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

Nicole Mende, Erika E. Kuchen, Mathias Lesche, Tatyana Grinenko, Konstantinos D. Kokkaliaris, Helmut Hanenberg, Dirk Lindemann, Andreas Dahl, Alexander Platz, Thomas Höfer, Federico Calegari, Claudia Waskow

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1171-1183
Number of pages13
JournalJournal of Experimental Medicine
Volume212
Issue number8
DOIs
StatePublished - Jul 27 2015

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Hematopoietic Stem Cells
Cell Cycle
Stem Cells
Hematopoiesis
Leukocytes
Cell Count
Maintenance
Phenotype

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Mende, N., Kuchen, E. E., Lesche, M., Grinenko, T., Kokkaliaris, K. D., Hanenberg, H., ... Waskow, C. (2015). CCND1-CDK4-mediated cell cycle progression provides a competitive advantage for human hematopoietic stem cells in vivo. Journal of Experimental Medicine, 212(8), 1171-1183. https://doi.org/10.1084/jem.20150308

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.

In: Journal of Experimental Medicine, Vol. 212, No. 8, 27.07.2015, p. 1171-1183.

Research output: Contribution to journalArticle

Mende, N, Kuchen, EE, Lesche, M, Grinenko, T, Kokkaliaris, KD, Hanenberg, H, Lindemann, D, Dahl, A, Platz, A, Höfer, T, Calegari, F & Waskow, C 2015, 'CCND1-CDK4-mediated cell cycle progression provides a competitive advantage for human hematopoietic stem cells in vivo', Journal of Experimental Medicine, vol. 212, no. 8, pp. 1171-1183. https://doi.org/10.1084/jem.20150308
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. In: Journal of Experimental Medicine. 2015 ; Vol. 212, No. 8. pp. 1171-1183.
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