title: CCND1-CDK4-mediated cell cycle progression provides a competitive advantage for human hematopoietic stem cells in vivo.
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.
authors.affiliation: Regeneration in Hematopoiesis and Animal Models in Hematopoiesis, Institute for Immunology, Institute of Virology, Center for Regenerative Therapies, Faculty of Medicine; Deep Sequencing Group SFB655, Biotechnology Center, TU Dresden, 01307 Dresden, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Mende
authors.affiliation: Division of Theoretical Systems Biology, German Cancer Research Center, 69120 Heidelberg, Germany Bioquant Center, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Erika E
authors.initials: EE
authors.lastname: Kuchen
authors.affiliation: Regeneration in Hematopoiesis and Animal Models in Hematopoiesis, Institute for Immunology, Institute of Virology, Center for Regenerative Therapies, Faculty of Medicine; Deep Sequencing Group SFB655, Biotechnology Center, TU Dresden, 01307 Dresden, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Lesche
authors.affiliation: Regeneration in Hematopoiesis and Animal Models in Hematopoiesis, Institute for Immunology, Institute of Virology, Center for Regenerative Therapies, Faculty of Medicine; Deep Sequencing Group SFB655, Biotechnology Center, TU Dresden, 01307 Dresden, Germany.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Grinenko
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.
authors.forename: Konstantinos D
authors.initials: KD
authors.lastname: Kokkaliaris
authors.affiliation: Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202.
authors.forename: Helmut
authors.initials: H
authors.lastname: Hanenberg
authors.affiliation: Regeneration in Hematopoiesis and Animal Models in Hematopoiesis, Institute for Immunology, Institute of Virology, Center for Regenerative Therapies, Faculty of Medicine; Deep Sequencing Group SFB655, Biotechnology Center, TU Dresden, 01307 Dresden, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Lindemann
authors.affiliation: Regeneration in Hematopoiesis and Animal Models in Hematopoiesis, Institute for Immunology, Institute of Virology, Center for Regenerative Therapies, Faculty of Medicine; Deep Sequencing Group SFB655, Biotechnology Center, TU Dresden, 01307 Dresden, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Dahl
authors.affiliation: DKMS Lifeline Cord Blood Bank, 01277 Dresden, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Platz
authors.affiliation: Division of Theoretical Systems Biology, German Cancer Research Center, 69120 Heidelberg, Germany Bioquant Center, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Höfer
authors.affiliation: Regeneration in Hematopoiesis and Animal Models in Hematopoiesis, Institute for Immunology, Institute of Virology, Center for Regenerative Therapies, Faculty of Medicine; Deep Sequencing Group SFB655, Biotechnology Center, TU Dresden, 01307 Dresden, Germany.
authors.forename: Federico
authors.initials: F
authors.lastname: Calegari
authors.affiliation: Regeneration in Hematopoiesis and Animal Models in Hematopoiesis, Institute for Immunology, Institute of Virology, Center for Regenerative Therapies, Faculty of Medicine; Deep Sequencing Group SFB655, Biotechnology Center, TU Dresden, 01307 Dresden, Germany claudia.waskow@tu-dresden.de.
authors.forename: Claudia
authors.initials: C
authors.lastname: Waskow
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000502:physiology*; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D059014:High-Throughput Nucleotide Sequencing; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D016133:Polymerase Chain Reaction
chemical_list: C530104:CCND1 protein, human; D017931:DNA Primers; D019938:Cyclin D1; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4