Prolonged maintenance of hematopoietic stem cells that escape from Thrombopoietin deprivation

Blood ◽  
2021 ◽  
Author(s):  
Ayako Nakamura-Ishizu ◽  
Desmond Chin ◽  
Takayoshi Matsumura ◽  
Darren Qiancheng Tan ◽  
Makiko Kashio Mochizuki ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Cell Cycle Progression ◽  
Dependent Manner ◽  
Cycle Progression ◽  
Hematopoietic Stem ◽  
Mitochondrial Mass ◽  
Cell Phenotypes ◽  
Dose Dependent

Hematopoietic stem cells (HSC) rarely divide, rest in quiescence and proliferate only upon stress hematopoiesis. The cytokine thrombopoietin (Thpo) has been perplexingly described to induce quiescence and promote self-renewal divisions in HSCs. In order to clarify the contradictory effect of Thpo, we conducted a detailed analysis on conventional (Thpo-/-) and liver-specific (Thpofl/fl;AlbCre+/-) Thpo deletion models. Thpo-/- HSCs exhibited profound loss of quiescence, impaired cell cycle progression and increased apoptosis. Thpo-/- HSCs also exhibited diminished mitochondrial mass and impaired mitochondrial bioenergetics. Abnormal HSC phenotypes in Thpo-/- mice were reversible after HSC transplantation into wild type recipients. Moreover, Thpo-/- HSCs acquired quiescence with extended administration of a Thpo-receptor agonist, Romiplostim, and were prone to subsequent stem cell exhaustion during competitive bone marrow (BM) transplantation. Thpofl/fl;AlbCre+/- HSCs exhibited similar stem cell phenotypes but at a lesser extent than Thpo-/- HSCs. HSCs that survive Thpo deficiency acquire quiescence in a dose-dependent manner through the modification of their metabolic state.

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

2010 ◽  
Vol 19 (4) ◽  
pp. 453-460 ◽  
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

CCND1–CDK4–mediated cell cycle progression provides a competitive advantage for human hematopoietic stem cells in vivo

2015 ◽  
Vol 210 (2) ◽  
pp. 2102OIA144
Author(s):  
Nicole Mende ◽  
Erika E Kuchen ◽  
Mathias Lesche ◽  
Tatyana Grinenko ◽  
Konstantinos D Kokkaliaris ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Competitive Advantage ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Hematopoietic Stem

scholarly journals Stroma-Derived Connective Tissue Growth Factor Maintains Cell Cycle Progression and Repopulation Activity of Hematopoietic Stem Cells In Vitro

2015 ◽  
Vol 5 (5) ◽  
pp. 702-715 ◽  
Author(s):  
Rouzanna Istvánffy ◽  
Baiba Vilne ◽  
Christina Schreck ◽  
Franziska Ruf ◽  
Charlotta Pagel ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Growth Factor ◽  
Connective Tissue ◽  
Hematopoietic Stem Cells ◽  
Cell Cycle Progression ◽  
Tissue Growth ◽  
Cycle Progression ◽  
Hematopoietic Stem

Prolonged Expression of c-fos Suppresses Cell Cycle Entry of Dormant Hematopoietic Stem Cells

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 816-825 ◽  
Author(s):  
Seiji Okada ◽  
Tetsuya Fukuda ◽  
Kunimasa Inada ◽  
Takeshi Tokuhisa
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Colony Formation ◽  
Cell Cycle Progression ◽  
Fetal Liver ◽  
Cycle Progression ◽  
Hematopoietic Stem ◽  
Fetal Liver Cells ◽  
Deficient Mice

The proto-oncogene c-fos was transiently upregulated in primitive hematopoietic stem (Lin−Sca-1+) cells stimulated with stem cell factor, interleukin-3 (IL-3), and IL-6. To investigate a role of the c-fos in hematopoietic stem cells, we used bone marrow (BM) cells from transgenic mice carrying the c-fos gene under the control of the interferon-/β–inducible Mx-promoter (Mx–c-fos), and fetal liver cells from c-fos–deficient mice. Prolonged expression of the c-fos in Lin−Sca-1+ BM cells inhibited factor-dependent colony formation and hematopoiesis on a stromal cell layer by keeping them at G0/G1 phase of the cell cycle. These Lin−Sca-1+ BM cells on a stromal layer entered into the cell cycle whenever exogenous c-fos was downregulated. However, ectopic c-fos did not perturb colony formation by Lin−Sca-1+ BM cells after they entered the cell cycle. Furthermore, endogenous c-fos is not essential to cell cycle progression of hematopoietic stem cells because the factor-dependent and the stroma-dependent hematopoiesis by Lin−Sca-1+ fetal liver cells from c-fos–deficient mice was not impaired. These results suggest that the c-fos induced in primitive hematopoietic stem cells negatively controls cell cycle progression and maintains them in a dormant state.

Cell cycle progression and fate decisions in hematopoietic stem cells

2017 ◽  
Vol 53 ◽  
pp. S102
Author(s):  
Tatyana Grinenko ◽  
Anne Eugster ◽  
Lars Thielecke ◽  
Ingmar Glauche ◽  
Onur Basak ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Hematopoietic Stem

Prolonged Expression of c-fos Suppresses Cell Cycle Entry of Dormant Hematopoietic Stem Cells

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 816-825 ◽  
Author(s):  
Seiji Okada ◽  
Tetsuya Fukuda ◽  
Kunimasa Inada ◽  
Takeshi Tokuhisa
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Colony Formation ◽  
Cell Cycle Progression ◽  
Fetal Liver ◽  
Cycle Progression ◽  
Hematopoietic Stem ◽  
Fetal Liver Cells ◽  
Deficient Mice

Abstract The proto-oncogene c-fos was transiently upregulated in primitive hematopoietic stem (Lin−Sca-1+) cells stimulated with stem cell factor, interleukin-3 (IL-3), and IL-6. To investigate a role of the c-fos in hematopoietic stem cells, we used bone marrow (BM) cells from transgenic mice carrying the c-fos gene under the control of the interferon-/β–inducible Mx-promoter (Mx–c-fos), and fetal liver cells from c-fos–deficient mice. Prolonged expression of the c-fos in Lin−Sca-1+ BM cells inhibited factor-dependent colony formation and hematopoiesis on a stromal cell layer by keeping them at G0/G1 phase of the cell cycle. These Lin−Sca-1+ BM cells on a stromal layer entered into the cell cycle whenever exogenous c-fos was downregulated. However, ectopic c-fos did not perturb colony formation by Lin−Sca-1+ BM cells after they entered the cell cycle. Furthermore, endogenous c-fos is not essential to cell cycle progression of hematopoietic stem cells because the factor-dependent and the stroma-dependent hematopoiesis by Lin−Sca-1+ fetal liver cells from c-fos–deficient mice was not impaired. These results suggest that the c-fos induced in primitive hematopoietic stem cells negatively controls cell cycle progression and maintains them in a dormant state.

scholarly journals Gene expression fluctuations in murine hematopoietic stem cells with cell cycle progression

2007 ◽  
Vol 214 (3) ◽  
pp. 786-795 ◽  
Author(s):  
Gerri J. Dooner ◽  
Gerald A. Colvin ◽  
Mark S. Dooner ◽  
Kevin W. Johnson ◽  
Peter J. Quesenberry
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Hematopoietic Stem

scholarly journals CCND1–CDK4–mediated cell cycle progression provides a competitive advantage for human hematopoietic stem cells in vivo

2015 ◽  
Vol 212 (8) ◽  
pp. 1171-1183 ◽  
Author(s):  
Nicole Mende ◽  
Erika E. Kuchen ◽  
Mathias Lesche ◽  
Tatyana Grinenko ◽  
Konstantinos D. Kokkaliaris ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Competitive Advantage ◽  
Cell Cycle Progression ◽  
Cycle Phase ◽  
Cycle Progression ◽  
Hematopoietic Stem ◽  
Human Hscs

Maintenance of stem cell properties is associated with reduced proliferation. However, in mouse hematopoietic stem cells (HSCs), loss of quiescence results in a wide range of phenotypes, ranging from functional failure to extensive self-renewal. It remains unknown whether the function of human HSCs is controlled by the kinetics of cell cycle progression. Using human HSCs and human progenitor cells (HSPCs), we report here that elevated levels of CCND1–CDK4 complexes promoted the transit from G0 to G1 and shortened the G1 cell cycle phase, resulting in protection from differentiation-inducing signals in vitro and increasing human leukocyte engraftment in vivo. Further, CCND1–CDK4 overexpression conferred a competitive advantage without impacting HSPC numbers. In contrast, accelerated cell cycle progression mediated by elevated levels of CCNE1–CDK2 led to the loss of functional HSPCs in vivo. Collectively, these data suggest that the transition kinetics through the early cell cycle phases are key regulators of human HSPC function and important for lifelong hematopoiesis.

Sign in / Sign up

Export Citation Format

Share Document