Responsiveness of Hematopoietic Tissue to Erythropoietin in Relation to the Time of Administration and Duration of Action of the Hormone

Abstract Following the injection of erythropoietin either in a single large dose or in multiple doses, a change in the responsiveness of the hematopoietic tissue occurs. The fact that different doses of erythropoietin stimulate erythropoiesis to the same extent when the action of the hormone is limited to 6 hours by the injection of antibody suggests that the stem cells are receptive to the action of erythropoietin only at some limited time in their individual life cycle. It is suggested that this period is sometime after metaphase and before the commencement of DNA synthesis in the interphase state of individual stem cells. It is further suggested that the increased responsiveness of the hematopoietic tissue to erythropoietin following injection is due to recruitment of stem cells into this receptive state. This recruitment may be due to both the division of stem cells and the movement of cells through cell cycle into the receptive state. The results are discussed in relation to two recent models of stem cell kinetics.

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Bmi1 Augments Proliferation and Survival of Cortical Bone-Derived Stem Cells after Injury through Novel Epigenetic Signaling via Histone 3 Regulation

International Journal of Molecular Sciences ◽

10.3390/ijms22157813 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7813

Author(s):

Lindsay Kraus ◽

Chris Bryan ◽

Marcus Wagner ◽

Tabito Kino ◽

Melissa Gunchenko ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Dna Damage ◽

Stem Cell ◽

Histone Modification ◽

Epigenetic Regulation ◽

Critical Role ◽

Proliferative Potential ◽

Therapeutic Effects ◽

Histone 3

Ischemic heart disease can lead to myocardial infarction (MI), a major cause of morbidity and mortality worldwide. Multiple stem cell types have been safely transferred into failing human hearts, but the overall clinical cardiovascular benefits have been modest. Therefore, there is a dire need to understand the basic biology of stem cells to enhance therapeutic effects. Bmi1 is part of the polycomb repressive complex 1 (PRC1) that is involved in different processes including proliferation, survival and differentiation of stem cells. We isolated cortical bones stem cells (CBSCs) from bone stroma, and they express significantly high levels of Bmi1 compared to mesenchymal stem cells (MSCs) and cardiac-derived stem cells (CDCs). Using lentiviral transduction, Bmi1 was knocked down in the CBSCs to determine the effect of loss of Bmi1 on proliferation and survival potential with or without Bmi1 in CBSCs. Our data show that with the loss of Bmi1, there is a decrease in CBSC ability to proliferate and survive during stress. This loss of functionality is attributed to changes in histone modification, specifically histone 3 lysine 27 (H3K27). Without the proper epigenetic regulation, due to the loss of the polycomb protein in CBSCs, there is a significant decrease in cell cycle proteins, including Cyclin B, E2F, and WEE as well as an increase in DNA damage genes, including ataxia-telangiectasia mutated (ATM) and ATM and Rad3-related (ATR). In conclusion, in the absence of Bmi1, CBSCs lose their proliferative potential, have increased DNA damage and apoptosis, and more cell cycle arrest due to changes in epigenetic modifications. Consequently, Bmi1 plays a critical role in stem cell proliferation and survival through cell cycle regulation, specifically in the CBSCs. This regulation is associated with the histone modification and regulation of Bmi1, therefore indicating a novel mechanism of Bmi1 and the epigenetic regulation of stem cells.

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Quiescent, Slow-Cycling Stem Cell Populations in Cancer: A Review of the Evidence and Discussion of Significance

Journal of Oncology ◽

10.1155/2011/396076 ◽

2011 ◽

Vol 2011 ◽

pp. 1-11 ◽

Cited By ~ 159

Author(s):

Nathan Moore ◽

Stephen Lyle

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Adult Stem Cells ◽

Cell Populations ◽

Proliferative Potential ◽

Cell Cycle Regulators ◽

Slow Cycling ◽

Stem Cell Populations

Long-lived cancer stem cells (CSCs) with indefinite proliferative potential have been identified in multiple epithelial cancer types. These cells are likely derived from transformed adult stem cells and are thought to share many characteristics with their parental population, including a quiescent slow-cycling phenotype. Various label-retaining techniques have been used to identify normal slow cycling adult stem cell populations and offer a unique methodology to functionally identify and isolate cancer stem cells. The quiescent nature of CSCs represents an inherent mechanism that at least partially explains chemotherapy resistance and recurrence in posttherapy cancer patients. Isolating and understanding the cell cycle regulatory mechanisms of quiescent cancer cells will be a key component to creation of future therapies that better target CSCs and totally eradicate tumors. Here we review the evidence for quiescent CSC populations and explore potential cell cycle regulators that may serve as future targets for elimination of these cells.

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

The Journal of Cell Biology ◽

10.1083/jcb.201501053 ◽

2015 ◽

Vol 210 (5) ◽

pp. 717-726 ◽

Cited By ~ 27

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.

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Loss of foxo rescues stem cell aging in Drosophila germ line

eLife ◽

10.7554/elife.27842 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 8

Author(s):

Filippo Artoni ◽

Rebecca E Kreipke ◽

Ondina Palmeira ◽

Connor Dixon ◽

Zachary Goldberg ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Stem Cell ◽

Ionizing Radiation ◽

Cell Injury ◽

Germ Line ◽

Adult Stem Cell ◽

Cell Aging ◽

Germline Stem Cells ◽

Cell Cycle Reentry

Aging stem cells lose the capacity to properly respond to injury and regenerate their residing tissues. Here, we utilized the ability of Drosophila melanogaster 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 foxo and mTOR homologue, Tor as important regulators of GSC quiescence following exposure to ionizing radiation. foxo is required for entry in quiescence, while Tor 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 foxo.

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Abstract 2621: OLIG2 regulates stem cell maintenance and cell cycle in glioma stem cells

10.1158/1538-7445.sabcs18-2621 ◽

2019 ◽

Author(s):

Norihiko Saito ◽

Nozomi Hirai ◽

Kazuya Aoki ◽

Satoshi Fujita ◽

Haruo Nakayama ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Stem Cell ◽

Glioma Stem Cells ◽

Stem Cell Maintenance ◽

Cell Maintenance

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Proteomic Analysis of Breast Cancer Resistance to the Anticancer Drug RH1 Reveals the Importance of Cancer Stem Cells

Cancers ◽

10.3390/cancers11070972 ◽

2019 ◽

Vol 11 (7) ◽

pp. 972

Author(s):

Dalius Kuciauskas ◽

Nadezda Dreize ◽

Marija Ger ◽

Algirdas Kaupinis ◽

Kristijonas Zemaitis ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Proteomic Analysis ◽

Acquired Resistance ◽

Cancer Resistance ◽

Resistant Cells

Antitumor drug resistance remains a major challenge in cancer chemotherapy. Here we investigated the mechanism of acquired resistance to a novel anticancer agent RH1 designed to be activated in cancer cells by the NQO1 enzyme. Data show that in some cancer cells RH1 may act in an NQO1-independent way. Differential proteomic analysis of breast cancer cells with acquired resistance to RH1 revealed changes in cell energy, amino acid metabolism and G2/M cell cycle transition regulation. Analysis of phosphoproteomics and protein kinase activity by multiplexed kinase inhibitor beads showed an increase in the activity of protein kinases involved in the cell cycle and stemness regulation and downregulation of proapoptotic kinases such as JNK in RH1-resistant cells. Suppression of JNK leads to the increase of cancer cell resistance to RH1. Moreover, resistant cells have enhanced expression of stem cell factor (SCF) and stem cell markers. Inhibition of SCF receptor c-KIT resulted in the attenuation of cancer stem cell enrichment and decreased amounts of tumor-initiating cells. RH1-resistant cells also acquire resistance to conventional therapeutics while remaining susceptible to c-KIT-targeted therapy. Data show that RH1 can be useful to treat cancers in the NQO1-independent way, and targeting of the cancer stem cells might be an effective approach for combating resistance to RH1 therapy.

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

Blood ◽

10.1182/blood.v96.13.4185 ◽

2000 ◽

Vol 96 (13) ◽

pp. 4185-4193 ◽

Cited By ~ 181

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.

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Brief Note: Effect of Erythropoietin on Polycythemic Mouse Spleen in Vitro IV. Response of the Colony-forming Cells to Erythropoietin

Blood ◽

10.1182/blood.v32.2.271.271 ◽

1968 ◽

Vol 32 (2) ◽

pp. 271-277 ◽

Cited By ~ 1

Author(s):

HIDEAKI MIZOGUCHI ◽

YASUSADA MIURA ◽

FUMIMARO TAKAKU ◽

KIKU NAKAO

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Bone Marrow ◽

Stem Cell ◽

Bone Marrow Transplantation ◽

Marrow Transplantation ◽

In Vitro System ◽

Cell Pool ◽

Stem Cell Pool

Abstract It is shown that an in vitro system of assaying the size of an erythropoietin-responsive stem cell pool could be applied to the spleens of polycythemic mice after irradiation and bone marrow transplantation. With this method, the presence of erythropoietin-responsive cells in the spleen was first detected on the second day after transplantation. Therefore, it is considered probable that colony-forming cells and erythropoietin-responsive cells are at different stages of maturation or cell cycle. Furthermore, necessity of erythropoietin for further differentiation of transplanted stem cells into erythroblasts is also suggested.

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Centrosome misorientation mediates slowing of the cell cycle under limited nutrient conditions in Drosophila male germline stem cells

Molecular Biology of the Cell ◽

10.1091/mbc.e11-12-0999 ◽

2012 ◽

Vol 23 (8) ◽

pp. 1524-1532 ◽

Cited By ~ 21

Author(s):

Therese M. Roth ◽

C.-Y. Ason Chiang ◽

Mayu Inaba ◽

Hebao Yuan ◽

Viktoria Salzmann ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Cell Proliferation ◽

Stem Cell ◽

Germline Stem Cells ◽

Self Renewal ◽

Stem Cell Regulation ◽

Male Germline ◽

Male Germline Stem Cells ◽

Nutrient Conditions

Drosophila male germline stem cells (GSCs) divide asymmetrically, balancing self-renewal and differentiation. Although asymmetric stem cell division balances between self-renewal and differentiation, it does not dictate how frequently differentiating cells must be produced. In male GSCs, asymmetric GSC division is achieved by stereotyped positioning of the centrosome with respect to the stem cell niche. Recently we showed that the centrosome orientation checkpoint monitors the correct centrosome orientation to ensure an asymmetric outcome of the GSC division. When GSC centrosomes are not correctly oriented with respect to the niche, GSC cell cycle is arrested/delayed until the correct centrosome orientation is reacquired. Here we show that induction of centrosome misorientation upon culture in poor nutrient conditions mediates slowing of GSC cell proliferation via activation of the centrosome orientation checkpoint. Consistently, inactivation of the centrosome orientation checkpoint leads to lack of cell cycle slowdown even under poor nutrient conditions. We propose that centrosome misorientation serves as a mediator that transduces nutrient information into stem cell proliferation, providing a previously unappreciated mechanism of stem cell regulation in response to nutrient conditions.

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Bone Morphogenetic Proteins Regulate the Developmental Program of Human Hematopoietic Stem Cells

Journal of Experimental Medicine ◽

10.1084/jem.189.7.1139 ◽

1999 ◽

Vol 189 (7) ◽

pp. 1139-1148 ◽

Cited By ~ 270

Author(s):

Mickie Bhatia ◽

Dominique Bonnet ◽

Dongmei Wu ◽

Barbara Murdoch ◽

Jeff Wrana ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Hematopoietic Stem Cells ◽

Bone Morphogenetic Proteins ◽

Transforming Growth Factor ◽

Critical Role ◽

Type I ◽

Hematopoietic Tissue ◽

Hematopoietic Stem ◽

Proliferation And Differentiation

The identification of molecules that regulate human hematopoietic stem cells has focused mainly on cytokines, of which very few are known to act directly on stem cells. Recent studies in lower organisms and the mouse have suggested that bone morphogenetic proteins (BMPs) may play a critical role in the specification of hematopoietic tissue from the mesodermal germ layer. Here we report that BMPs regulate the proliferation and differentiation of highly purified primitive human hematopoietic cells from adult and neonatal sources. Populations of rare CD34+CD38−Lin− stem cells were isolated from human hematopoietic tissue and were found to express the BMP type I receptors activin-like kinase (ALK)-3 and ALK-6, and their downstream transducers SMAD-1, -4, and -5. Treatment of isolated stem cell populations with soluble BMP-2, -4, and -7 induced dose-dependent changes in proliferation, clonogenicity, cell surface phenotype, and multilineage repopulation capacity after transplantation in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Similar to transforming growth factor β, treatment of purified cells with BMP-2 or -7 at high concentrations inhibited proliferation yet maintained the primitive CD34+CD38− phenotype and repopulation capacity. In contrast, low concentrations of BMP-4 induced proliferation and differentiation of CD34+ CD38−Lin− cells, whereas at higher concentrations BMP-4 extended the length of time that repopulation capacity could be maintained in ex vivo culture, indicating a direct effect on stem cell survival. The discovery that BMPs are capable of regulating repopulating cells provides a new pathway for controlling human stem cell development and a powerful model system for studying the biological mechanism of BMP action using primary human cells.

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