scholarly journals Age-related changes in Polycomb gene regulation disrupt lineage fidelity in intestinal stem cells

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Helen M Tauc ◽  
Imilce A Rodriguez-Fernandez ◽  
Jason A Hackney ◽  
Michal Pawlak ◽  
Tal Ronnen Oron ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Tissue Homeostasis ◽  
Intestinal Stem Cells ◽  
Chromatin Regulation ◽  
Somatic Stem Cells ◽  
Cell Specification ◽  
Age Related ◽  
The Impact ◽  
Age Related Changes

Tissue homeostasis requires long-term lineage fidelity of somatic stem cells. Whether and how age-related changes in somatic stem cells impact the faithful execution of lineage decisions remains largely unknown. Here, we address this question using genome-wide chromatin accessibility and transcriptome analysis as well as single cell RNA-seq to explore stem cell-intrinsic changes in the aging Drosophila intestine. These studies indicate that in stem cells of old flies, promoters of Polycomb (Pc) target genes become differentially accessible, resulting in the increased expression of enteroendocrine (EE) cell specification genes. Consistently, we find age-related changes in the composition of the EE progenitor cell population in aging intestines, as well as a significant increase in the proportion of EE-specified intestinal stem cells (ISCs) and progenitors in aging flies. We further confirm that Pc-mediated chromatin regulation is a critical determinant of EE cell specification in the Drosophila intestine. Pc is required to maintain expression of stem cell genes while ensuring repression of differentiation and specification genes. Our results identify Pc group proteins as central regulators of lineage identity in the intestinal epithelium and highlight the impact of age-related decline in chromatin regulation on tissue homeostasis.

scholarly journals Anti-Aging Effect of the Ketone Metabolite β-Hydroxybutyrate in Drosophila Intestinal Stem Cells

2020 ◽  
Vol 21 (10) ◽  
pp. 3497 ◽  
Author(s):  
Joung-Sun Park ◽  
Yung-Jin Kim
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Stem Cell ◽  
Adult Stem Cells ◽  
Intestinal Stem Cells ◽  
Aging Effects ◽  
Age Related ◽  
Tissue Aging ◽  
And Oxidative Stress ◽  
Age Related Changes

Age-related changes in tissue-resident adult stem cells may be closely linked to tissue aging and age-related diseases, such as cancer. β-Hydroxybutyrate is emerging as an important molecule for exhibiting the anti-aging effects of caloric restriction and fasting, which are generally considered to be beneficial for stem cell maintenance and tissue regeneration. The effects of β-hydroxybutyrate on adult stem cells remain largely unknown. Therefore, this study was undertaken to investigate whether β-hydroxybutyrate supplementation exerts beneficial effects on age-related changes in intestinal stem cells that were derived from the Drosophila midgut. Our results indicate that β-hydroxybutyrate inhibits age- and oxidative stress-induced changes in midgut intestinal stem cells, including centrosome amplification (a hallmark of cancers), hyperproliferation, and DNA damage accumulation. Additionally, β-hydroxybutyrate inhibits age- and oxidative stress-induced heterochromatin instability in enterocytes, an intestinal stem cells niche cells. Our results suggest that β-hydroxybutyrate exerts both intrinsic as well as extrinsic influence in order to maintain stem cell homeostasis.

scholarly journals Age-Related Changes in Methylome and Transcriptome of Hematopotietic Stem Cells Underlie Natural Genetic Variations

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2660-2660
Author(s):  
Ying Liang
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Stem Cell ◽  
Aging Process ◽  
Expression Patterns ◽  
Genetic Variations ◽  
Cell Aging ◽  
Hematopoietic Stem ◽  
Age Related ◽  
Age Related Changes

The aging of hematopoietic stem cells (HSCs) contributes to the aging of blood system and perhaps the whole organism. The aging process is coordinately determined by both genetic and epigenetic factors, and demonstrates inter-individual variations. We used high-throughput sequencing methods to study the age-dependent changes of genome-wide DNA methylation and gene expression patterns in HSCs of C57BL/6 (B6) and DBA/2 mouse strains, which have shown natural variations in HSC aging process. We observed global age-associated decrease of DNA methylation in both strains, but D2 HSCs have a stronger loss of epigenetic control than B6 stem cells during aging. Majority age-related changes of DNA methylation occur from young to mid-aged stages. We identified stable strain-specific differentially methylated regions (DMRs) that overlap with cis-eQTLs. Moreover, transcription factor binding site motifs are more likely to be disrupted in the DMRs, suggesting the potential impact of genetic variations on epigenetic regulation of HSC aging. We further demonstrated that strain-specific DMRs have more profound effects on the aging of B6 HSCs than D2 stem cells. Transposons are differentially regulated by the DMRs in the two strains, in which D2 HSCs are prone to transposon insertion. This study comprehensively investigated the effects of natural genetic and epigenetic variations on HSC aging. Loss of DNA methylation is an epigenetic signature of stem cell aging, and DNA methylation variations correlates with genetic variations, both contributing to inter-individual differences in stem cell and perhaps organismal aging. Disclosures No relevant conflicts of interest to declare.

scholarly journals A Review of the Impact of Calorie Restriction on Stem Cell Potency

2021 ◽  
Vol 28 (4) ◽  
pp. 5-13
Author(s):  
Marcello Mikhael Kadharusman ◽  
Radiana Dhewayani Antarianto ◽  
Novi Silvia Hardiany
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Calorie Restriction ◽  
Oxygen Demand ◽  
Hair Follicles ◽  
Self Renewal ◽  
Age Related ◽  
Regenerative Ability ◽  
The Cost ◽  
The Impact

Calorie restriction (CR) prolongs lifespan in various species and also minimises pathologies caused by aging. One of the characteristics seen in age-related pathologies is stem cell exhaustion. Here, we review the various impacts of CR on mammalian health mediated through stem cell potency in various tissues. This study comprised of a literature search through NCBI, Science Direct, Google Scholar and PubMed, focusing on the impact of CR on pluripotency. In the skeletal muscle, CR acts as an anti-inflammatory agent and increases the presence of satellite cells endogenously to improve regeneration, thus causing a metabolic shift to oxidation to meet oxygen demand. In the intestinal epithelium, CR suppresses the mechanistic target of rapamycin complex 1 (mTORC1) signalling in Paneth cells to shift the stem cell equilibrium towards self-renewal at the cost of differentiation. In haematopoiesis, CR prevents deterioration or maintains the function of haematopoietic stem cells (HSCs) depending on the genetic variation of the mice. In skin and hair follicles, CR increases the thickness of the epidermis and hair growth and improves hair retention through stem cells. CR mediates the proliferation and self-renewal of stem cells in various tissues, thus increasing its regenerative ability.

scholarly journals JNK-mediated spindle reorientation in stem cells promotes dysplasia in the aging intestine

2018 ◽  
Author(s):  
Daniel Jun-Kit Hu ◽  
Heinrich Jasper
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Critical Role ◽  
Dynamic Control ◽  
Tissue Homeostasis ◽  
Intestinal Stem Cells ◽  
Spindle Orientation ◽  
Mitotic Spindles ◽  
High Turnover ◽  
Intestinal Physiology

AbstractHomeostasis in high-turnover tissues depends on precise yet plastic regulation of stem cell daughter fates. In Drosophila, intestinal stem cells (ISCs) respond to unknown signals to switch from asymmetric to symmetric divisions during feeding-induced growth. Here, we show that this switch is controlled by dynamic reorientation of mitotic spindles by a Jun-N-terminal Kinase (JNK) / Wdr62 / Kif1a interaction. JNK promotes Wdr62 localization at the spindle and represses transcription of the kinesin Kif1a. This activity of JNK results in over-abundance of symmetric divisions in stress conditions, and contributes to the loss of tissue homeostasis in the aging animal. Restoring normal ISC spindle orientation by perturbing the JNK/Wdr62/Kif1a axis is sufficient to improve intestinal physiology and extend lifespan. Our findings reveal a critical role for the dynamic control of SC spindle orientation in epithelial maintenance.

scholarly journals A Computational Model of Stem Cell Molecular Mechanism to Maintain Tissue Homeostasis

2020 ◽  
Author(s):  
Najme Khorasani ◽  
Mehdi Sadeghi ◽  
Abbas Nowzari-Dalini
Keyword(s):  
Decision Making ◽  
Stem Cells ◽  
Stem Cell ◽  
Computational Model ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Tissue Homeostasis ◽  
Short Period ◽  
Dynamic Stochastic ◽  
The Impact

Stem cells, with their capacity to self-renew and to differentiate to more specialized cell types, play a key role to maintain homeostasis in adult tissues. To investigate how, in the dynamic stochastic environment of a tissue, non-genetic diversity and the precise balance between proliferation and differentiation are achieved, it is necessary to understand the molecular mechanisms of the stem cells in decision making process. By focusing on the impact of stochasticity, we proposed a computational model describing the regulatory circuitry as a tri-stable dynamical system to reveal the mechanism which orchestrate this balance. Our model explains how the distribution of noise in genes, linked to the cell regulatory networks, controls cell decision-making to maintain homeostatic state. The noise control over tissue homeostasis is achieved by regulating the probability of differentiation and self-renewal through symmetric and/or asymmetric cell divisions. Our model reveals, when mutations due to the replication of DNA in stem cell division, are inevitable, how mutations contribute to either aging gradually or the development of cancer in a short period of time. Furthermore, our model sheds some light on the impact of more complex regulatory networks on the system robustness against perturbations.

scholarly journals Mitochondria deliver a gut check to intestinal stem cells

2017 ◽  
Vol 216 (8) ◽  
pp. 2231-2231
Author(s):  
Ben Short
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Tissue Homeostasis ◽  
Intestinal Stem Cells ◽  
Stem Cell Proliferation ◽  
Mitochondrial Turnover

Mitochondrial turnover regulates stem cell proliferation and tissue homeostasis in Drosophila intestines.

scholarly journals Correlation of Age and Bone Marrow Derived CD 34+ Cells and Leucocytes in 873 Patients.

2020 ◽  
Author(s):  
Christof Pabinger ◽  
Dietmar Dammerer ◽  
Harald Lothaller ◽  
Sandra Gieringer ◽  
Marcel Krall ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Donor Site ◽  
Fatty Degeneration ◽  
Cd 34 ◽  
Age Related ◽  
The Impact

Abstract Background:The use of regenerative medicine, such as autologous chondrocyte implantation (ACI), matrix associated stem cell therapy (MAST) and bone marrow derived stem cell therapy against arthritis is the gold standard for certain indications. However, the clinical improvement of patients using these novel therapies remains heterogeneous and the reasons for this are not fully understood. The impact of age is always a concern for patients and doctors and elderly patients can only be mobilized with lower total collected CD34+ cells, older age correlates with inferior results, fatty degeneration of the bone marrow, delayed fracture-healing and osteoporosis, but solid data are missing. Purpose:This is the first study to determine the average quantity of leukocytes and CD 34+ cells and their relationship in human bone marrow. Study design: Descriptive Laboratory Study Methods:We evaluated the laboratory results of 873 patients (aged 1-90 years), who underwent stem cell transplantation for non malignant diseases. Results:We found no age-related decrease regarding the number and the vitality of leukocytes and CD 34+ stem cells. The number of bone marrow derived leucocytes and CD 34+ cells showed a strong and significant correlation.Conclusion:The amount of bone marrow derived stem cells can be predicted by leukocytes. This study makes further research possible in order to link clinical outcome to the absolute number of stem cells and leukocytes.An upper age-limit for stem cell therapy can therefore not be defined from the donor-site perspective.Clinical Relevance:The number of leucocytes might be used to predict the amount of stem cells in order to select the ideal patient.

scholarly journals A Transient Niche Regulates the Specification of Drosophila Intestinal Stem Cells

Science ◽  
2010 ◽  
Vol 327 (5962) ◽  
pp. 210-213 ◽  
Author(s):  
Divya Mathur ◽  
Alyssa Bost ◽  
Ian Driver ◽  
Benjamin Ohlstein
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Intestinal Stem Cells ◽  
Bone Morphogenetic Protein 2 ◽  
Cell Specification ◽  
Stem Cell Fate ◽  
Morphogenetic Protein ◽  
Undifferentiated State ◽  
Cell Niche

Stem cell niches are locations where stem cells reside and self-renew. Although studies have shown how niches maintain stem cell fate during tissue homeostasis, less is known about their roles in establishing stem cells. The adult Drosophila midgut is maintained by intestinal stem cells (ISCs); however, how they are established is unknown. Here, we show that an ISC progenitor generates a niche cell via Notch signaling. This niche uses the bone morphogenetic protein 2/4 homolog, decapentaplegic, to allow progenitors to divide in an undifferentiated state and subsequently breaks down and dies, resulting in the specification of ISCs in the adult midgut. Our results demonstrate a paradigm for stem cell–niche biology, where progenitors generate transient niches that determine stem cell fate and may give insights into stem cell specification in other tissues.

scholarly journals Three-Dimensional Gastrointestinal Organoid Culture in Combination with Nerves or Fibroblasts: A Method to Characterize the Gastrointestinal Stem Cell Niche

2016 ◽  
Vol 2016 ◽  
pp. 1-16 ◽  
Author(s):  
Agnieszka Pastuła ◽  
Moritz Middelhoff ◽  
Anna Brandtner ◽  
Moritz Tobiasch ◽  
Bettina Höhl ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Stem Cell Niche ◽  
3D Culture ◽  
Intestinal Stem Cells ◽  
Organoid Culture ◽  
Gastrointestinal Epithelium ◽  
Cell Niche ◽  
The Impact

The gastrointestinal epithelium is characterized by a high turnover of cells and intestinal stem cells predominantly reside at the bottom of crypts and their progeny serve to maintain normal intestinal homeostasis. Accumulating evidence demonstrates the pivotal role of a niche surrounding intestinal stem cells in crypts, which consists of cellular and soluble components and creates an environment constantly influencing the fate of stem cells. Here we describe different 3D culture systems to culture gastrointestinal epithelium that should enable us to study the stem cell nichein vitroin the future: organoid culture and multilayered systems such as organotypic cell culture and culture of intestinal tissue fragmentsex vivo. These methods mimic thein vivosituationin vitroby creating 3D culture conditions that reflect the physiological situation of intestinal crypts. Modifications of the composition of the culture media as well as coculturing epithelial organoids with previously described cellular components such as myofibroblasts, collagen, and neurons show the impact of the methods applied to investigate niche interactionsin vitro. We further present a novel method to isolate labeled nerves from the enteric nervous system using Dclk1-CreGFP mice.

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