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‣ Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size

Stier, Sebastian; Ko, Yon; Forkert, Randolf; Lutz, Christoph; Neuhaus, Thomas; Grünewald, Elisabeth; Cheng, Tao; Dombkowski, David; Calvi, Laura M.; Rittling, Susan R.; Scadden, David T.
Fonte: The Rockefeller University Press Publicador: The Rockefeller University Press
Tipo: Artigo de Revista Científica
Publicado em 06/06/2005 Português
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Stem cells reside in a specialized niche that regulates their abundance and fate. Components of the niche have generally been defined in terms of cells and signaling pathways. We define a role for a matrix glycoprotein, osteopontin (OPN), as a constraining factor on hematopoietic stem cells within the bone marrow microenvironment. Osteoblasts that participate in the niche produce varying amounts of OPN in response to stimulation. Using studies that combine OPN-deficient mice and exogenous OPN, we demonstrate that OPN modifies primitive hematopoietic cell number and function in a stem cell–nonautonomous manner. The OPN-null microenvironment was sufficient to increase the number of stem cells associated with increased stromal Jagged1 and Angiopoietin-1 expression and reduced primitive hematopoietic cell apoptosis. The activation of the stem cell microenvironment with parathyroid hormone induced a superphysiologic increase in stem cells in the absence of OPN. Therefore, OPN is a negative regulatory element of the stem cell niche that limits the size of the stem cell pool and may provide a mechanism for restricting excess stem cell expansion under conditions of niche stimulation.

‣ On the adaptation of endosteal stem cell niche function in response to stress

Jiang, Yi; Bonig, Halvard; Ulyanova, Tatiana; Chang, KaiHsin; Papayannopoulou, Thalia
Fonte: American Society of Hematology Publicador: American Society of Hematology
Tipo: Artigo de Revista Científica
Publicado em 29/10/2009 Português
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Although the influence of microenvironmental “niche” on the function of a variety of stem cells is undisputed, the details of hematopoietic stem cell/niche interactions at the cellular and molecular level have sparked a continuous debate. We studied the microanatomic partitioning of transplanted normal and α4 integrin-deficient Lin−kit+ cells in trabecular and compact bone before and after irradiation and present robust quantitative data on both. We found that (1) the microanatomic distribution of normal highly enriched progenitor cells is random in nonirradiated recipients based on area distribution analyses, (2) in contrast, in irradiated hosts normal cells distribute preferentially near the endosteum, (3) the overall cell seeding efficiency was higher in trabecular versus compact bone both before and after irradiation, and (4) α4 integrin-deficient cells not only lodge with reduced overall efficiency confirming previous data, but fail to preferentially partition themselves into endosteal regions in irradiated hosts, as normal cells do. A similar phenotype was observed with cells rendered Gi-protein signaling incompetent by pertussis toxin treatment, supporting an active stromal-derived factor 1 (SDF-1) gradient near endosteum after irradiation.

‣ An in vivo model to study and manipulate the hematopoietic stem cell niche

Song, Junhui; Kiel, Mark J.; Wang, Zhou; Wang, Jingcheng; Taichman, Russell S.; Morrison, Sean J.; Krebsbach, Paul H.
Fonte: American Society of Hematology Publicador: American Society of Hematology
Tipo: Artigo de Revista Científica
Publicado em 01/04/2010 Português
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Because the microenvironment that supports hematopoietic stem cell (HSC) proliferation and differentiation is not fully understood, we adapted a heterotopic bone formation model as a new approach for studying the HSC microenvironment in vivo. Endogenous HSCs homed to tissue-engineered ossicles and individually sorted HSCs from ossicles were able to reconstitute lethally irradiated mice. To further explore this model as a system to study the stem cell niche, ossicles were established with or without anabolic parathyroid hormone (PTH) treatment during the 4-week course of bone development. Histology and micro–computed tomography showed higher bone area-to-total area ratios, thicker cortical bone and trabecular bone, significantly higher bone mineral density and bone volume fraction in PTH-treated groups than in controls. By an in vivo competitive long-term reconstitution assay, HSC frequency in the ossicle marrow was 3 times greater in PTH groups than in controls. When whole bone marrow cells were directly injected into the ossicles after lethal irradiation, the PTH-treated groups showed an enhanced reconstitution rate compared with controls. These findings suggest the residence of HSCs in heterotopic bone marrow and support the future use of this ossicle model in elucidating the composition and regulation of the HSC niche.

‣ The zebrafish flotte lotte mutant reveals that the local retinal environment promotes the differentiation of proliferating precursors emerging from their stem cell niche

Cerveny, Kara L.; Cavodeassi, Florencia; Turner, Katherine J.; de Jong-Curtain, Tanya A.; Heath, Joan K.; Wilson, Stephen W.
Fonte: Company of Biologists Publicador: Company of Biologists
Tipo: Artigo de Revista Científica
Publicado em 01/07/2010 Português
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It is currently unclear how intrinsic and extrinsic mechanisms cooperate to control the progression from self-renewing to neurogenic divisions in retinal precursor cells. Here, we use the zebrafish flotte lotte (flo) mutant, which carries a mutation in the elys (ahctf1) gene, to study the relationship between cell cycle progression and neuronal differentiation by investigating how proliferating progenitor cells transition towards differentiation in a retinal stem cell niche termed the ciliary marginal zone (CMZ). In zebrafish embryos without Elys, CMZ cells retain the capacity to proliferate but lose the ability to enter their final neurogenic divisions to differentiate as neurons. However, mosaic retinae composed of wild-type and flo cells show that despite inherent cell cycle defects, flo mutant cells progress from proliferation to differentiation when in the vicinity of wild-type retinal neurons. We propose that the differentiated retinal environment limits the proliferation of precursors emerging from the CMZ in a manner that explains the spatial organisation of cells in the CMZ and ensures that proliferative retinal progenitors are driven towards differentiation.

‣ Organ aging and susceptibility to cancer may be related to the geometry of the stem cell niche

Blagoev, Krastan B.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
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Telomere loss at each cell replication limits the proliferative capacity of normal cells, including adult stem cells. Entering replicative senescence protects dividing cells from neoplastic transformation, but also contributes to aging of the tissue. Recent experiments have shown that intestinal mouse stem cells divide symmetrically, at random make decisions to remain stem cells or to differentiate, and gradually lose telomeric DNA. A cell’s decision whether to differentiate or to remain a stem cell depends on the local cellular and chemical environment and thus tissue architecture is expected to play role in cell proliferation dynamics. To take into account the structure of the stem cell niche in determining its proliferative potential and susceptibility to cancer, a theoretical model is introduced and the niche proliferative potential is quantified for different architectures. The niche proliferative potential is quantitatively related to the proliferative potential of the individual stem cells for different structural classes of the stem cell niche. Stem cells at the periphery of a niche are under pressure to divide and to differentiate, as well as to maintain the stem cell niche boundary, and thus the geometry of the stem cell niche is expected to play a role in determining the stem cell division sequence and differentiation. Smaller surface-to-volume ratio is associated with higher susceptibility to cancer...

‣ Stem Cell Niche Structure as an Inherent Cause of Undulating Epithelial Morphologies

Ovadia, Jeremy; Nie, Qing
Fonte: The Biophysical Society Publicador: The Biophysical Society
Tipo: Artigo de Revista Científica
Publicado em 08/01/2013 Português
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726.3592%
The spatial organization of stem cells into a niche is a key factor for growth and continual tissue renewal during development, sustenance, and regeneration. Stratified epithelia serve as a great context to study the spatial aspects of the stem cell niche and cell lineages by organizing into layers of different cell types. Several types of stratified epithelia develop morphologies with advantageous, protruding structures where stem cells reside, such as rete pegs and palisades of Vogt. Here, multistage, spatial cell lineage models for epithelial stratification are used to study how the stem cell niche influences epithelial morphologies. When the stem cell niche forms along a rigid basal lamina, relatively regular morphologies are maintained. In contrast, stem cell niche formation along a free-moving basal lamina may prompt distorted epithelial morphologies with stem cells accumulating at the tips of fingerlike structures that form. The correspondence between our simulated morphologies and developmental stages of the human epidermis is also explored. Overall, our work provides an understanding of how stratified epithelia may attain distorted morphologies and sheds light on the importance of the spatial aspects of the stem cell niche.

‣ Adhesion in the stem cell niche: biological roles and regulation

Chen, Shuyi; Lewallen, Michelle; Xie, Ting
Fonte: Company of Biologists Publicador: Company of Biologists
Tipo: Artigo de Revista Científica
Publicado em 15/01/2013 Português
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726.43875%
Stem cell self-renewal is tightly controlled by the concerted action of stem cell-intrinsic factors and signals within the niche. Niche signals often function within a short range, allowing cells in the niche to self-renew while their daughters outside the niche differentiate. Thus, in order for stem cells to continuously self-renew, they are often anchored in the niche via adhesion molecules. In addition to niche anchoring, however, recent studies have revealed other important roles for adhesion molecules in the regulation of stem cell function, and it is clear that stem cell-niche adhesion is crucial for stem cell self-renewal and is dynamically regulated. Here, we highlight recent progress in understanding adhesion between stem cells and their niche and how this adhesion is regulated.

‣ AtMMS21, an SMC5/6 Complex Subunit, Is Involved in Stem Cell Niche Maintenance and DNA Damage Responses in Arabidopsis Roots1[C][W]

Xu, Panglian; Yuan, Dongke; Liu, Ming; Li, Chunxin; Liu, Yiyang; Zhang, Shengchun; Yao, Nan; Yang, Chengwei
Fonte: American Society of Plant Biologists Publicador: American Society of Plant Biologists
Tipo: Artigo de Revista Científica
Português
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AtMMS21 acts in double-strand break amelioration and stem cell niche maintenance during Arabidopsis root development.

‣ THE GERMLINE STEM CELL NICHE UNIT IN MAMMALIAN TESTES

Oatley, Jon M.; Brinster, Ralph L.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /04/2012 Português
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This review addresses current understanding of the germline stem cell niche unit in mammalian testes. Spermatogenesis is a classic model of tissue-specific stem cell function relying on self-renewal and differentiation of spermatogonial stem cells (SSCs). These fate decisions are influenced by a niche microenvironment composed of a growth factor milieu that is provided by several testis somatic support cell populations. Investigations over the last two decades have identified key determinants of the SSC niche including cytokines that regulate SSC functions and support cells providing these factors, adhesion molecules that influence SSC homing, and developmental heterogeneity of the niche during postnatal aging. Emerging evidence suggests that Sertoli cells are a key support cell population influencing the formation and function of niches by secreting soluble factors and possibly orchestrating contributions of other support cells. Investigations with mice have shown that niche influence on SSC proliferation differs during early postnatal development and adulthood. Moreover, there is mounting evidence of an age-related decline in niche function, which is likely influenced by systemic factors. Defining the attributes of stem cell niches is key to developing methods to utilize these cells for regenerative medicine. The SSC population and associated niche comprise a valuable model system for study that provides fundamental knowledge about the biology of tissue-specific stem cells and their capacity to sustain homeostasis of regenerating tissue lineages. While the stem cell is essential for maintenance of all self-renewing tissues and has received considerable attention...

‣ WOX5 Suppresses CYCLIN D Activity to Establish Quiescence at the Center of the Root Stem Cell Niche

Forzani, Celine; Aichinger, Ernst; Sornay, Emily; Willemsen, Viola; Laux, Thomas; Dewitte, Walter; Murray, James A.H.
Fonte: Cell Press Publicador: Cell Press
Tipo: Artigo de Revista Científica
Publicado em 18/08/2014 Português
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In Arabidopsis, stem cells maintain the provision of new cells for root growth. They surround a group of slowly dividing cells named the quiescent center (QC), and, together, they form the stem cell niche (SCN). The QC acts as the signaling center of the SCN, repressing differentiation of the surrounding stem cells [1] and providing a pool of cells able to replace damaged stem cells [2, 3]. Maintenance of the stem cells depends on the transcription factor WUSCHEL-RELATED HOMEOBOX 5 (WOX5), which is specifically expressed in the QC [4]. However, the molecular mechanisms by which WOX5 promotes stem cell fate and whether WOX5 regulates proliferation of the QC are unknown. Here, we reveal a new role for WOX5 in restraining cell division in the cells of the QC, thereby establishing quiescence. In contrast, WOX5 and CYCD3;3/CYCD1;1 both promote cell proliferation in the nascent columella. The additional QC divisions occurring in wox5 mutants are suppressed in mutant combinations with the D type cyclins CYCD3;3 and CYCD1;1. Moreover, ectopic expression of CYCD3;3 in the QC is sufficient to induce cell division in the QC. WOX5 thus suppresses QC divisions that are otherwise promoted by CYCD3;3 and CYCD1;1, in part by interacting with the CYCD3;3 promoter to repress CYCD3;3 expression in the QC. Therefore...

‣ Highly Upregulated Lhx2 in the Foxn1(^{−/−}) Nude Mouse Phenotype Reflects a Dysregulated and Expanded Epidermal Stem Cell Niche

Bohr, Stefan; Patel, Suraj J; Vasko, Radovan; Shen, Keyue; Huang, Guofeng; Yarmush, Martin Leon; Berthiaume, Francois
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
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Hair cycling is a prime example of stem cell dependent tissue regeneration and replenishment, and its regulatory mechanisms remain poorly understood. In the present study, we evaluated the effect of a blockage in terminal keratinocytic lineage differentiation in the Foxn1(^{−/−}) nude phenotype on the epithelial progeny. Most notably we found a constitutive upregulation of LIM homeobox protein 2 (Lhx2), a marker gene of epithelial stem cellness indispensible for hair cycle progression. However, histological evidence along with an erratic, acyclic rise of otherwise suppressed CyclinD1 levels along with several key markers of keratinocyte lineage differentiation indicate a frustrated expansion of epithelial stem cell niches in skin. In addition, CD49f/CD34/CD200–based profiling demonstrated highly significant shifts in subpopulations of epithelial progeny. Intriguingly this appeared to include the expansion of Oct4+ stem cells in dermal fractions of skin isolates in the Foxn1 knock-out opposed to wild type. Overall our findings indicate that the Foxn1(^{−/−}) phenotype has a strong impact on epithelial progeny and thus offers a promising model to study maintenance and regulation of stem cell niches within skin not feasible in other in vitro or in vivo models.

‣ Basolateral Junction Proteins Regulate Competition for the Follicle Stem Cell Niche in the Drosophila Ovary

Kronen, Maria R.; Schoenfelder, Kevin P.; Klein, Allon M.; Nystul, Todd G.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
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Epithelial stem cells are routinely lost or damaged during adult life and must therefore be replaced to maintain homeostasis. Recent studies indicate that stem cell replacement occurs through neutral competition in many types of epithelial tissues, but little is known about the factors that determine competitive outcome. The epithelial follicle stem cells (FSCs) in the Drosophila ovary are regularly lost and replaced during normal homeostasis, and we show that FSC replacement conforms to a model of neutral competition. In addition, we found that FSCs mutant for the basolateral junction genes, lethal giant larvae (lgl) or discs large (dlg), undergo a biased competition for niche occupancy characterized by increased invasion of neighboring FSCs and reduced loss. Interestingly, FSCs mutant for a third basolateral junction gene, scribble (scrib), do not exhibit biased competition, suggesting that Lgl and Dlg regulate niche competition through a Scrib-independent process. Lastly, we found that FSCs have a unique cell polarity characterized by broadly distributed adherens junctions and the lack of a mature apical domain. Collectively, these observations indicate that Lgl and Dlg promote the differentiation of FSC progeny to a state in which they are less prone to invade the neighboring niche. In addition...

‣ EphB/ephrin-B interaction mediates adult stem cell attachment spreading and migration: Implications for dental tissue repair

Arthur, A.; Shi, S.; Sun, T.; Bartold, P.; Koblar, S.; Gronthos, S.
Fonte: Alphamed Press Publicador: Alphamed Press
Tipo: Artigo de Revista Científica
Publicado em //2007 Português
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Human adult dental pulp stem cells (DPSCs) reside predominantly within the perivascular niche of dental pulp and are thought to originate from migrating neural crest cells during development. The Eph family of receptor tyrosine kinases and their ligands, the ephrin molecules, play an essential role in the migration of neural crest cells during development and stem cell niche maintenance. The present study examined the expression and function of the B-subclass Eph/ephrin molecules on DPSCs. Multiple receptors were primarily identified on DPSCs within the perivascular niche, whereas ephrin-B1 and ephrin-B3 were expressed by the surrounding pulp tissue. EphB/ephrin-B bidirectional signaling inhibited cell attachment and spreading, predominately via the mitogen-activated protein kinase (MAPK) pathway for forward signaling and phosphorylation of Src family tyrosine kinases via reverse ephrin-B signaling. DPSC migration was restricted through unidirectional ephrin-B1-activated EphB forward signaling, primarily signaling through the MAPK pathway. Furthermore, we observed that ephrin-B1 was downregulated in diseased adult teeth compared with paired uninjured controls. Collectively, these studies suggest that EphB/ephrin-B molecules play a role in restricting DPSC attachment and migration to maintain DPSCs within their stem cell niche under steady-state conditions. These results may have implications for dental pulp development and regeneration.; Agnieszka Stokowski...

‣ Critical reviews in oral biology & medicine: Mesenchymal stem cells derived from dental tissues vs. those from other sources: their biology and role in regenerative medicine

Huang, G.J.; Gronthos, S.; Shi, S.
Fonte: Inter Amer Assoc Dental Research Publicador: Inter Amer Assoc Dental Research
Tipo: Artigo de Revista Científica
Publicado em //2009 Português
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810.3308%
To date, 5 different human dental stem/progenitor cells have been isolated and characterized: dental pulp stem cells (DPSCs), stem cells from exfoliated deciduous teeth (SHED), periodontal ligament stem cells (PDLSCs), stem cells from apical papilla (SCAP), and dental follicle progenitor cells (DFPCs). These postnatal populations have mesenchymal-stem-cell-like (MSC) qualities, including the capacity for self-renewal and multilineage differentiation potential. MSCs derived from bone marrow (BMMSCs) are capable of giving rise to various lineages of cells, such as osteogenic, chondrogenic, adipogenic, myogenic, and neurogenic cells. The dental-tissue-derived stem cells are isolated from specialized tissue with potent capacities to differentiate into odontogenic cells. However, they also have the ability to give rise to other cell lineages similar to, but different in potency from, that of BMMSCs. This article will review the isolation and characterization of the properties of different dental MSC-like populations in comparison with those of other MSCs, such as BMMSCs. Important issues in stem cell biology, such as stem cell niche, homing, and immunoregulation, will also be discussed.; G.T.-J. Huang, S. Gronthos and S. Shi; Copyright © 2009 by International & American Associations for Dental Research

‣ Biomimetic three-dimensional microenvironment for controlling stem cell fate

Zhang, H.; Dai, S.; Bi, J.; Liu, K.K.
Fonte: The Royal Society Publishing Publicador: The Royal Society Publishing
Tipo: Artigo de Revista Científica
Publicado em //2011 Português
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796.9935%
Stem cell therapy is an emerging technique which is being translated into treatment of degenerated tissues. However, the success of translation relies on the stem cell lineage commitment in the degenerated regions of interest. This commitment is precisely controlled by the stem cell microenvironment. Engineering a biomimetic three-dimensional microenvironment enables a thorough understanding of the mechanisms of governing stem cell fate. We review the individual microenvironment components, including soluble factors, extracellular matrix, cell–cell interaction and mechanical stimulation. The perspectives in creating the biomimetic microenvironments are discussed with emerging techniques.; Hu Zhang, Sheng Dai, Jingxiu Bi and Kuo-Kang Liu

‣ Exploring the mesenchymal stem cell niche using high throughput screening

Ghaemi, S.; Harding, F.; Delalat, B.; Gronthos, S.; Voelcker, N.
Fonte: Elsevier Sci Ltd Publicador: Elsevier Sci Ltd
Tipo: Artigo de Revista Científica
Publicado em //2013 Português
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In the field of stem cell technology, future advancements rely on the effective isolation, scale-up and maintenance of specific stem cell populations and robust procedures for their directed differentiation. The stem cell microenvironment - or niche - encompasses signal inputs from stem cells, supporting cells and from the extracellular matrix. In this context, the contribution of physicochemical surface variables is being increasingly recognised. This paradigm can be exploited to exert control over cellular behaviour. However, the number of parameters at play, and their complex interactions, presents a formidable challenge in delineating how the decisions of cell fate are orchestrated within the niche. Additionally, in the case of mesenchymal stem cells (MSC), more than one type of stem cell niche has been identified. By employing high throughput screening (HTS) strategies, common and specific attributes of each MSC niche can be probed. Here, we explore biological, chemical and physical parameters that are known to influence MSC self-renewal and differentiation. We then review techniques and strategies that allow the HTS of surface properties for conditions that direct stem cell fate, using MSC as a case study. Finally, challenges in recapturing the niche...

‣ The dynamic stem cell microenvironment is orchestrated by microvesicle-mediated transfer of genetic information

Deregibus, Maria Chiara; Tetta, Ciro; Camussi, Giovanni
Fonte: Murcia : F. Hernández Publicador: Murcia : F. Hernández
Tipo: Artigo de Revista Científica Formato: application/pdf
Português
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It has been commonly supposed that adultstem cells co-localize with supporting cells withinspecific regions or specialized microenvironment in eachtissue/organ, called stem cell niche. This concept wasbased on the assumption that stem cells are intrinsicallyhierarchical in nature. However, recent data indicate thatstem cells may represent a continuum with reversiblealterations in phenotype taking place during the transitthrough cell cycle. Based on this dynamic interpretationit has been suggested that the so-called niche isrepresented by a single or only few cell types continuallyadjusting their phenotype and function to individualcircumstances. A critical component in the regulation ofthe continuum of stem cell phenotypes is themicroenvironment. In this context, microvesicles (MVs)account for the transfer of genetic information betweencells. Originally considered inert cellular debris, MVsare increasingly recognized to be important mediators ofcell-to-cell communication. MVs may transfer receptors,proteins, mRNA and microRNA to target cells viaspecific receptor-mediated interaction. In stem cellbiology the exchange of genetic information may bebidirectional from stromal to stem cells. In the context oftissue injury the MV-mediated transfer of geneticinformation may reprogram the phenotype of stem cellsto acquire features of the injured tissue cells. In addition...

‣ Vascular signalling mediated by ZWILLE potentiates WUSCHEL function during shoot meristem stem cell development in the Arabidopsis embryo

Tucker, M.; Hinze, A.; Tucker, E.; Takada, S.; Jurgens, G.; Laux, T.
Fonte: Company of Biologists Ltd Publicador: Company of Biologists Ltd
Tipo: Artigo de Revista Científica
Publicado em //2008 Português
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Stem cells are maintained in an undifferentiated state by signals from their microenvironment, the stem cell niche. Despite its central role for organogenesis throughout the plant's life, little is known about how niche development is regulated in the Arabidopsis embryo. Here we show that, in the absence of functional ZWILLE (ZLL), which is a member of the ARGONAUTE (AGO) family, stem cell-specific expression of the signal peptide gene CLAVATA3 (CLV3) is not maintained despite increased levels of the homeodomain transcription factor WUSCHEL (WUS), which is expressed in the organising centre (OC) of the niche and normally promotes stem cell identity. Tissue-specific expression indicates that ZLL acts to maintain the stem cells from the neighbouring vascular primordium, providing direct evidence for a non-cell-autonomous mechanism. Furthermore, mutant and marker gene analyses suggest that during shoot meristem formation, ZLL functions in a similar manner but in a sequential order with its close homologue AGO1, which mediates RNA interference. Thus, WUS-dependent OC signalling to the stem cells is promoted by AGO1 and subsequently maintained by a provascular ZLL-dependent signalling pathway.; Matthew R. Tucker, Annika Hinze, Elise J. Tucker...

‣ The galactocerebrosidase enzyme contributes to the maintenance of a functional hematopoietic stem cell niche

Visigalli, Ilaria; Ungari, Silvia; Martino, Sabata; Park, Hyejung; Cesani, Martina; Gentner, Bernhard; Sergi Sergi, Lucia; Orlacchio, Aldo; Naldini, Luigi; Biffi, Alessandra
Fonte: American Society of Hematology Publicador: American Society of Hematology
Tipo: Artigo de Revista Científica
Publicado em 16/09/2010 Português
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The balance between survival and death in many cell types is regulated by small changes in the intracellular content of bioactive sphingolipids. Enzymes that either produce or degrade these sphingolipids control this equilibrium. The findings here described indicate that the lysosomal galactocerebrosidase (GALC) enzyme, defective in globoid cell leukodystrophy, is involved in the maintenance of a functional hematopoietic stem/progenitor cell (HSPC) niche by contributing to the control of the intracellular content of key sphingolipids. Indeed, we show that both insufficient and supraphysiologic GALC activity—by inherited genetic deficiency or forced gene expression in patients' cells and in the disease model—induce alterations of the intracellular content of the bioactive GALC downstream products ceramide and sphingosine, and thus affect HSPC survival and function and the functionality of the stem cell niche. Therefore, GALC and, possibly, other enzymes for the maintenance of niche functionality and health tightly control the concentration of these sphingolipids within HSPCs.

‣ Genetic dissection of a stem cell niche: the case of the Drosophila ovary

Bolívar, Jorge; Pearson, John; López-Onieva, Lourdes; González-Reyes, Acaimo
Fonte: John Wiley & Sons Publicador: John Wiley & Sons
Tipo: Artículo Formato: 21457 bytes; application/pdf
Português
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11 páginas, 6 figuras, 2 tablas.-- El material suplementario referido en este artículo puede verse en www.interscience.wiley.com/jpages/1058-8388/suppmat; In this work, we demonstrate a powerful new tool for the manipulation of the stromal component of a well-established Drosophila stem cell niche. We have generated a bric-a-brac 1 (bab1)-Gal4 line that drives UAS expression in many somatic ovary cell types from early larval stages. Using this Gal4 line, we could effectively induce FLP/FRT-mediated recombination in the stromal cells of the ovarian germline stem cell niche. Mutant clones were observed in the developing ovary of larvae and pupae, including in somatic cell types that do not divide in the adult, such as the cap cells and the terminal filament cells. Exploiting the ability of bab1-Gal4 to generate large clones, we demonstrate that bab1-Gal4 is an effective tool for analyzing stem cell niche morphogenesis and cyst formation in the germarium. We have identified a novel requirement for engrailed in the correct organization of the terminal filaments. We also demonstrate an involvement for integrins in cyst formation and follicle cell encapsulation. Finally using bab1-Gal4 in conjunction with the Gal80 system, we show that while ectopic dpp expression from stromal cells is sufficient to induce hyperplastic stem cell growth...