scholarly journals p107 mediated mitochondrial function controls muscle stem cell proliferative fates

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Debasmita Bhattacharya ◽  
Vicky Shah ◽  
Oreoluwa Oresajo ◽  
Anthony Scimè
Keyword(s):  
Cell Cycle ◽  
Stem Cell ◽  
Mitochondrial Function ◽  
Chain Complex ◽  
Cell Types ◽  
Atp Production ◽  
Transport Chain ◽  
Metabolic States ◽  
Proliferation And Differentiation ◽  
A Cell

AbstractMuscle diseases and aging are associated with impaired myogenic stem cell self-renewal and fewer proliferating progenitors (MPs). Importantly, distinct metabolic states induced by glycolysis or oxidative phosphorylation have been connected to MP proliferation and differentiation. However, how these energy-provisioning mechanisms cooperate remain obscure. Herein, we describe a mechanism by which mitochondrial-localized transcriptional co-repressor p107 regulates MP proliferation. We show p107 directly interacts with the mitochondrial DNA, repressing mitochondrial-encoded gene transcription. This reduces ATP production by limiting electron transport chain complex formation. ATP output, controlled by the mitochondrial function of p107, is directly associated with the cell cycle rate. Sirt1 activity, dependent on the cytoplasmic glycolysis product NAD+, directly interacts with p107, impeding its mitochondrial localization. The metabolic control of MP proliferation, driven by p107 mitochondrial function, establishes a cell cycle paradigm that might extend to other dividing cell types.

scholarly journals p107 mediated mitochondrial function controls muscle stem cell proliferative fates

2020 ◽  
Author(s):  
Debasmita Bhattacharya ◽  
Oreoluwa Oresajo ◽  
Anthony Scimè
Keyword(s):  
Cell Cycle ◽  
Stem Cell ◽  
Mitochondrial Function ◽  
Control Cell ◽  
Chain Complex ◽  
Cell Types ◽  
New Paradigm ◽  
Transport Chain ◽  
Metabolic States ◽  
And Function

AbstractMuscle wasting diseases and aging are associated with impaired myogenic stem cell selfrenewal and a diminished number of their proliferating progenitors (MPs). Importantly, distinct metabolic states govern MP proliferation and differentiation. Central to this is the regulation between glycolysis and oxidative phosphorylation (Oxphos). However, the mechanisms that connect these energy provisioning centers to control cell behaviour remain obscure. Herein, our results reveal a mechanism by which mitochondrial-localized transcriptional co-repressor p107 governs MP proliferation. We found p107 directly interacts at the mitochondrial DNA promoter, repressing mitochondrial-encoded genes. This reduces mitochondrial ATP generation, by limiting the electron transport chain complex formation. Importantly, the amount of ATP generated by the mitochondrial function of p107 is directly associated to the cell cycle rate. Sirt1, whose activity is dependent on the cytoplasmic by-product of glycolysis, NAD+, directly interacts with p107 impeding its mitochondrial localization and function. The metabolic control of cell cycle, driven by differential p107 mitochondrial function, establishes a new paradigm to manipulate muscle cell proliferative fates that is likely to extend to most other dividing cell types.

scholarly journals Mitochondria regulate Drosophila intestinal stem cell differentiation through FOXO

2020 ◽  
Author(s):  
Fan Zhang ◽  
Mehdi Pirooznia ◽  
Hong Xu
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Stem Cell Differentiation ◽  
Common Belief ◽  
Atp Production ◽  
Transport Chain ◽  
Ros Accumulation ◽  
Proliferation And Differentiation

AbstractStem cells often rely on glycolysis for energy production, and switching to oxidative phosphorylation is believed to be essential for their differentiation. To explore the link between mitochondrial respiration and stem cell differentiation, we genetically disrupted electron transport chain (ETC) complexes in the intestinal stem cells (ISCs) of Drosophila. We found that ISCs carrying impaired ETC proliferated much more slowly than normal, produced very few intestinal progenitors, or enteroblasts, and failed to differentiate into enterocytes or enteroendocrine cells. One of the main impediments to ISCs’ differentiation appeared to be abnormally elevated forkhead box O (FOXO) signaling in the ETC-deficient ISCs, as genetically suppressing the signaling pathway partially rescued the differentiation defect. Contrary to common belief, neither reactive oxygen species (ROS) accumulation nor adenosine triphosphate (ATP) reduction appeared to mediate the ETC mutant phenotype. Our results demonstrate that ETC is essential for Drosophila ISC proliferation and differentiation in vivo, and acts at least partially by repressing endogenous FOXO signaling. They also raise the possibility that ETC complexes have a role in stem cell differentiation beyond electron transfer and ATP production.

scholarly journals MicroRNA let-7b regulates neural stem cell proliferation and differentiation by targeting nuclear receptor TLX signaling

2010 ◽  
Vol 107 (5) ◽  
pp. 1876-1881 ◽  
Author(s):  
Chunnian Zhao ◽  
GuoQiang Sun ◽  
Shengxiu Li ◽  
Ming-Fei Lang ◽  
Su Yang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Cyclin D1 ◽  
Neural Stem Cell ◽  
Neural Differentiation ◽  
Stem Cell Proliferation ◽  
Neural Stem Cell Proliferation ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation

Neural stem cell self-renewal and differentiation is orchestrated by precise control of gene expression involving nuclear receptor TLX. Let-7b, a member of the let-7 microRNA family, is expressed in mammalian brains and exhibits increased expression during neural differentiation. However, the role of let-7b in neural stem cell proliferation and differentiation remains unknown. Here we show that let-7b regulates neural stem cell proliferation and differentiation by targeting the stem cell regulator TLX and the cell cycle regulator cyclin D1. Overexpression of let-7b led to reduced neural stem cell proliferation and increased neural differentiation, whereas antisense knockdown of let-7b resulted in enhanced proliferation of neural stem cells. Moreover, in utero electroporation of let-7b to embryonic mouse brains led to reduced cell cycle progression in neural stem cells. Introducing an expression vector of Tlx or cyclin D1 that lacks the let-7b recognition site rescued let-7b-induced proliferation deficiency, suggesting that both TLX and cyclin D1 are important targets for let-7b-mediated regulation of neural stem cell proliferation. Let-7b, by targeting TLX and cyclin D1, establishes an efficient strategy to control neural stem cell proliferation and differentiation.

scholarly journals Compartmentalization within the nucleus: discovery of a novel subnuclear region.

1991 ◽  
Vol 115 (4) ◽  
pp. 919-931 ◽  
Author(s):  
W S Saunders ◽  
C A Cooke ◽  
W C Earnshaw
Keyword(s):  
Cell Cycle ◽  
Phase Contrast ◽  
Nuclear Organization ◽  
Cell Types ◽  
Preliminary Evidence ◽  
Mrna Processing ◽  
Structural Domain ◽  
Structural Rearrangements ◽  
Nuclear Rna ◽  
A Cell

Antibodies to a set of structurally related autoantigens (p23-25) bind to a previously uncharacterized, large structural domain in the nucleus of a variety of human cell types. This subnuclear domain is visible by phase contrast alone as a region of decreased density after several different fixation protocols. The morphology of this region changes dramatically during the cell cycle and we have given it the name PIKA (for polymorphic interphase karyosomal association) based on preliminary evidence that the PIKA proteins may be associated with chromatin. The function of the PIKA is not yet known, but our immunolocalization data indicate that it is unlikely to be associated with regions of ongoing DNA replication, heterogeneous nuclear RNA storage, or mRNA processing. The discovery of the PIKA provides evidence supporting an emerging model of nuclear structure. It now appears that the nucleus is organized into distinct domains which include not only the nucleolus, but also previously unidentified regions such as the PIKAs. Furthermore, structural rearrangements undergone by the nucleolus and the PIKAs may be indicative of a broad tendency for nuclear organization to change in a cell cycle-specific fashion.

scholarly journals APC is required for muscle stem cell proliferation and skeletal muscle tissue repair

2015 ◽  
Vol 210 (5) ◽  
pp. 717-726 ◽  
Author(s):  
Alice Parisi ◽  
Floriane Lacour ◽  
Lorenzo Giordani ◽  
Sabine Colnot ◽  
Pascal Maire ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Skeletal Muscle ◽  
Stem Cells ◽  
Stem Cell ◽  
Cell Cycle Progression ◽  
Cell Types ◽  
Double Knockout ◽  
Muscle Stem Cells ◽  
Adult Muscle ◽  
Canonical Wnt

The tumor suppressor adenomatous polyposis coli (APC) is a crucial regulator of many stem cell types. In constantly cycling stem cells of fast turnover tissues, APC loss results in the constitutive activation of a Wnt target gene program that massively increases proliferation and leads to malignant transformation. However, APC function in skeletal muscle, a tissue with a low turnover rate, has never been investigated. Here we show that conditional genetic disruption of APC in adult muscle stem cells results in the abrogation of adult muscle regenerative potential. We demonstrate that APC removal in adult muscle stem cells abolishes cell cycle entry and leads to cell death. By using double knockout strategies, we further prove that this phenotype is attributable to overactivation of β-catenin signaling. Our results demonstrate that in muscle stem cells, APC dampens canonical Wnt signaling to allow cell cycle progression and radically diverge from previous observations concerning stem cells in actively self-renewing tissues.

Human hematopoietic stem cells stimulated to proliferate in vitro lose engraftment potential during their S/G2/M transit and do not reenter G0

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4185-4193 ◽  
Author(s):  
Hanno Glimm ◽  
IL-Hoan Oh ◽  
Connie J. Eaves
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Cell Activity ◽  
Human Cord Blood ◽  
Hematopoietic Stem ◽  
A Cell

Abstract An understanding of mechanisms regulating hematopoietic stem cell engraftment is of pivotal importance to the clinical use of cultured and genetically modified transplants. Human cord blood (CB) cells with lymphomyeloid repopulating activity in NOD/SCID mice were recently shown to undergo multiple self-renewal divisions within 6 days in serum-free cultures containing Flt3-ligand, Steel factor, interleukin 3 (IL-3), IL-6, and granulocyte colony-stimulating factor. The present study shows that, on the fifth day, the transplantable stem cell activity is restricted to the G1fraction, even though both colony-forming cells (CFCs) and long-term culture-initiating cells (LTC-ICs) in the same cultures are approximately equally distributed between G0/G1and S/G2/M. Interestingly, the G0 cells defined by their low levels of Hoechst 33342 and Pyronin Y staining, and reduced Ki67 and cyclin D expression (representing 21% of the cultured CB population) include some mature erythroid CFCs but very few primitive CFCs, LTC-ICs, or repopulating cells. Although these findings suggest a cell cycle–associated change in in vivo stem cell homing, the cultured G0/G1 and S/G2/M CD34+ CB cells exhibited no differences in levels of expression of VLA-4, VLA-5, or CXCR-4. Moreover, further incubation of these cells for 1 day in the presence of a concentration of transforming growth factor β1 that increased the G0/G1 fraction did not enhance detection of repopulating cells. The demonstration of a cell cycle–associated mechanism that selectively silences the transplantability of proliferating human hematopoietic stem cells poses both challenges and opportunities for the future improvement of ex vivo–manipulated grafts.

Human hematopoietic stem cells stimulated to proliferate in vitro lose engraftment potential during their S/G2/M transit and do not reenter G0

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4185-4193 ◽  
Author(s):  
Hanno Glimm ◽  
IL-Hoan Oh ◽  
Connie J. Eaves
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Cell Activity ◽  
Human Cord Blood ◽  
Hematopoietic Stem ◽  
A Cell

An understanding of mechanisms regulating hematopoietic stem cell engraftment is of pivotal importance to the clinical use of cultured and genetically modified transplants. Human cord blood (CB) cells with lymphomyeloid repopulating activity in NOD/SCID mice were recently shown to undergo multiple self-renewal divisions within 6 days in serum-free cultures containing Flt3-ligand, Steel factor, interleukin 3 (IL-3), IL-6, and granulocyte colony-stimulating factor. The present study shows that, on the fifth day, the transplantable stem cell activity is restricted to the G1fraction, even though both colony-forming cells (CFCs) and long-term culture-initiating cells (LTC-ICs) in the same cultures are approximately equally distributed between G0/G1and S/G2/M. Interestingly, the G0 cells defined by their low levels of Hoechst 33342 and Pyronin Y staining, and reduced Ki67 and cyclin D expression (representing 21% of the cultured CB population) include some mature erythroid CFCs but very few primitive CFCs, LTC-ICs, or repopulating cells. Although these findings suggest a cell cycle–associated change in in vivo stem cell homing, the cultured G0/G1 and S/G2/M CD34+ CB cells exhibited no differences in levels of expression of VLA-4, VLA-5, or CXCR-4. Moreover, further incubation of these cells for 1 day in the presence of a concentration of transforming growth factor β1 that increased the G0/G1 fraction did not enhance detection of repopulating cells. The demonstration of a cell cycle–associated mechanism that selectively silences the transplantability of proliferating human hematopoietic stem cells poses both challenges and opportunities for the future improvement of ex vivo–manipulated grafts.

scholarly journals Changes in ionizing radiation dose rate affect cell cycle progression in adipose derived stem cells

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0250160
Author(s):  
Matthew Rusin ◽  
Nardine Ghobrial ◽  
Endre Takacs ◽  
Jeffrey S. Willey ◽  
Delphine Dean
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Radiation Therapy ◽  
Stem Cell ◽  
Regenerative Medicine ◽  
Ionizing Radiation ◽  
Dose Rate ◽  
Cell Types ◽  
High Energy ◽  
Adipose Derived Stem Cells

Biomedical use of radiation is utilized in effective diagnostic and treatment tools, yet can introduce risks to healthy tissues. High energy photons used for diagnostic purposes have high penetration depth and can discriminate multiple tissues based on attenuation properties of different materials. Likewise, the ability to deposit energy at various targets within tumors make the use of photons effective treatment for cancer. Radiation focused on a tumor will deposit energy when it interacts with a biological structure (e.g. DNA), which will result in cell kill should repair capacity of the tissue be overwhelmed. Likewise, damage to normal, non-cancerous tissues is a consequence of radiation that can lead to acute or late, chronic toxicity profiles. Adipose derived stem cells (ADSCs) are mesenchymal stem cells that have been proven to have similar characteristics to bone marrow derived stem cells, except that they are much easier to obtain. Within the body, ADSCs act as immunomodulators and assist with the maintenance and repair of tissues. They have been shown to have excellent differentiation capability, making them an extremely viable option for stem cell therapies and regenerative medicine applications. Due to the tissue ADSCs are derived from, they are highly likely to be affected by radiation therapy, especially when treating tumors localized to structures with relatively high ADSC content (eg., breast cancer). For this reason, the purpose behind this research is to better understand how ADSCs are affected by doses of radiation comparable to a single fraction of radiation therapy. We also measured the response of ADSCs to exposure at different dose rates to determine if there is a significant difference in the response of ADSCs to radiation therapy relevant doses of ionizing radiation. Our findings indicate that ADSCs exposed to Cesium (Cs 137)-gamma rays at a moderate dose of 2Gy and either a low dose rate (1.40Gy/min) or a high dose rate (7.31Gy/min) slow proliferation rate, and with cell cycle arrest in some populations. These responses ADSCs were not as marked as previously measured in other stem cell types. In addition, our results indicate that differences in dose rate in the Gy/min range typically utilized in small animal or cell irradiation platforms have a minimal effect on the function of ADSCs. The potential ADSCs have in the space of regenerative medicine makes them an ideal candidate for study with ionizing radiation, as they are one of the main cell types to promote tissue healing.

Early determination in the C. elegans embryo: a gene, cib-1, required to specify a set of stem-cell-like blastomeres

Development ◽  
1990 ◽  
Vol 108 (1) ◽  
pp. 107-119 ◽  
Author(s):  
R. Schnabel ◽  
H. Schnabel
Keyword(s):  
Cell Cycle ◽  
Decision Making ◽  
Stem Cell ◽  
Early Embryo ◽  
Cell Cycles ◽  
C Elegans ◽  
Lethal Mutations ◽  
A Cell ◽  
Early Decision ◽  
P Cells

The early somatic blastomeres founding the tissues in the C. elegans embryo are derived in a stem-cell-like lineage from the P cells. We have isolated maternal effect lethal mutations defining the gene cib-1 in which the P cells, P1-P3, skip a cell cycle and acquire the fates of only their somatic daughters. Therefore, the cib-1 gene is required for the specification of the stem-cell-like fate of these cells. The analysis of the development of these mutants suggests that the clock controlling the cell cycles in the early embryo is directly coupled to the fate of a cell and that there must be another developmental clock that activates the determinative inventory for the early decision-making.

scholarly journals Cell Cycle-Driven Heterogeneity: On the Road to Demystifying the Transitions between “Poised” and “Restricted” Pluripotent Cell States

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Amar M. Singh
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Pluripotent Stem Cells ◽  
Cell Types ◽  
Cellular Heterogeneity ◽  
The Road ◽  
Developmental Factors ◽  
On The Road ◽  
G1 Cells

Cellular heterogeneity is now considered an inherent property of most stem cell types, including pluripotent stem cells, somatic stem cells, and cancer stem cells, and this heterogeneity can exist at the epigenetic, transcriptional, and posttranscriptional levels. Several studies have indicated that the stochastic activation of signaling networks may promote heterogeneity and further that this heterogeneity may be reduced by their inhibition. But why different cells in the same culture respond in a nonuniform manner to the identical exogenous signals has remained unclear. Recent studies now demonstrate that the cell cycle position directly influences lineage specification and specifically that pluripotent stem cells initiate their differentiation from the G1 phase. These studies suggest that cells in G1 are uniquely “poised” to undergo cell specification. G1 cells are therefore more prone to respond to differentiation cues, which may explain the heterogeneity of developmental factors, such as Gata6, and pluripotency factors, such as Nanog, in stem cell cultures. Overall, this raises the possibility that G1 serves as a “Differentiation Induction Point.” In this review, we will reexamine the literature describing heterogeneity of pluripotent stem cells, while highlighting the role of the cell cycle as a major determinant.

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