, chondrocytes, osteoblasts, and hematopoiesis-supporting stroma. Apart from this fact, most aspects of MSC biology, including their ontogeny, anatomical location in marrow, and in vivo functions remain vague. Attempts to clarify these issues have produced confounding results, principally due to the fact that many researchers employ different methods to culture MSCs, assess their differentiation potential, and evaluate their capacity for self-renewal. Accordingly, the current status of the field appears fragmentary with no clear consensus on how to define the cells. In describing past and present contributions to the field of MSC research, I will demonstrate that the apparent incongruity of the literature is misleading, and that an unbiased interpretation reveals a fairly cohesive picture of MSC biology. J. Cell. Biochem. Suppl. 38: 7,12, 2002. © 2002 Wiley-Liss, Inc. [source] Glutamate is a determinant of cellular proliferation through modulation of nuclear factor E2 p45-related factor-2 expression in osteoblastic MC3T3-E1 cells,JOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2007Kyosuke Uno Activation of particular glutamate (Glu) receptors is shown to promote cellular differentiation toward maturation during osteoblastogenesis. In the present study, we have evaluated the possible modulation by Glu of cellular proliferation in osteoblastic cells endowed to proliferate for self-renewal and to differentiate toward matured osteoblasts. Exposure to Glu significantly suppressed the proliferation activity at a concentration over 500 µM without inducing cell death in osteoblastic MC3T3-E1 cells before differentiation. The suppression by Glu occurred in a manner sensitive to the prevention by either cystine or reduced glutathione. Expression of mRNA was for the first time shown with the cystine/Glu antiporter composed of xCT and 4F2hc subunits in these undifferentiated osteoblastic cells. A significant decrease was seen in intracellular total glutathione levels in undifferentiated MC3T3-E1 cells cultured with Glu, indeed, whereas the cellular proliferation activity was drastically decreased by the addition of the glutathione depleter cyclohexene-1-one and the glutathione biosynthesis inhibitor L -buthionine-[S,R]-sulfoximine, respectively. Exposure to Glu led to a significant increase in mRNA expression of nuclear factor E2 p45-related factor 2 (Nrf2) together with the generation of reactive oxygen species, while a significant decrease was seen in the proliferation activity in MC3T3-E1 cells with stable overexpression of Nrf2. These results suggest that Glu could suppress the cellular proliferation toward self-renewal through a mechanism associated with the upregulation of Nrf2 expression in association with the depletion of intracellular glutathione after promoting the retrograde operation of the cystine/Glu antiporter in undifferentiated MC3T3-E1 cells. J. Cell. Physiol. 213: 105,114, 2007. © 2007 Wiley-Liss, Inc. [source] Mesenchymal stem cells in tissue engineeringJOURNAL OF CHEMICAL TECHNOLOGY & BIOTECHNOLOGY, Issue 4 2008Pankaj Godara Abstract Mesenchymal stem cells (MSC) offer great promise in therapies aimed at repairing, replacing or regenerating damaged or diseased tissues and organs. This potential is due to their capacity for self-renewal, ability to differentiate down a range of lineages, and potential in autologous therapies, free from major ethical concerns. This review examines the issues around the use of MSC in tissue engineering (TE) applications. Key issues facing widespread MSC therapeutic use include both the scarcity in adult tissues and the current lack of a simple unambiguous identifying marker. These major challenges facing the isolation, characterization and expansion of MSC to therapeutically significant numbers currently limit their usefulness as ,off the shelf' therapies. Balanced against this, recent evidence suggests that MSC have a much wider tissue distribution and greater plasticity than originally envisaged. Although therapeutic applications of MSC initially focused on mesenchymal lineages such as cartilage and bone, this is now broadening to include organs such as the heart and skin. Ultimately, the clinical utility of such MSC-based therapies will depend on their performance and cost. Copyright © 2008 Society of Chemical Industry [source] p16INK4a -mediated suppression of telomerase in normal and malignant human breast cellsAGING CELL, Issue 5 2010Alexey V. Bazarov Summary The cyclin-dependent kinase inhibitor p16INK4a (CDKN2A) is an important tumor suppressor gene frequently inactivated in human tumors. p16 suppresses the development of cancer by triggering an irreversible arrest of cell proliferation termed cellular senescence. Here, we describe another anti-oncogenic function of p16 in addition to its ability to halt cell cycle progression. We show that transient expression of p16 stably represses the hTERT gene, encoding the catalytic subunit of telomerase, in both normal and malignant breast epithelial cells. Short-term p16 expression increases the amount of histone H3 trimethylated on lysine 27 (H3K27) bound to the hTERT promoter, resulting in transcriptional silencing, likely mediated by polycomb complexes. Our results indicate that transient p16 exposure may prevent malignant progression in dividing cells by irreversible repression of genes, such as hTERT, whose activity is necessary for extensive self-renewal. [source] Tendon-derived stem/progenitor cell aging: defective self-renewal and altered fateAGING CELL, Issue 5 2010Zuping Zhou Summary Aging is a major risk factor for tendon injury and impaired tendon healing, but the basis for these relationships remains poorly understood. Here we show that rat tendon-derived stem/progenitor cells (TSPCs) differ in both self-renewal and differentiation capability with age. The frequency of TSPCs in tendon tissues of aged animals is markedly reduced based on colony formation assays. Proliferation rate is decreased, cell cycle progression is delayed and cell fate patterns are also altered in aged TSPCs. In particular, expression of tendon lineage marker genes is reduced while adipocytic differentiation increased. Cited2, a multi-stimuli responsive transactivator involved in cell growth and senescence, is also downregulated in aged TSPCs while CD44, a matrix assembling and organizing protein implicated in tendon healing, is upregulated, suggesting that these genes participate in the control of TSPC function. [source] Hot topics in stem cells and self-renewal: 2010AGING CELL, Issue 4 2010Norman E. Sharpless Summary In many tissues, mammalian aging is associated with a decline in the replicative and functional capacity of somatic stem cells and other self-renewing compartments. Understanding the basis of this decline is a major goal of aging research. In particular, therapeutic approaches to ameliorate or reverse the age-associated loss of stem function could be of use in clinical geriatrics. Such approaches include attempts to protect stem cells from age-promoting damage, to ,rejuvenate' stem cells through the use of pharmacologic agents that mitigate aging-induced alterations in signaling, and to replace lost stem cells through regenerative medicine approaches. Some headway has been made in each of these arenas over the last 18 months including advances in the production of donor-specific totipotent stem cells through induced pluripotency (iPS), gains in our understanding of how tumor suppressor signaling is controlled in self-renewing compartments to regulate aging, and further demonstration of extracellular ,milieu' factors that perturb stem cell function with age. This period has also been marked by the recent award of the Nobel Prize in Physiology or Medicine for elucidation of telomeres and telomerase, a topic of critical importance to stem cell aging. [source] Possible promotion of neuronal differentiation in fetal rat brain neural progenitor cells after sustained exposure to static magnetismJOURNAL OF NEUROSCIENCE RESEARCH, Issue 11 2009Noritaka Nakamichi Abstract We have previously shown significant potentiation of Ca2+ influx mediated by N-methyl- D -aspartate receptors, along with decreased microtubules-associated protein-2 (MAP2) expression, in hippocampal neurons cultured under static magnetism without cell death. In this study, we investigated the effects of static magnetism on the functionality of neural progenitor cells endowed to proliferate for self-replication and differentiate into neuronal, astroglial, and oligodendroglial lineages. Neural progenitor cells were isolated from embryonic rat neocortex and hippocampus, followed by culture under static magnetism at 100 mT and subsequent determination of the number of cells immunoreactive for a marker protein of particular progeny lineages. Static magnetism not only significantly decreased proliferation of neural progenitor cells without affecting cell viability, but also promoted differentiation into cells immunoreactive for MAP2 with a concomitant decrease in that for an astroglial marker, irrespective of the presence of differentiation inducers. In neural progenitors cultured under static magnetism, a significant increase was seen in mRNA expression of several activator-type proneural genes, such as Mash1, Math1, and Math3, together with decreased mRNA expression of the repressor type Hes5. These results suggest that sustained static magnetism could suppress proliferation for self-renewal and facilitate differentiation into neurons through promoted expression of activator-type proneural genes by progenitor cells in fetal rat brain. © 2009 Wiley-Liss, Inc. [source] MRG15, a component of HAT and HDAC complexes, is essential for proliferation and differentiation of neural precursor cellsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 7 2009Meizhen Chen Abstract Neurogenesis during development depends on the coordinated regulation of self-renewal and differentiation of neural precursor cells (NPCs). Chromatin regulation is a key step in self-renewal activity and fate decision of NPCs. However, the molecular mechanism or mechanisms of this regulation is not fully understood. Here, we demonstrate for the first time that MRG15, a chromatin regulator, is important for proliferation and neural fate decision of NPCs. Neuroepithelia from Mrg15 -deficient embryonic brain are much thinner than those from control, and apoptotic cells increase in this region. We isolated NPCs from Mrg15 -deficient and wild-type embryonic whole brains and produced neurospheres to measure the self-renewal and differentiation abilities of these cells in vitro. Neurospheres culture from Mrg15 -deficient embryo grew less efficiently than those from wild type. Measurement of proliferation by means of BrdU (bromodeoxyuridine) incorporation revealed that Mrg15 -deficient NPCs have reduced proliferation ability and apoptotic cells do not increase during in vitro culture. The reduced proliferation of Mrg15 -deficient NPCs most likely accounts for the thinner neuroepithelia in Mrg15 -deficient embryonic brain. Moreover, we also demonstrate Mrg15 -deficient NPCs are defective in differentiation into neurons in vitro. Our results demonstrate that MRG15 has more than one function in neurogenesis and defines a novel role for this chromatin regulator that integrates proliferation and cell-fate determination in neurogenesis during development. © 2008 Wiley-Liss, Inc. [source] Kainic acid triggers oligodendrocyte precursor cell proliferation and neuronal differentiation from striatal neural stem cellsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 6 2007Carolina Redondo Abstract Glutamate is an excitatory amino acid that serves important functions in mammalian brain development through ,-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/ kainate receptor stimulation. Neural stem cells with self-renewal and multilineage potential are a useful tool to study the signals involved in the regulation of brain development. We have investigated the role played by AMPA/kainate receptors during the differentiation of neural stem cells derived from fetal rat striatum. The application of 1 and 10 ,M kainic acid increased significantly the phosphorylation of the cyclic AMP response element binding protein (CREB), raised bromodeoxyuridine incorporation in O4-positive oligodendrocyte precursors, and increased the number of O1-positive cells in the cultures. Increased CREB phosphorylation and proliferation were prevented by the AMPA receptor antagonist 4-4(4-aminophenyl)-1,2-dihydro-1-methyl-2-propylcarbamoyl-6,7-methylenedioxyphthalazine (SYM 2206) and by protein kinase A and protein kinase C inhibitors. Cultures treated with 100 ,M kainic acid showed decreased proliferation, a lower proportion of O1-positive cells, and apoptosis of O4-positive cells. None of these effects were prevented by SYM 2206, suggesting that kainate receptors take part in these events. We conclude that AMPA receptor stimulation by kainic acid promotes the proliferation of oligodendrocyte precursors derived from neural stem cells through a mechanism that requires the activation of CREB by protein kinase A and C. In the neurons derived from these cells, either AMPA or kainate receptor stimulation produces neuritic growth and larger cell bodies. © 2007 Wiley-Liss, Inc. [source] Pituitary adenylate cyclase-activating polypeptide regulates forebrain neural stem cells and neurogenesis in vitro and in vivoJOURNAL OF NEUROSCIENCE RESEARCH, Issue 6 2006Shigeki Ohta Abstract Recent studies suggest that adult neurogenesis can contribute significantly to recovery from brain damage. As a result, there is strong interest in the field in identifying potentially therapeutic factors capable of promoting increased expansion of endogenous neural stem cell (NSC) populations and increased neurogenesis. In the present study, we have investigated the effects of PACAP on the NSC populations of the embryonic and adult forebrain. Our results demonstrate that the PACAP receptor, PAC1-R, is expressed by both embryonic and adult NSCs. The activation of PACAP signaling in vitro enhanced NSC proliferation/survival through a protein kinase A (PKA)-independent mechanism. In contrast, PACAP promoted NSC self-renewal and neurogenesis through a mechanism dependent on PKA activation. Finally, we determined that the intracerebroventricular infusion of PACAP into the adult forebrain was sufficient to increase neurogenesis significantly in both the hippocampus and the subventricular zone. These results demonstrate PACAP is unique in that it is capable of promoting NSC proliferation/survival, self-renewal, and neurogenesis and, therefore, may be ideal for promoting the endogenous regeneration of damaged brain tissue. © 2006 Wiley-Liss, Inc. [source] Updates on stem cells and their applications in regenerative medicineJOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE, Issue 4 2008Stefan Bajada Abstract Stem cells have the capacity for self-renewal and capability of differentiation to various cell lineages. Thus, they represent an important building block for regenerative medicine and tissue engineering. These cells can be broadly classified into embryonic stem cells (ESCs) and non-embryonic or adult stem cells. ESCs have great potential but their use is still limited by several ethical and scientific considerations. The use of bone marrow-, umbilical cord-, adipose tissue-, skin- and amniotic fluid-derived mesenchymal stem cells might be an adequate alternative for translational practice. In particular, bone marrow-derived stem cells have been used successfully in the clinic for bone, cartilage, spinal cord, cardiac and bladder regeneration. Several preclinical experimental studies are under way for the application of stem cells in other conditions where current treatment options are inadequate. Stem cells can be used to improve healthcare by either augmenting the body's own regenerative potential or developing new therapies. This review is not meant to be exhaustive but gives a brief outlook on the past, present and the future of stem cell-based therapies in clinical practice. Copyright © 2008 John Wiley & Sons, Ltd. [source] Trafficking of Murine Hematopoietic Stem and Progenitor Cells in Health and Vascular DiseaseMICROCIRCULATION, Issue 6 2009CHRISTIAN SCHULZ ABSTRACT Hematopoietic stem cells (HSCs) possess the unique capacity for self-renewal and differentiation into various hematopoietic cell lineages. Here we summarize the processes that underlie their mobilization and directed migration from bone marrow into peripheral tissues and back to the bone marrow compartment. We specifically focus on the potential role of hematopoietic stem and progenitor cell (HSPC) migration in vascular diseases and review data from recent studies on mice. A better understanding of the mechanisms that guide HSPCs to vascular tissues will be critical for the development of novel therapeutic strategies to prevent or reverse cardiovascular diseases. [source] | |||||||||||||||||||||||||||||||||||||