GSC
Homeobox protein goosecoid
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Proper stem cell activity in tissues ensures the correct balance between proliferation and differentiation, thus allowing tissue homeostasis and repair. The [i]Drosophila[/i] ovary develops well-defined niches that contain on average 2-4 germline stem cells (GSCs), whose maintenance depends on systemic signals and local factors. A known player in the decline of tissue homeostasis is ageing, which correlates with the waning of resident stem cell populations. In [i]Drosophila[/i], ovaries from old females contain fewer GSCs than those from young flies. We isolated niche cells of aged ovaries, performed a transcriptomic analysis and identified [i]mastermind (mam)[/i] as a factor for [i]Drosophila[/i] ovarian niche functionality during ageing. We show that [i]mam[/i] is upregulated in aged niche cells and that we can induce premature GSC loss by overexpressing [i]mam[/i] in otherwise young niche cells. High [i]mam[/i] levels in niche cells induce reduced [i]Hedgehog[/i] amounts, a decrease in cadherin levels and a likely increase in reactive oxygen species, three scenarios known to provoke GSC loss. Mam is a canonical co-activator of the Notch pathway in many [i]Drosophila[/i] tissues. However, we present evidence to support a Notch-independent role for [i]mam[/i] in the ovarian germline niche.
MeSH Terms
- Aging
- Animals
- Cellular Senescence
- Drosophila Proteins
- Drosophila melanogaster
- Female
- Germ Cells
- Nuclear Proteins
- Ovary
- Receptors, Notch
- Signal Transduction
- Stem Cell Niche
- Transcriptome
Keywords
- DE-cadherin
- Drosophila oogenesis
- Hedgehog
- mastermind
- niche ageing
- reactive oxygen species
In many species, germline stem cells (GSCs) function to sustain gametogenesis throughout the life of organismal life span. As the source of gametes, the only cell type that can pass the genetic information to the next generation, GSCs play a fundamental role in maximizing the quantity of gametes that animals produce, while ensuring their highest quality. GSCs are maintained by the signals from their niches, and germ cells that exited the niche undergo differentiation to generate functional gametes. GSC population is sustained by a multitude of mechanisms such as asymmetric stem cell divisions and dedifferentiation of partially differentiated germ cells. In this review, we summarize the mechanisms that maintain GSC homeostasis to ensure life-long production of functional gametes.
MeSH Terms
- Animals
- Asymmetric Cell Division
- Cell Death
- Cell Dedifferentiation
- Genome
- Germ Cells
- Homeostasis
Keywords
- Aging
- Asymmetric stem cell division
- Dedifferentiation
- Germ cell immortality
- Germline stem cells
- Stem cell niche
Germline stem cells (GSCs) are critical for the generation of sperms and eggs in most animals including the fruit fly Drosophila melanogaster. It is well known that self-renewal and differentiation of female D. melanogaster GSCs are regulated by local niche signals. However, little is known about whether and how the GSC number is regulated by paracrine signals. In the last decade, however, multiple humoral factors, including insulin and ecdysteroids, have been recognized as key regulators of female D. melanogaster GSCs. This review paper summarizes the role of humoral factors in female D. melanogaster GSC proliferation and maintenance in response to internal and external conditions, such as nutrients, mating stimuli, and aging.
MeSH Terms
- Aging
- Animals
- Copulation
- Drosophila melanogaster
- Endocrine System
- Female
- Germ Cells
- Stem Cells
The stem cell niche, a regulatory microenvironment, houses and regulates stem cells for maintenance of tissues throughout an organism's lifespan. While it is known that stem cell function declines with age, the role of niche cells in this decline is not completely understood. [i]Drosophila[/i] exhibits a short lifespan with well-characterized ovarian germline stem cells (GSCs) and niche compartments, providing a good model with which to study stem cell biology. However, no inducible tools for temporal and spatial control of gene expression in the GSC-niche unit have been previously developed for aging studies. The current UAS-GAL4 systems are not ideal for aging studies because fly physiological aging may be affected by the temperature shifts used to manipulate GAL4 activity. Additionally, the actual needs of the aged niche may be masked by continuously driven gene expression. Since GeneSwitch GAL4 is conveniently activated by the steroid RU486 (mifepristone), we conducted an enhancer-trap screen to isolate GeneSwitch GAL4 lines with expression in the GSC-niche unit. We identified six lines with expression in germarial somatic cells, and two lines (#2305 and #2261) with expression in niche cap cells, the major constituent of the GSC niche. The use of lines #2305 or #2261 to overexpress [i]Drosophila[/i] insulin-like peptide 2, which maintains GSC lifespan, in aged niche cap cells significantly delayed age-dependent GSC loss. These results support the notion that insulin signaling is beneficial for maintaining aged stem cells and also validate the utility of our GeneSwitch GAL4 lines for studying stem cell aging.
MeSH Terms
- Animals
- Animals, Genetically Modified
- Crosses, Genetic
- Drosophila
- Drosophila Proteins
- Female
- Fluorescent Antibody Technique
- Gene Expression
- Gene Order
- Genetic Vectors
- Immunohistochemistry
- Male
- Oogonial Stem Cells
- Phenotype
- Quantitative Trait Loci
- Stem Cell Niche
- Transcription Factors
Keywords
- Dilp
- GS GAL4
- GSC
- P{Switch}
- aging
- inducible GAL4
- insulin
The properties and behaviour of stem cells rely heavily on signaling from the local microenvironment. At the apical end of Drosophila testis, self-renewal and differentiation of germline stem cells (GSCs) are tightly controlled by distinct somatic cells that comprise a specialised stem cell niche known as the hub. The hub maintains GSC homeostasis through adhesion and cell signaling. The Salvador/Warts/Hippo (SWH) pathway, which suppresses the transcriptional co-activator YAP/Yki via a kinase cascade, is a known regulator of stem cell proliferation and differentiation. Here, we show that increasing YAP/Yki expression in the germline, as well as reducing Warts levels, blocks the decrease of GSC numbers observed in aging flies, with only a small increase on their proliferation. An increased expression of YAP/Yki in the germline or a reduction in Warts levels also stymies an age-related reduction in hub cell number, suggesting a bilateral relationship between GSCs and the hub. Conversely, RNAi-based knockdown of YAP/Yki in the germline leads to a significant drop in hub cell number, further suggesting the existence of such a SC-to-niche relationship. All together, our data implicate the SWH pathway in Drosophila GSC maintenance and raise questions about its role in stem cell homeostasis in aging organisms.
MeSH Terms
- Adult Germline Stem Cells
- Aging
- Animals
- Animals, Genetically Modified
- Cell Cycle Proteins
- Drosophila Proteins
- Drosophila melanogaster
- Female
- Fertility
- Gene Knockdown Techniques
- Male
- Models, Animal
- Nuclear Proteins
- Protein Kinases
- RNA Interference
- Signal Transduction
- Stem Cell Niche
- Testis
- Trans-Activators
Tissue renewal becomes compromised with age. Although defects in niche and stem cell behavior have been implicated in promoting age-related decline, the causes of early-onset aging defects are unknown. We have identified an early consequence of aging in germline stem cells (GSCs) in the Drosophila testis. Aging disrupts the unique program of GSC cytokinesis, with GSCs failing to abscise from their daughter cells. Abscission failure significantly disrupts both self-renewal and the generation of differentiating germ cells. Extensive live imaging and genetic analyses show that abscission failure is due to inappropriate retention of F-actin at the intercellular bridges between GSC-daughter cells. Furthermore, F-actin is regulated by the Jak/STAT pathway-increasing or decreasing pathway activity can rescue or exacerbate the age-induced abscission defect, respectively. Even subtle decreases to STAT activity are sufficient to precociously age young GSCs and induce abscission failure. Thus, this work has identified the earliest age-related defect in GSCs and has revealed a unique role for an established niche signaling pathway in controlling stem cell cytokinesis and in regulating stem cell behavior with age.
MeSH Terms
- Aging
- Animals
- Cytokinesis
- Drosophila melanogaster
- Germ Cells
- Male
- Signal Transduction
- Stem Cells
- Testis
Keywords
- Jak/STAT
- abscission
- aging
- cytokinesis
- germline stem cells
Exhaustion of stem cells is a hallmark of aging. In the [i]Drosophila[/i] testis, dedifferentiated germline stem cells (GSCs) derived from spermatogonia increase during lifespan, leading to the model that dedifferentiation counteracts the decline of GSCs in aged males. To test this, we blocked dedifferentiation by mis-expressing the differentiation factor [i]bag of marbles[/i] ([i]bam[/i]) in spermatogonia while lineage-labeling these cells. Strikingly, blocking [i]bam[/i]-lineage dedifferentiation under normal conditions in virgin males has no impact on the GSC pool. However, in mated males or challenging conditions, inhibiting [i]bam[/i]-lineage dedifferentiation markedly reduces the number of GSCs and their ability to proliferate and differentiate. We find that [i]bam[/i]-lineage derived GSCs have significantly higher proliferation rates than sibling GSCs in the same testis. We determined that Jun N-terminal kinase (JNK) activity is autonomously required for [i]bam[/i]-lineage dedifferentiation. Overall, we show that dedifferentiation provides a mechanism to maintain the germline and ensure fertility under chronically stressful conditions.
MeSH Terms
- Aging
- Animals
- Cell Dedifferentiation
- Cell Lineage
- Drosophila melanogaster
- Enzyme Activation
- MAP Kinase Signaling System
- Male
- Models, Biological
- Spermatogenesis
- Spermatogonia
- Stem Cells
- Stress, Physiological
- Testis
Keywords
- D. melanogaster
- Jun N-terminal kinase
- aging
- dedifferentiation
- developmental biology
- differentiation
- germline stem cell
- regenerative medicine
- stem cells
- testis
It is well documented that older adults recruit additional brain regions compared to those recruited by younger adults while performing a wide variety of cognitive tasks. However, it is unclear how such age-related over-recruitment interacts with different types of cognitive control, and whether this over-recruitment is compensatory. To test this, we used a multitasking paradigm, which allowed us to examine age-related over-activation associated with three types of cognitive costs (i.e., global switch, local switch, compatibility-switch costs). We found age-related impairments in global switch cost (GSC), evidenced by slower response times for maintaining and coordinating two tasks vs. performing only one task. However, no age-related declines were observed in either local switch cost (LSC), a cognitive cost associated with switching between the two tasks while maintaining two task loads, or compatibility-switch cost (CSC), a cognitive cost associated with incompatible vs. compatible stimulus-response mappings across the two tasks. The fMRI analyses allowed for identification of distinct cognitive cost-sensitive brain regions associated with GSC and LSC. In fronto-parietal GSC and LSC regions, older adults' increased activations were associated with poorer performance (greater costs), whereas a reverse relationship was observed in younger adults. Older adults also recruited additional fronto-parietal brain regions outside the cognitive cost-sensitive areas, which was associated with poorer performance or no behavioral benefits. Our results suggest that older adults exhibit a combination of inefficient activation within cognitive cost-sensitive regions, specifically the GSC and LSC regions, and non-compensatory over-recruitment in age-sensitive regions. Age-related declines in global switching, compared to local switching, was observed earlier in old age at both neural and behavioral levels.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Brain
- Brain Mapping
- Cognition
- Executive Function
- Female
- Humans
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Reaction Time
- Young Adult
Keywords
- Aging
- Cognitive control
- Cognitive costs
- Task switching
- fMRI
Glioblastoma multiforme (GBM) is an aggressive incurable brain cancer. The cells that fuel the growth of tumours resemble neural stem cells found in the developing and adult mammalian forebrain. These are referred to as glioma stem cells (GSCs). Similar to neural stem cells, GSCs exhibit a variety of phenotypic states: dormant, quiescent, proliferative and differentiating. How environmental cues within the brain influence these distinct states is not well understood. Laboratory models of GBM can be generated using either genetically engineered mouse models, or via intracranial transplantation of cultured tumour initiating cells (mouse or human). Unfortunately, these approaches are expensive, time-consuming, low-throughput and ill-suited for monitoring live cell behaviours. Here, we explored whole adult brain coronal organotypic slices as an alternative model. Mouse adult brain slices remain viable in a serum-free basal medium for several weeks. GSCs can be easily microinjected into specific anatomical sites [i]ex vivo[/i], and we demonstrate distinct responses of engrafted GSCs to diverse microenvironments in the brain tissue. Within the subependymal zone - one of the adult neural stem cell niches - injected tumour cells could effectively engraft and respond to endothelial niche signals. Tumour-transplanted slices were treated with the antimitotic drug temozolomide as proof of principle of the utility in modelling responses to existing treatments. Engraftment of mouse or human GSCs onto whole brain coronal organotypic brain slices therefore provides a simplified, yet flexible, experimental model. This will help to increase the precision and throughput of modelling GSC-host brain interactions and complements ongoing [i]in vivo[/i] studies. This article has an associated First Person interview with the first author of the paper.
MeSH Terms
- Aging
- Animals
- Antigens, CD
- Biomarkers, Tumor
- Brain
- Brain Neoplasms
- Cell Communication
- Cell Proliferation
- Coculture Techniques
- Culture Media, Serum-Free
- Cytarabine
- Dacarbazine
- Disease Models, Animal
- Endothelial Cells
- Glioblastoma
- Humans
- Mice, Inbred C57BL
- Neoplastic Stem Cells
- Neural Stem Cells
- Organ Specificity
- Stem Cell Niche
- Temozolomide
- Tumor Microenvironment
- Xenograft Model Antitumor Assays
Keywords
- Adult brain
- Glioblastoma
- Niche
- Proliferation
- Quiescence
- Slice culture
Aging stem cells lose the capacity to properly respond to injury and regenerate their residing tissues. Here, we utilized the ability of [i]Drosophila melanogaster[/i] germline stem cells (GSCs) to survive exposure to low doses of ionizing radiation (IR) as a model of adult stem cell injury and identified a regeneration defect in aging GSCs: while aging GSCs survive exposure to IR, they fail to reenter the cell cycle and regenerate the germline in a timely manner. Mechanistically, we identify [i]foxo[/i] and mTOR homologue, [i]Tor[/i] as important regulators of GSC quiescence following exposure to ionizing radiation. [i]foxo[/i] is required for entry in quiescence, while [i]Tor[/i] is essential for cell cycle reentry. Importantly, we further show that the lack of regeneration in aging germ line stem cells after IR can be rescued by loss of [i]foxo[/i].
MeSH Terms
- Animals
- Cell Proliferation
- Cellular Senescence
- Drosophila Proteins
- Drosophila melanogaster
- Forkhead Transcription Factors
- Germ Cells
- Radiation, Ionizing
- Receptor Protein-Tyrosine Kinases
- Stem Cells
Keywords
- D. melanogaster
- adult stem cells
- aging
- cell biology
- developmental biology
- foxo
- germline stem cells
- irradiation-induced quiescence
- stem cells
- tor
Under replete growth conditions, abundant nutrient uptake leads to the systemic activation of insulin/IGF-1 signalling (IIS) and the promotion of stem cell growth/proliferation. Activated IIS can stimulate the ERK/MAPK pathway, the activation of which also supports optimal stem cell proliferation in various systems. Stem cell proliferation rates can further be locally refined to meet the resident tissue's need for differentiated progeny. We have recently shown that the accumulation of mature oocytes in the C. elegans germ line, through DAF-18/PTEN, inhibits adult germline stem cell (GSC) proliferation, despite high systemic IIS activation. We show here that this feedback occurs through a novel cryptic signalling pathway that requires PAR-4/LKB1, AAK-1/AMPK and PAR-5/14-3-3 to inhibit the activity of MPK-1/MAPK, antagonize IIS, and inhibit both GSC proliferation and the production of additional oocytes. Interestingly, our results imply that DAF-18/PTEN, through PAR-4/LKB1, can activate AAK-1/AMPK in the absence of apparent energy stress. As all components are conserved, similar signalling cascades may regulate stem cell activities in other organisms and be widely implicated in cancer.
MeSH Terms
- AMP-Activated Protein Kinases
- Aging
- Animals
- Caenorhabditis elegans
- Caenorhabditis elegans Proteins
- Cell Differentiation
- Cell Proliferation
- Germ Cells
- Insulin
- Insulin-Like Growth Factor I
- Longevity
- Mitogen-Activated Protein Kinase 1
- Oocytes
- PTEN Phosphohydrolase
- Protein-Serine-Threonine Kinases
- Signal Transduction
- Stem Cells
The purpose of this study is to investigate the effect of risk factors including International Normalized Ratio (INR) as well as the Partial Thromboplastin Time (PTT) scores on several outcomes, including hospital length of stay (LOS) and The Extended Glasgow Outcome Scale (GOSE) following TBI in the elderly population. Data were retrospectively collected on patients (n=982) aged 65 and above who were admitted post TBI to the McGill University Health Centre-Montreal General Hospital from 2000 to 2011. Age, Injury Severity Score (ISS), Glasgow Coma Scale score (GCS), type of trauma (isolated TBI vs polytrauma including TBI), initial CT scan results according to the Marshall Classification and the INR and PTT scores and prescriptions of antiplatelet or anticoagulant agents (AP/AC) were collected. Results also indicated that age, ISS and GSC score have an effect on the GOSE score. We also found that taking AC/AP has an effect on GOSE outcome, but that this effects depends on PTT, with lower odds of a worse outcome for those taking AC/AP agents as the PTT value goes up. However, this effect only becomes significant as the PTT value reaches 60 and above. Age and injury severity rather than antithrombotic agent intake are associated with adverse acute outcome such as GOSE in hospitalized elderly TBI patients.
MeSH Terms
- Age Factors
- Aged
- Aged, 80 and over
- Brain Injuries, Traumatic
- Female
- Fibrinolytic Agents
- Glasgow Outcome Scale
- Hospitalization
- Humans
- Injury Severity Score
- Length of Stay
- Male
- Prospective Studies
- Retrospective Studies
- Risk Factors
- Treatment Outcome
Keywords
- Aging
- Level 1 trauma center
- Older age
- Outcome
- Traumatic brain injury
Glioma stem-like cells (GSCs) are proposed to be responsible for high resistance in glioblastoma multiforme (GBM) treatment. In order to find new strategies aimed at reducing GSC stemness and improving GBM patient survival, we investigated the effects and mechanism of a histone deacetylases (HDACs) inhibitor, suberoylanilide hydroxamic acid (SAHA), since HDAC activity has been linked to cancer stem-like cell (CSC) abundance and properties. Human GBM cell lines were plated in serum-free suspension cultures allowed for sphere forming and CSC enrichment. Subsequently, upon SAHA treatment, the stemness markers, cell proliferation, and viability of GSCs as well as cellular apoptosis and senescence were examined in order to clarify whether inhibition of GSCs occurs. We demonstrated that SAHA attenuated cell proliferation and diminished the expression stemness-related markers (CD133 and Bmi1) in GSCs. Furthermore, at high concentrations (more than 5 μM), SAHA triggered apoptosis of GSCs accompanied by increases in both activation of caspase 8- and caspase 9-mediated pathways. Interestingly, we found that a lower dose of SAHA (1 μM and 2.5 μM) inhibited GSCs via cell cycle arrest and induced premature senescence through p53 up-regulation and p38 activation. SAHA induces apoptosis and functions as a potent modulator of senescence via the p38-p53 pathway in GSCs. Our results provide a perspective on targeting GSCs via SAHA treatment, and suggest that SAHA could be used as a potent agent to overcome drug resistance in GBM patients.
MeSH Terms
- Animals
- Apoptosis
- Cell Cycle Checkpoints
- Cell Line, Tumor
- Cell Proliferation
- Drug Resistance, Neoplasm
- Gene Expression Regulation, Neoplastic
- Glioblastoma
- Glioma
- Histone Deacetylase Inhibitors
- Histone Deacetylases
- Humans
- Hydroxamic Acids
- Mice
- Neoplastic Stem Cells
- Signal Transduction
- Tumor Suppressor Protein p53
- Vorinostat
- Xenograft Model Antitumor Assays
- p38 Mitogen-Activated Protein Kinases
Keywords
- Apoptosis
- GBM stem-like cells
- Senescence
- Suberoylanilide hydroxamic acid
- p38
- p53
Senescence is a key developmental process occurring during the life cycle of plants that can be induced also by environmental conditions, such as starvation and/or darkness. During senescence, strict control of genes regulates ordered degradation and dismantling events, the most remarkable of which are genetically programmed cell death (PCD) and, in most cases, an upregulation of flavonoid biosynthesis in the presence of light. Flavonoids are secondary metabolites that play multiple essential roles in development, reproduction and defence of plants, partly due to their well-known antioxidant properties, which could affect also the same cell death machinery. To understand further the effect of endogenously-produced flavonoids and their interplay with different environment (light or dark) conditions, two portions (red and green) of a senescing grapevine callus were used to obtain suspension cell cultures. Red Suspension cell Cultures (RSC) and Green Suspension cell Cultures (GSC) were finally grown under either dark or light conditions for 6 days. Darkness enhanced cell death (mainly necrosis) in suspension cell culture, when compared to those grown under light condition. Furthermore, RSC with high flavonoid content showed a higher viability compared to GSC and were more protected toward PCD, in accordance to their high content in flavonoids, which might quench ROS, thus limiting the relative signalling cascade. Conversely, PCD was mainly occurring in GSC and further increased by light, as it was shown by cytochrome c release and TUNEL assays. Endogenous flavonoids were shown to be good candidates for exploiting an efficient protection against oxidative stress and PCD induction. Light seemed to be an important environmental factor able to induce PCD, especially in GSC, which lacking of flavonoids were not capable of preventing oxidative damage and signalling leading to senescence.
MeSH Terms
- Apoptosis
- Cell Culture Techniques
- Darkness
- Flavonoids
- Light
- Signal Transduction
- Vitis
Keywords
- Cell cultures
- Flavonoids
- PCD
- Senescence
- Vitis vinifera
Stem cells in adult tissues are constantly exposed to genotoxic stress and also accumulate DNA damage with age. However, it remains largely unknown how DNA damage affects both stem cell self-renewal and differentiation. In this study, we show that DNA damage retards germline stem cell (GSC) self-renewal and progeny differentiation in a Lok kinase-dependent manner in the Drosophila ovary. Both heatshock-inducible endonuclease I-CreI expression and X-ray irradiation can efficiently introduce double-strand breaks in GSCs and their progeny, resulting in a rapid GSC loss and a GSC progeny differentiation defect. Surprisingly, the elimination of Lok or its kinase activity can almost fully rescue the GSC loss and the progeny differentiation defect caused by DNA damage induced by I-CreI or X-ray. In addition, the reduction in bone morphogenetic protein signaling and Shotgun expression only makes a limited contribution to DNA damage-induced GSC loss. Finally, DNA damage also decreases the expression of the master differentiation factor Bam in a Lok-dependent manner, which helps explain the GSC progeny differentiation defect. Therefore, this study demonstrates, for the first time in vivo, that Lok kinase activation is required for the DNA damage-mediated disruption of adult stem cell self-renewal and lineage differentiation, and might also offer novel insight into how DNA damage causes tissue aging and cancer formation.
MeSH Terms
- Aging
- Animals
- Cell Differentiation
- Cell Lineage
- Cell Self Renewal
- Cell Transformation, Neoplastic
- Checkpoint Kinase 2
- DNA Damage
- DNA Restriction Enzymes
- Deoxyribonuclease I
- Drosophila
- Drosophila Proteins
- Enzyme Activation
- Germ Cells
- Stem Cells
Keywords
- CHK2
- Differentiation
- Germline stem cell
- Lok
- Niche
- Self-renewal
The mechanisms that modulate and limit the signaling output of adult stem cell niches remain poorly understood. To gain further insights into how these microenvironments are regulated in vivo, we performed a candidate gene screen designed to identify factors that restrict BMP signal production to the cap cells that comprise the germline stem cell (GSC) niche of Drosophila ovaries. Through these efforts, we found that disruption of Wnt4 and components of the canonical Wnt pathway results in a complex germ cell phenotype marked by an expansion of GSC-like cells, pre-cystoblasts and cystoblasts in young females. This phenotype correlates with an increase of decapentaplegic (dpp) mRNA levels within escort cells and varying levels of BMP responsiveness in the germline. Further genetic experiments show that Wnt4, which exhibits graded expression in somatic cells of germaria, activates the Wnt pathway in posteriorly positioned escort cells. The activation of the Wnt pathway appears to be limited by the BMP pathway itself, as loss of Mad in escort cells results in the expansion of Wnt pathway activation. Wnt pathway activity changes within germaria during the course of aging, coincident with changes in dpp production. These data suggest that mutual antagonism between the BMP and Wnt pathways in somatic cells helps to regulate germ cell differentiation.
MeSH Terms
- Aging
- Animals
- Bone Morphogenetic Proteins
- Cell Communication
- Cell Differentiation
- DNA-Binding Proteins
- Drosophila
- Drosophila Proteins
- Female
- Germ Cells
- Glycoproteins
- Ovary
- Phenotype
- RNA, Messenger
- Signal Transduction
- Stem Cell Niche
- Stem Cells
- Transcription Factors
- Wnt Proteins
- Wnt Signaling Pathway
Keywords
- BMP
- Germline
- Niche
- Stem cells
- Wnt
Previously, we identified a group of nuclear hormone receptors (NHRs) that promote longevity in the nematode Caenorhabditis elegans following germline-stem cell (GSC) loss. This group included NHR-49, the worm protein that performs functions similar to vertebrate PPARα, a key regulator of lipid metabolism. We showed that NHR-49/PPARα enhances mitochondrial β-oxidation and fatty acid desaturation upon germline removal, and through the coordinated enhancement of these processes allows the animal to retain lipid homeostasis and undergo lifespan extension. NHR-49/PPARα expression is elevated in GSC-ablated animals, in part, by DAF-16/FOXO3A and TCER-1/TCERG1, two other conserved, pro-longevity transcriptional regulators that are essential for germline-less longevity. In exploring the roles of the other pro-longevity NHRs, we discovered that one of them, NHR-71/HNF4, physically interacted with NHR-49/PPARα. NHR-71/HNF4 did not have a broad impact on the expression of β-oxidation and desaturation targets of NHR-49/PPARα. But, both NHR-49/PPARα and NHR-71/HNF4 were essential for the increased expression of DAF-16/FOXO3A- and TCER-1/TCERG1-downstream target genes. In addition, nhr-49 inactivation caused a striking membrane localization of KRI-1, the only known common upstream regulator of DAF-16/FOXO3A and TCER-1/TCERG1, suggesting that it may operate in a positive feedback loop to potentiate the activity of this pathway. These data underscore how selective interactions between NHRs that function as nodes in metabolic networks, confer functional specificity in response to different physiological stimuli.
Keywords
- Aging
- C. elegans
- FOXO
- PPARα
- TCERG1
- daf-16
- lipid homeostasis
- metabolism
- nhr-49
- reproduction
- tcer-1
Glioblastoma (GBM) is a lethal brain tumor composed of heterogeneous cellular populations including glioma stem cells (GSCs) and differentiated non-stem glioma cells (NSGCs). While GSCs are involved in tumor initiation and propagation, NSGCs' role remains elusive. Here, we demonstrate that NSGCs undergo senescence and secrete pro-angiogenic proteins, boosting the GSC-derived tumor formation in vivo. We used a GSC model that maintains stemness in neurospheres, but loses the stemness and differentiates into NSGCs upon serum stimulation. These NSGCs downregulated telomerase, shortened telomeres, and eventually became senescent. The senescent NSGCs released pro-angiogenic proteins, including vascular endothelial growth factors and senescence-associated interleukins, such as IL-6 and IL-8. Conditioned medium from senescent NSGCs promoted proliferation of brain microvascular endothelial cells, and mixed implantation of GSCs and senescent NSGCs into mice enhanced the tumorigenic potential of GSCs. The senescent NSGCs seem to be clinically relevant, because both clinical samples and xenografts of GBM contained tumor cells that expressed the senescence markers. Our data suggest that senescent NSGCs promote malignant progression of GBM in part via paracrine effects of the secreted proteins.
MeSH Terms
- Angiogenic Proteins
- Animals
- Carcinogenesis
- Cell Differentiation
- Cell Line, Tumor
- Cell Proliferation
- Cellular Senescence
- Glioma
- Humans
- Mice
- Mice, SCID
- Neoplastic Stem Cells
Keywords
- Angiogenesis
- Cancer stem cell
- Glioblastoma
- Paracrine effect
- Senescence
In Caenorhabditis elegans, ablation of germline stem cells (GSCs) extends lifespan, but also increases fat accumulation and alters lipid metabolism, raising the intriguing question of how these effects might be related. Here, we show that a lack of GSCs results in a broad transcriptional reprogramming in which the conserved detoxification regulator SKN-1/Nrf increases stress resistance, proteasome activity, and longevity. SKN-1 also activates diverse lipid metabolism genes and reduces fat storage, thereby alleviating the increased fat accumulation caused by GSC absence. Surprisingly, SKN-1 is activated by signals from this fat, which appears to derive from unconsumed yolk that was produced for reproduction. We conclude that SKN-1 plays a direct role in maintaining lipid homeostasis in which it is activated by lipids. This SKN-1 function may explain the importance of mammalian Nrf proteins in fatty liver disease and suggest that particular endogenous or dietary lipids might promote health through SKN-1/Nrf.
MeSH Terms
- Animals
- Caenorhabditis elegans
- Caenorhabditis elegans Proteins
- DNA-Binding Proteins
- Gene Expression Regulation
- Germ Cells
- Lipid Metabolism
- Transcription Factors
Keywords
- C. elegans
- SKN-1/Nrf
- aging
- cell biology
- chromosomes
- fatty acid signaling
- genes
- germline stem cells
- lipid metabolism
- proteostasis
Stem cells have an innate ability to occupy their stem cell niche, which in turn, is optimized to house stem cells. Organ aging is associated with reduced stem cell occupancy in the niche, but the mechanisms involved are poorly understood. Here, we report that Notch signaling is increased with age in Drosophila female germline stem cells (GSCs), and this results in their removal from the niche. Clonal analysis revealed that GSCs with low levels of Notch signaling exhibit increased adhesiveness to the niche, thereby out-competing their neighbors with higher levels of Notch; adhesiveness is altered through regulation of E-cadherin expression. Experimental enhancement of Notch signaling in GSCs hastens their age-dependent loss from the niche, and such loss is at least partially mediated by Sex lethal. However, disruption of Notch signaling in GSCs does not delay GSC loss during aging, and nor does it affect BMP signaling, which promotes self-renewal of GSCs. Finally, we show that in contrast to GSCs, Notch activation in the niche (which maintains niche integrity, and thus mediates GSC retention) is reduced with age, indicating that Notch signaling regulates GSC niche occupancy both intrinsically and extrinsically. Our findings expose a novel role of Notch signaling in controlling GSC-niche adhesion in response to aging, and are also of relevance to metastatic cancer cells, in which Notch signaling suppresses cell adhesion.
MeSH Terms
- Aging
- Animals
- Bone Morphogenetic Proteins
- Cdh1 Proteins
- Cell Adhesion
- Cell Proliferation
- Drosophila Proteins
- Drosophila melanogaster
- Female
- RNA-Binding Proteins
- Receptors, Notch
- Signal Transduction
- Stem Cell Niche
- Stem Cells
Aging influences stem cells, but the processes involved remain unclear. Insulin signaling, which controls cellular nutrient sensing and organismal aging, regulates the G2 phase of Drosophila female germ line stem cell (GSC) division cycle in response to diet; furthermore, this signaling pathway is attenuated with age. The role of insulin signaling in GSCs as organisms age, however, is also unclear. Here, we report that aging results in the accumulation of tumorous GSCs, accompanied by a decline in GSC number and proliferation rate. Intriguingly, GSC loss with age is hastened by either accelerating (through eliminating expression of Myt1, a cell cycle inhibitory regulator) or delaying (through mutation of insulin receptor (dinR) GSC division, implying that disrupted cell cycle progression and insulin signaling contribute to age-dependent GSC loss. As flies age, DNA damage accumulates in GSCs, and the S phase of the GSC cell cycle is prolonged. In addition, GSC tumors (which escape the normal stem cell regulatory microenvironment, known as the niche) still respond to aging in a similar manner to normal GSCs, suggesting that niche signals are not required for GSCs to sense or respond to aging. Finally, we show that GSCs from mated and unmated females behave similarly, indicating that female GSC-male communication does not affect GSCs with age. Our results indicate the differential effects of aging and diet mediated by insulin signaling on the stem cell division cycle, highlight the complexity of the regulation of stem cell aging, and describe a link between ovarian cancer and aging.
MeSH Terms
- Aging
- Animals
- Biomarkers
- Cell Count
- Cell Proliferation
- DNA
- DNA Damage
- Drosophila melanogaster
- Female
- Flow Cytometry
- G1 Phase
- Germ Cells
- Insulin
- Male
- Neoplastic Stem Cells
- Ovary
- S Phase
- Signal Transduction
- Stem Cell Niche
Keywords
- GSCs
- IGF
- aging
- cell cycle
- tumor
- tumor stem cell
The objective of this work was to study the influence of combined transplantation of stem cells (multypotent mesenchimal stromal and haemopoetic stem cells) on the haemopoesis of old and mature laboratory animals under the condition of ionizing radiation. The result of the experiment shows that under physiological conditions the combined transplantation brings the erithropoesis activation, under the ionizing radiation conditions it brings the erythroid and granulocytopoesis activation. Moreover the combined MMSC and HSC transplantation gives cytoprotective action on the myeloid tissue due to decrease of cyto genically changed cells in the mature animals under the condition of ionizing radiation, but in the old animals this effect can be seen even under physiological condition. Combined transplantation of MMSC and GSC can be used in the mature and old laboratory animals under the conditions of ionising radiation for the haemopoesis activation.
MeSH Terms
- Age Factors
- Aging
- Animals
- Bone Marrow Cells
- Cytoprotection
- Hematopoiesis
- Hematopoietic Stem Cell Transplantation
- Male
- Mesenchymal Stem Cell Transplantation
- Mice
- Models, Animal
- Radiation, Ionizing
- Time Factors
All cells rely on highly conserved protein folding and clearance pathways to detect and resolve protein damage and to maintain protein homeostasis (proteostasis). Because age is associated with an imbalance in proteostasis, there is a need to understand how protein folding is regulated in a multicellular organism that undergoes aging. We have observed that the ability of Caenorhabditis elegans to maintain proteostasis declines sharply following the onset of oocyte biomass production, suggesting that a restricted protein folding capacity may be linked to the onset of reproduction. To test this hypothesis, we monitored the effects of different sterile mutations on the maintenance of proteostasis in the soma of C. elegans. We found that germline stem cell (GSC) arrest rescued protein quality control, resulting in maintenance of robust proteostasis in different somatic tissues of adult animals. We further demonstrated that GSC-dependent modulation of proteostasis requires several different signaling pathways, including hsf-1 and daf-16/kri-1/tcer-1, daf-12, daf-9, daf-36, nhr-80, and pha-4 that differentially modulate somatic quality control functions, such that each signaling pathway affects different aspects of proteostasis and cannot functionally complement the other pathways. We propose that the effect of GSCs on the collapse of proteostasis at the transition to adulthood is due to a switch mechanism that links GSC status with maintenance of somatic proteostasis via regulation of the expression and function of different quality control machineries and cellular stress responses that progressively lead to a decline in the maintenance of proteostasis in adulthood, thereby linking reproduction to the maintenance of the soma.
MeSH Terms
- Aging
- Animals
- Caenorhabditis elegans
- Caenorhabditis elegans Proteins
- Female
- Germ Cells
- Longevity
- Male
- Protein Folding
- Proteostasis Deficiencies
- Signal Transduction
- Stem Cells
Keywords
- aging
- daf-16
- germline stem cells
- hsf-1
- proteostasis
- reproduction