scholarly journals Chaperone-Mediated Autophagy Plays an Important Role in Regulating Retinal Progenitor Cell Homeostasis

2021 ◽  
Author(s):  
Caixia Jin ◽  
Qingjian Ou ◽  
Jie Chen ◽  
Tao Wang ◽  
Jieping Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Viability ◽  
Progenitor Cell ◽  
Time Course ◽  
Rna Seq ◽  
Sequencing Data ◽  
Self Renewal ◽  
Retinal Progenitor ◽  
Significant Difference

Abstract Purpose: Autophagy is a key regulator of stem cell quiescence and self-renewal, especially in mesenchymal stem cells but related research on neural retinal stem cells is still limited. We are aimed to explore the function and mechanism of autophagy in the neural retinal stem cell.Methods: The published single cell sequencing data was involved to analysis the expression time course of IFITM3 in the mouse neural retinal progenitor cells (mNRPCs). The RNA interference was used to knock down the expression of IFITM3 in the mNRPCs. And the normal mNRPCs and mNRPCs with knockdown of IFITM3 were analysis with the CCK8 for the cell viability, RNA-seq for the mRNA expression, real-time quantitative PCR, immunofluorescence assay for the location of relative proteins, western blot for the levels of relative proteins and autophagy flux assay.Results: This study showed the mNRPCs in vivo and in vitro high expressed IFITM3 which are expressed in the mNRPCs. The proliferation of mNRPCs was greatly inhibited, and cell viability was greatly reduced after IFITM3 knockdown. Moreover, RNA-seq analysis showed that lysosomes were significant changed after IFITM3 knockdown. When cells were treated with rapamycin (RAMP), lysosome activation and agglomeration were evident in all groups. However, there was no significant difference between IFITM3 knockdown groups. The expression of LAMP1 was significantly increased, accompanied by increased lysosome agglomeration, in RAMP-treated cells and especially in IFITM3-knockdown cells. Further detection showed that SQSTM1/p62, HSC70 and LAMP-2A were upregulated, while there was no significant difference in LC3A/B expression, which demonstrated that the MA pathway was not activated but the CMA pathway was activated when knockdown of IFITM3. Conclusion: Our findings indicate that IFITM3 participates in regulating mNRPC viability and proliferation mainly through the CMA pathway, indicating that IFITM3 plays a significant role in maintaining the homeostasis of progenitor cell self-renewal by sustaining low-level activation of the CMA pathway to eliminate factors that are deleterious to cells and acts as a very important protector of RPCs.

Gastrointestinal Stem Cells. III. Emergent themes of liver stem cell biology: niche, quiescence, self-renewal, and plasticity

2006 ◽  
Vol 290 (2) ◽  
pp. G189-G193 ◽  
Author(s):  
Neil D. Theise
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Cell Biology ◽  
Stem Cell Niche ◽  
Progenitor Cell ◽  
Stem Cell Biology ◽  
Cell Plasticity ◽  
Self Renewal ◽  
Cell Niche

This essay will address areas of liver stem/progenitor cell studies in which consensus has emerged and in which controversy still prevails over consensus, but it will also highlight important themes that inevitably should be a focus of liver stem/progenitor cell investigations in coming years. Thus concepts regarding cell plasticity, the existence of a physiological/anatomic stem cell niche, and whether intrahepatic liver stem/progenitor cells comprise true stem cells or progenitor cells (or both) will be approached in some detail.

Genome-Wide Epigenetic Analysis of Cancer Stem Cells (CSCs) In Acute Myeloid Leukemia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3640-3640 ◽  
Author(s):  
Jumpei Yamazaki ◽  
Marcos R Estecio ◽  
Jaroslav Jelinek ◽  
David Graber ◽  
Yue Lu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Cell Population ◽  
Progenitor Cell ◽  
Cpg Island ◽  
Methylation Status ◽  
Cpg Islands ◽  
Significant Difference

Abstract Abstract 3640 Background & Aims: The hypothesis that cancer is driven by Cancer Stem Cells (CSCs or Cancer-Initiating Cell) has recently attracted a great deal of attention. Epigenetic mechanism such as DNA methylation and histone modification play an important role in cancer cells and also in normal stem cells. However, their role remains unclear in CSCs. We sought to determine if CSCs have distinct epigenetic patterns in acute myeloid leukemia (AML). Methods: Peripheral blood samples in AML patients were separated to obtain stem cells (CD34+CD38-) and progenitor cells (CD34+CD38+) by magnetic cell sorting (MACS®, Myltenyi biotec). To study DNA methylation in CSCs in AML, we performed genome wide screening using methylated CpG island microarray (MCAM), which detects 7202 promoter CpG islands, 1348 non-promoter CpG islands, and 632 non-CpG island promoter methylation. MCAM was performed on 4 AML patient samples Next, we evaluated the methylation status of 7 genes which showed apparent higher DNA methylation in stem cells or progenitor cells in MCAM analysis, using a quantitative bisulfite-pyrosequencing for each population of stem cell, progenitor cell, and mature cells (CD34-) from peripheral blood samples in 6 AML patients. For histone modification analysis, we used Chromation immuprecipitation followed by massively parallel sequencing (ChIP-Seq) for stem cell and progenitor cell populations for H3K4me3 which is known to be a marker for activated genes. Results: By MCAM, we found minimal differences between stem cells and progenitor cells present in 2 out of 4 AML patients. Those few genes (<1%) which were shown to have higher DNA methylation in stem or progenitor cells by MCAM analysis were likely false positives, as no significant difference was found when analyzed by quantitative bisulfite-pyrosequencing. DNA methylation status for stem cell-related gene (OCT4, SOX2, MYC, HOXB4, and KLF4) also showed no significant difference. By ChIP-seq analysis, we found differences in 2362 genes between stem cells and progenitor cells. In stem cells, H3K4me3 was enriched in genes (Bmi1, Notch1, Wnt1, and etc) which are known to be important for stem cell function, but they were not enriched in the progenitor cell population. In pathway analysis of the H3K4me3 data, Hypoxia-Inducible Factor signaling, NFkB signaling, and p53 signaling are found to be enriched specifically in the stem cell population whereas Cellular Growth and Cell Cycle, and DNA Damage Response signaling are found in the progenitor cell population. Conclusions: There is no significant difference in DNA methylation between stem cell, progenitor cell or mature cell populations in AML. DNA methylation of promoter CpG islands is unlikely to explain tumor hierarchy in AML. Rather, histone modifications seem to have a greater significance in this regard. Disclosures: No relevant conflicts of interest to declare.

Foxo3 Modulation of ATM and Oxidative Stress Mediates Distinct Functions in the Regulation of Hematopoietic Stem and Progenitor Cell Fate.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1272-1272 ◽  
Author(s):  
Safak Yalcin ◽  
Julia P. Luciano ◽  
Xin Zhang ◽  
Cecile Vercherat ◽  
Reshma Taneja ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Cell Fate ◽  
Hematopoietic Stem Cell ◽  
Progenitor Cell ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Atm Gene

Abstract FOXO transcription factors are required for hematopoietic stem cell self renewal. In this study, we demonstrate that Foxo3 plays a specific and essential function in the regulation of both hematopoietic stem and progenitor cell fate. Foxo3 null mice display a myeloproliferative syndrome characterized by splenomegaly, a major expansion of the myeloid compartment in the blood, bone marrow and spleen, cytokine hypersensitivity of progenitors in hematopoietic organs and associated with the repression of the B lymphoid compartment. In addition, loss of Foxo3 leads to significant defects in hematopoietic stem cell numbers and activity. In particular, the numbers of long-term culture initiating cells (LTC-IC) was significantly reduced and the ability to repopulate lethally irradiated mice was severely compromised in Foxo3-defcient mice. This effect was mediated at least partially by enhanced accumulation of reactive oxygen species (ROS) in Foxo3-deficient hematopoietic stem cells as demonstrated by reduced QRT-PCR expression of several anti-oxidant enzymes leading to accumulation of ROS, (as measured by chloromethyl,dichlorodihydrofluorescein diacetate assay) in Foxo3 null hematopoietic stem cells, and in vitro and in vivo rescue of the phenotype using ROS scavengers. Furthermore, we demonstrate that while ROS accumulation results in suppression of Foxo3 null hematopoietic stem cell compartment, it enhances the activity of multipotential cells. By measuring RNA versus DNA content, and BrdU uptake, we determined that Foxo3-deficient hematopoietic stem cells exit quiescence (G0) and are impaired in their cycling at the G2/M phase. In particular, we identified ROS activation of p19ARF/p53 pathway and ROS-independent modulation of ataxia telangiectasia mutated (ATM) gene and p16INK4a, as major contributors to the interference with Foxo3-deficient hematopoietic stem cell self renewal and cycling. Loss of ATM has been shown to lead to hematopoietic stem cell deficiency. Importantly, we show that ATM gene expression is significantly suppressed in Foxo3-deficient hematopoietic stem cells suggesting that ATM lies downstream of Foxo3. Retroviral expression of a constitutively active form of Foxo3 in Foxo3-deficient bone marrow mononuclear cells enhances significantly the ATM expression suggesting that Foxo3 regulate expression of ATM gene. These combined findings suggest that Foxo3 functions in a tumor suppressor network to protect hematopoietic stem cells against deleterious effects of oxidative damage, to maintain hematopoietic lineage fate determination and to restrict the activity of long term repopulating hematopoietic stem cells. These findings provide insights into the mechanisms underlying hematopoietic stem cell fate.

Chronic Myeloid Leukemia Stem Cells

Hematology ◽  
2008 ◽  
Vol 2008 (1) ◽  
pp. 436-442 ◽  
Author(s):  
Catriona H. Jamieson
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Targeted Therapy ◽  
Chronic Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Progenitor Cell ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Self Renewal

Abstract Chronic myeloid leukemia (CML) is typified by robust marrow and extramedullary myeloid cell production. In the absence of therapy or sometimes despite it, CML has a propensity to progress from a relatively well tolerated chronic phase to an almost uniformly fatal blast crisis phase. The discovery of the Philadelphia chromosome followed by identification of its BCR-ABL fusion gene product and the resultant constitutively active P210 BCR-ABL tyrosine kinase, prompted the unraveling of the molecular pathogenesis of CML. Ground-breaking research demonstrating that BCR-ABL was necessary and sufficient to initiate chronic phase CML provided the rationale for targeted therapy. However, regardless of greatly reduced mortality rates with BCR-ABL targeted therapy, most patients harbor quiescent CML stem cells that may be a reservoir for disease progression to blast crisis. While the hematopoietic stem cell (HSC) origin of CML was first suggested over 30 years ago, only recently have the HSC and progenitor cell–specific effects of the molecular mutations that drive CML been investigated. This has provided the impetus for investigating the genetic and epigenetic events governing HSC and progenitor cell resistance to therapy and their role in disease progression. Accumulating evidence suggests that the acquired BCR-ABL mutation initiates chronic phase CML and results in aberrant stem cell differentiation and survival. This eventually leads to the production of an expanded progenitor population that aberrantly acquires self-renewal capacity resulting in leukemia stem cell (LSC) generation and blast crisis transformation. Therapeutic recalcitrance of blast crisis CML provides the rationale for targeting the molecular pathways that drive aberrant progenitor differentiation, survival and self-renewal earlier in disease before LSC predominate.

scholarly journals Characteristics of Mesenchymal Stem Cells Are Independent of Bone Marrow Storage Temperatures

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Valentin Schrodi ◽  
Claudia Neunaber ◽  
Katrin Bundkirchen ◽  
Weikang Ye ◽  
Zhida Jiang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Room Temperature ◽  
Storage Conditions ◽  
Self Renewal ◽  
Significant Difference ◽  
Multipotent Differentiation ◽  
Storage Temperatures

Mesenchymal stem cells play an important role in regenerative medicine due to their capability of self-renewal and multipotent differentiation. For research or clinical application, bone marrow aspirates are harvested during elective surgeries to isolate MSCs. If an immediate purification of the MSCs is not possible, the bone marrow must be stored. Therefore, the aim of this study was to investigate possible differences of stem cell characteristics regarding the self-renewal capability, the adipogenic, chondrogenic, and osteogenic differentiation, and the expression of surface antigens after different storage conditions of the bone marrow aspirates. Three groups were analysed: the first group was purified immediately after harvesting, the other two groups were processed after they were stored 18 to 24 hours at 22°C (room temperature) or at 4°C. Comparisons between the groups were performed using the Kruskal-Wallis test for nonparametric data. The final results showed no significant difference between the different storage conditions. Therefore, storage of bone marrow aspirates for 18 to 24 hours at room temperature or 4°C is possible without loss of stem cell characteristics.

Reversion to an Embryonic Alternative Splicing Program Enhances Leukemia Stem Cell Self-Renewal

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1227-1227
Author(s):  
Frida Linnea Holm ◽  
Eva Hellqvist ◽  
Cayla N Mason ◽  
Shawn Ali ◽  
Nathaniel Delos Santos ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Alternative Splicing ◽  
Blast Crisis ◽  
Embryonic Stem ◽  
Chronic Phase ◽  
Cell Reprogramming ◽  
Rna Seq ◽  
Self Renewal ◽  
Splice Isoform

Abstract Background Formative research suggests that a human embryonic stem cell-specific alternative splicing gene regulatory network, which is repressed by Muscleblind-like (MBNL) RNA binding proteins, is involved in cell reprogramming. However, its role in malignant reprogramming of progenitors into self-renewing leukemia stem cells (LSCs) had not been established. Methods Whole transcriptome RNA sequencing (RNA-seq) was performed on FACS purified progenitors from normal, chronic phase and blast crisis chronic myeloid leukemia samples and analyzed using Cuff-links, GSEA and IPA software. Splice isoform specific qRT-PCR, confocal microscopy, lentiviral overexpression and shRNA knockdown experiments were performed according to published methods (Jamieson NEJM 2004; Geron et al Cancer Cell 2008; Goff et al Cell Stem Cell 2013). Results We performed LSC RNA-seq, lentiviral overexpression and knockdown and discovered that decreased expression of MBNL3, a repressor of an embryonic alternative splicing program and reprogramming, activated a pluripotency network and increased expression of a pro-survival isoform of CD44v3, which is more commonly expressed in human embryonic stem cells. This resulted in malignant reprogramming of progenitors in blast crisis CML endowing them with unbridled survival and self-renewal capacity. This is the first description of MBNL3 downregulation as a mechanism of reversion to an embryonic alternative splicing program, which elicits malignant progenitor reprogramming of progenitors into self-renewing leukemia stem cells. While isoform specific lentiviral CD44v3 overexpression enhanced chronic phase CML progenitor replating capacity, lentiviral shRNA knockdown abrogated these effects. In keeping with activation of a stem cell reprogramming network, CD44v3 upregulation was associated with increased expression of pluripotency transcription factors, including OCT4, SOX2 and b-catenin in addition to the pro-survival long isoforms of MCL1 and BCLX resulting in increased self-renewal and apoptosis resistance. Conclusion In summary, MBNL3 downregulation activates an embryonic alternative splicing program, typified by CD44v3 overexpression, and represents a novel mechanism governing LSC generation in malignant microenvironments. Reversal of malignant reprogramming by epigenetic modulation of embryonic alternative splicing or via monoclonal antibody targeting of CD44v3 splice isoform may represent a pivotal opportunity for selective BC LSC eradication. Disclosures Jamieson: Johnson & Johnson: Research Funding; GlaxoSmithKline: Research Funding.

Integrin α6 (CD49f), The Microenvironment and Cancer Stem Cells

2019 ◽  
Vol 14 (5) ◽  
pp. 428-436 ◽  
Author(s):  
Gabriele D. Bigoni-Ordóñez ◽  
Daniel Czarnowski ◽  
Tyler Parsons ◽  
Gerard J. Madlambayan ◽  
Luis G. Villa-Diaz
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cancer Stem Cell ◽  
The Self ◽  
Self Renewal ◽  
Terminal Disease

Cancer is a highly prevalent and potentially terminal disease that affects millions of individuals worldwide. Here, we review the literature exploring the intricacies of stem cells bearing tumorigenic characteristics and collect evidence demonstrating the importance of integrin &#945;6 (ITGA6, also known as CD49f) in cancer stem cell (CSC) activity. ITGA6 is commonly used to identify CSC populations in various tissues and plays an important role sustaining the self-renewal of CSCs by interconnecting them with the tumorigenic microenvironment.

Metabolic Regulation and Related Molecular Mechanisms in Various Stem Cell Functions

2020 ◽  
Vol 15 (6) ◽  
pp. 531-546 ◽  
Author(s):  
Hwa-Yong Lee ◽  
In-Sun Hong
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Oxidative Phosphorylation ◽  
Metabolic Pathways ◽  
Critical Role ◽  
The Self ◽  
Specific Cell ◽  
Differentiation Potential ◽  
Self Renewal ◽  
Cell Functions

Recent studies on the mechanisms that link metabolic changes with stem cell fate have deepened our understanding of how specific metabolic pathways can regulate various stem cell functions during the development of an organism. Although it was originally thought to be merely a consequence of the specific cell state, metabolism is currently known to play a critical role in regulating the self-renewal capacity, differentiation potential, and quiescence of stem cells. Many studies in recent years have revealed that metabolic pathways regulate various stem cell behaviors (e.g., selfrenewal, migration, and differentiation) by modulating energy production through glycolysis or oxidative phosphorylation and by regulating the generation of metabolites, which can modulate multiple signaling pathways. Therefore, a more comprehensive understanding of stem cell metabolism could allow us to establish optimal culture conditions and differentiation methods that would increase stem cell expansion and function for cell-based therapies. However, little is known about how metabolic pathways regulate various stem cell functions. In this context, we review the current advances in metabolic research that have revealed functional roles for mitochondrial oxidative phosphorylation, anaerobic glycolysis, and oxidative stress during the self-renewal, differentiation and aging of various adult stem cell types. These approaches could provide novel strategies for the development of metabolic or pharmacological therapies to promote the regenerative potential of stem cells and subsequently promote their therapeutic utility.

Sign in / Sign up

Export Citation Format

Share Document