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 ◽  
...  

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.

2015 ◽  
Vol 210 (2) ◽  
pp. 2102OIA144
Author(s):  
Nicole Mende ◽  
Erika E Kuchen ◽  
Mathias Lesche ◽  
Tatyana Grinenko ◽  
Konstantinos D Kokkaliaris ◽  
...  

2010 ◽  
Vol 19 (4) ◽  
pp. 453-460 ◽  
Author(s):  
Peter J. Quesenberry ◽  
Gerri J. Dooner ◽  
Michael Del Tatto ◽  
Gerald A. Colvin ◽  
Kevin Johnson ◽  
...  

2015 ◽  
Vol 5 (5) ◽  
pp. 702-715 ◽  
Author(s):  
Rouzanna Istvánffy ◽  
Baiba Vilne ◽  
Christina Schreck ◽  
Franziska Ruf ◽  
Charlotta Pagel ◽  
...  

2002 ◽  
Vol 196 (9) ◽  
pp. 1141-1150 ◽  
Author(s):  
J. Cashman ◽  
B. Dykstra ◽  
I. Clark-Lewis ◽  
A. Eaves ◽  
C. Eaves

Human hematopoietic tissue contains rare stem cells with multilineage reconstituting ability demonstrable in receptive xenogeneic hosts. We now show that within 3 wk nonobese diabetic severe combined immunodeficiency (NOD/SCID) mice transplanted with human fetal liver cells regenerate near maximum levels of daughter human hematopoietic stem cells (HSCs) able to repopulate secondary NOD/SCID mice. At this time, most of the human HSCs (and other primitive progenitors) are actively proliferating as shown by their sensitivity to treatments that kill cycling cells selectively (e.g., exposure to high specific-activity [3H]thymidine in vitro or 5-fluorouracil in vivo). Interestingly, the proliferating human HSCs were rapidly forced into quiescence by in vivo administration of stromal-derived factor-1 (SDF-1) and this was accompanied by a marked increase in the numbers of human HSCs detectable. A similar result was obtained when transforming growth factor-β was injected, consistent with a reversible change in HSCs engrafting potential linked to changes in their cell cycle status. By 12 wk after transplant, most of the human HSCs had already entered Go and treatment with SDF-1 had no effect on their engrafting activity. These findings point to the existence of novel mechanisms by which inhibitors of HSC cycling can regulate the engrafting ability of human HSCs executing self-renewal divisions in vivo.


Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 816-825 ◽  
Author(s):  
Seiji Okada ◽  
Tetsuya Fukuda ◽  
Kunimasa Inada ◽  
Takeshi Tokuhisa

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.


2017 ◽  
Vol 53 ◽  
pp. S102
Author(s):  
Tatyana Grinenko ◽  
Anne Eugster ◽  
Lars Thielecke ◽  
Ingmar Glauche ◽  
Onur Basak ◽  
...  

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 816-825 ◽  
Author(s):  
Seiji Okada ◽  
Tetsuya Fukuda ◽  
Kunimasa Inada ◽  
Takeshi Tokuhisa

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.


2007 ◽  
Vol 214 (3) ◽  
pp. 786-795 ◽  
Author(s):  
Gerri J. Dooner ◽  
Gerald A. Colvin ◽  
Mark S. Dooner ◽  
Kevin W. Johnson ◽  
Peter J. Quesenberry

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