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

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...

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Autores principales: Mende, Nicole, Kuchen, Erika E., Lesche, Mathias, Grinenko, Tatyana, Kokkaliaris, Konstantinos D., Hanenberg, Helmut, Lindemann, Dirk, Dahl, Andreas, Platz, Alexander, Höfer, Thomas, Calegari, Federico, Waskow, Claudia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516798/
https://www.ncbi.nlm.nih.gov/pubmed/26150472
http://dx.doi.org/10.1084/jem.20150308
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author Mende, Nicole
Kuchen, Erika E.
Lesche, Mathias
Grinenko, Tatyana
Kokkaliaris, Konstantinos D.
Hanenberg, Helmut
Lindemann, Dirk
Dahl, Andreas
Platz, Alexander
Höfer, Thomas
Calegari, Federico
Waskow, Claudia
author_facet Mende, Nicole
Kuchen, Erika E.
Lesche, Mathias
Grinenko, Tatyana
Kokkaliaris, Konstantinos D.
Hanenberg, Helmut
Lindemann, Dirk
Dahl, Andreas
Platz, Alexander
Höfer, Thomas
Calegari, Federico
Waskow, Claudia
author_sort Mende, Nicole
collection PubMed
description 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.
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spelling pubmed-45167982016-01-27 CCND1–CDK4–mediated cell cycle progression provides a competitive advantage for human hematopoietic stem cells in vivo Mende, Nicole Kuchen, Erika E. Lesche, Mathias Grinenko, Tatyana Kokkaliaris, Konstantinos D. Hanenberg, Helmut Lindemann, Dirk Dahl, Andreas Platz, Alexander Höfer, Thomas Calegari, Federico Waskow, Claudia J Exp Med Article 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. The Rockefeller University Press 2015-07-27 /pmc/articles/PMC4516798/ /pubmed/26150472 http://dx.doi.org/10.1084/jem.20150308 Text en © 2015 Mende et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Mende, Nicole
Kuchen, Erika E.
Lesche, Mathias
Grinenko, Tatyana
Kokkaliaris, Konstantinos D.
Hanenberg, Helmut
Lindemann, Dirk
Dahl, Andreas
Platz, Alexander
Höfer, Thomas
Calegari, Federico
Waskow, Claudia
CCND1–CDK4–mediated cell cycle progression provides a competitive advantage for human hematopoietic stem cells in vivo
title CCND1–CDK4–mediated cell cycle progression provides a competitive advantage for human hematopoietic stem cells in vivo
title_full CCND1–CDK4–mediated cell cycle progression provides a competitive advantage for human hematopoietic stem cells in vivo
title_fullStr CCND1–CDK4–mediated cell cycle progression provides a competitive advantage for human hematopoietic stem cells in vivo
title_full_unstemmed CCND1–CDK4–mediated cell cycle progression provides a competitive advantage for human hematopoietic stem cells in vivo
title_short CCND1–CDK4–mediated cell cycle progression provides a competitive advantage for human hematopoietic stem cells in vivo
title_sort ccnd1–cdk4–mediated cell cycle progression provides a competitive advantage for human hematopoietic stem cells in vivo
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516798/
https://www.ncbi.nlm.nih.gov/pubmed/26150472
http://dx.doi.org/10.1084/jem.20150308
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