Cell cycle regulation in hematopoietic stem cells

Hematopoietic stem cells (HSCs) give rise to all lineages of blood cells. Because HSCs must persist for a lifetime, the balance between their proliferation and quiescence is carefully regulated to ensure blood homeostasis while limiting cellular damage. Cell cycle regulation therefore plays a critical role in controlling HSC function during both fetal life and in the adult. The cell cycle activity of HSCs is carefully modulated by a complex interplay between cell-intrinsic mechanisms and cell-extrinsic factors produced by the microenvironment. This fine-tuned regulatory network may become altered with age, leading to aberrant HSC cell cycle regulation, degraded HSC function, and hematological malignancy.

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Cell Cycle Regulation and Cell Fate Decisions in Hematopoietic Stem Cells.

Blood ◽

10.1182/blood.v106.11.1349.1349 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1349-1349

Author(s):

Emmanuelle Passegue ◽

Amy J. Wagers ◽

Sylvie Giuriato ◽

Wade C. Anderson ◽

Irving L. Weissman

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Hematopoietic Stem Cells ◽

Cell Fate ◽

Cell Cycle Regulation ◽

Self Renewal ◽

Hematopoietic Stem ◽

Cell Fate Decisions ◽

Cycle Regulation

Abstract The blood is a perpetually renewing tissue seeded by a rare population of adult bone marrow hematopoietic stem cells (HSC). During steady-state hematopoiesis, the HSC population is relatively quiescent but constantly maintains a low numbers of cycling cells that differentiate to produce the various lineage of mature blood cells. However, in response to hematological stress, the entire HSC population can be recruited into cycle to self-renew and regenerate the blood-forming system. HSC proliferation is therefore highly adaptative and requires appropriate regulation of cell cycle progression to drive both differentiation-associated and self-renewal-associated proliferation, without depletion of the stem cell pool. Although the molecular events controlling HSC proliferation are still poorly understood, they are likely determined, at least in part, by regulated expression and/or function of components and regulators of the cell cycle machinery. Here, we demonstrate that the long-term self-renewing HSC (defined as Lin−/c-Kit+/Sca-1+/Thy1.1int/Flk2−) exists in two distinct states that are both equally important for their in vivo functions as stem cells: a numerically dominant quiescent state, which is critical for HSC function in hematopoietic reconstitution; and a proliferative state, which represents almost a fourth of this population and is essential for HSC functions in differentiation and self-renewal. We show that when HSC exit quiescence and enter G1 as a prelude to cell division, at least two critical events occur: first, during the G1 and subsequent S-G2/M phases, they temporarily lose efficient in vivo engraftment activity, while retaining in vitro differentiation potential; and second, they select the particular cell cycle proteins that are associated with specific developmental outcomes (self-renewal vs. differentiation) and developmental fates (myeloid vs. lymphoid). Together, these findings provide a direct link between HSC proliferation, cell cycle regulation and cell fate decisions that have critical implications for both the therapeutic use of HSC and the understanding of leukemic transformation.

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Cell Cycle Regulation in Human Hematopoietic Stem Cells: From Isolation to Activation

Leukemia & Lymphoma ◽

10.1080/10428190290011967 ◽

2002 ◽

Vol 43 (3) ◽

pp. 493-501 ◽

Cited By ~ 5

Author(s):

Maria Marone ◽

Daniela de Ritis ◽

Giuseppina Bonanno ◽

Simona Mozzetti ◽

Sergio Rutella ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Hematopoietic Stem Cells ◽

Cell Cycle Regulation ◽

Hematopoietic Stem ◽

Cycle Regulation

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FLT3/ITD Expression Increases Expansion, Survival and Entry into Cell Cycle of Human Hematopoietic Stem Cells.

Blood ◽

10.1182/blood.v104.11.484.484 ◽

2004 ◽

Vol 104 (11) ◽

pp. 484-484

Author(s):

Li Li ◽

Obdulio Piloto ◽

Kyu-Tae Kim ◽

Zhaohui Ye ◽

Bao Nguyen ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Tyrosine Kinase ◽

Cell Cycle Regulation ◽

Cyclin D3 ◽

Leukemic Transformation ◽

Hematopoietic Stem ◽

Activating Mutations ◽

Juxtamembrane Region ◽

Cycle Regulation

Abstract FMS-like tyrosine kinase-3 (FLT3) is a Class III receptor tyrosine kinase that is important for normal hematopoiesis. Activating mutations of FLT3 by internal tandem duplications (ITDs) in the juxtamembrane region are the most common molecular aberrations found in acute myeloid leukemia (AML). The contributions of FLT3 activating mutations in the leukemic transformation of normal human hematopoietic stem/progenitor cells (HSCs) have not yet been fully elucidated. In this study, using a single lentiviral vector containing two promoters, we achieved consistent and efficient coexpression of FLT3/ITD and green fluorescent protein (GFP) in transduced human CD34+ HSCs. When cultured in medium containing SCF, TPO and FLT3 ligand (FL), FLT3/ITD-transduced cells survived with enhanced self-renewal and survival potential, which was not affected by the withdrawal of FL. These cells retained a surface immunophenotype typical of HSCs (CD34+CD38−). Compared to cells transduced with a vector expressing GFP alone, FLT3/ITD-transduced HSCs had a higher fraction of cells in cell cycle. Clonogenic assays showed that FLT3/ITD-transduced HSCs produced fewer CFU-GM, implying that they were at least partially blocked in their ability to differentiate along the myeloid lineage. FLT3/ITD-transduced HSCs were more sensitive to the induction of cytotoxicity by CEP-701, a selective FLT3 inhibitor. In the FLT3/ITD-transduced HSCs, we detected increased expression of Pim-1, a serine/threonine kinase with an important role in cell survival, proliferation and differentiation, c-myc, a transcription factor involved in cell proliferation and cell cycle regulation, and Cyclin D3, a key factor in cell cycle regulation, each of which may contribute to the altered genetic program instituted by FLT3/ITD signaling. These results together indicate that FLT3/ITD mutations may contribute to leukemic transformation of normal HSCs by prolonging survival, promoting proliferation, and blocking differentiation. CEP-701 may act as a potent agent for AML stem cells harboring FLT3/ITD mutations.

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Single-cell RNA-seq reveals a concomitant delay in differentiation and cell cycle of aged hematopoietic stem cells

BMC Biology ◽

10.1186/s12915-021-00955-z ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Léonard Hérault ◽

Mathilde Poplineau ◽

Adrien Mazuel ◽

Nadine Platet ◽

Élisabeth Remy ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Hematopoietic Stem Cells ◽

Cell Cycle Regulators ◽

Potential Mechanism ◽

Rna Seq ◽

Hematopoietic Stem ◽

Age Related ◽

Undifferentiated State ◽

Reference Map

Abstract Background Hematopoietic stem cells (HSCs) are the guarantor of the proper functioning of hematopoiesis due to their incredible diversity of potential. During aging, heterogeneity of HSCs changes, contributing to the deterioration of the immune system. In this study, we revisited mouse HSC compartment and its transcriptional plasticity during aging at unicellular scale. Results Through the analysis of 15,000 young and aged transcriptomes, we identified 15 groups of HSCs revealing rare and new specific HSC abilities that change with age. The implantation of new trajectories complemented with the analysis of transcription factor activities pointed consecutive states of HSC differentiation that were delayed by aging and explained the bias in differentiation of older HSCs. Moreover, reassigning cell cycle phases for each HSC clearly highlighted an imbalance of the cell cycle regulators of very immature aged HSCs that may contribute to their accumulation in an undifferentiated state. Conclusions Our results establish a new reference map of HSC differentiation in young and aged mice and reveal a potential mechanism that delays the differentiation of aged HSCs and could promote the emergence of age-related hematologic diseases.

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Expression of Cell Cycle–Related Genes With Cytokine-Induced Cell Cycle Progression of Primitive Hematopoietic Stem Cells

Stem Cells and Development ◽

10.1089/scd.2009.0283 ◽

2010 ◽

Vol 19 (4) ◽

pp. 453-460 ◽

Cited By ~ 5

Author(s):

Peter J. Quesenberry ◽

Gerri J. Dooner ◽

Michael Del Tatto ◽

Gerald A. Colvin ◽

Kevin Johnson ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Hematopoietic Stem Cells ◽

Cell Cycle Progression ◽

Cycle Progression ◽

Hematopoietic Stem

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Cell Cycle Regulation in Hematopoietic Stem/progenitor Cells

Journal of Biological Sciences ◽

10.3923/jbs.2005.50.60 ◽

2004 ◽

Vol 5 (1) ◽

pp. 50-60

Author(s):

Hirokazu Tanaka . ◽

Itaru Matsumura . ◽

Yuzuru Kanakura .

Keyword(s):

Cell Cycle ◽

Progenitor Cells ◽

Cell Cycle Regulation ◽

Hematopoietic Stem ◽

Cycle Regulation

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Increased proliferation and altered cell cycle regulation in pancreatic stem cells derived from patients with congenital hyperinsulinism

PLoS ONE ◽

10.1371/journal.pone.0222350 ◽

2019 ◽

Vol 14 (9) ◽

pp. e0222350 ◽

Cited By ~ 1

Author(s):

Sophie G. Kellaway ◽

Karolina Mosinska ◽

Zainaba Mohamed ◽

Alexander Ryan ◽

Stephen Richardson ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Cell Cycle Regulation ◽

Congenital Hyperinsulinism ◽

Pancreatic Stem Cells ◽

Altered Cell ◽

Cycle Regulation

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Babam2 Regulates Cell Cycle Progression and Pluripotency in Mouse Embryonic Stem Cells as Revealed by Induced DNA Damage

Biomedicines ◽

10.3390/biomedicines8100397 ◽

2020 ◽

Vol 8 (10) ◽

pp. 397

Author(s):

Cheuk Yiu Tenny Chung ◽

Paulisally Hau Yi Lo ◽

Kenneth Ka Ho Lee

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Dna Damage ◽

Gamma Irradiation ◽

Cellular Senescence ◽

Cell Cycle Regulation ◽

Cell Cycle Progression ◽

Embryonic Stem ◽

Cycle Progression ◽

Cycle Regulation

BRISC and BRCA1-A complex member 2 (Babam2) plays an essential role in promoting cell cycle progression and preventing cellular senescence. Babam2-deficient fibroblasts show proliferation defect and premature senescence compared with their wild-type (WT) counterpart. Pluripotent mouse embryonic stem cells (mESCs) are known to have unlimited cell proliferation and self-renewal capability without entering cellular senescence. Therefore, studying the role of Babam2 in ESCs would enable us to understand the mechanism of Babam2 in cellular aging, cell cycle regulation, and pluripotency in ESCs. For this study, we generated Babam2 knockout (Babam2−/−) mESCs to investigate the function of Babam2 in mESCs. We demonstrated that the loss of Babam2 in mESCs leads to abnormal G1 phase retention in response to DNA damage induced by gamma irradiation or doxorubicin treatments. Key cell cycle regulators, CDC25A and CDK2, were found to be degraded in Babam2−/− mESCs following gamma irradiation. In addition, Babam2−/− mESCs expressed p53 strongly and significantly longer than in control mESCs, where p53 inhibited Nanog expression and G1/S cell cycle progression. The combined effects significantly reduced developmental pluripotency in Babam2−/− mESCs. In summary, Babam2 maintains cell cycle regulation and pluripotency in mESCs in response to induced DNA damage.

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