title: Enhanced thrombopoietin but not G-CSF receptor stimulation induces self-renewing hematopoietic stem cell divisions in vivo.
abstract: In steady-state adult hematopoiesis, most hematopoietic stem cells (HSCs) are in the resting phase of the cell cycle. Upon enhanced hematopoietic demand, HSCs can be induced to divide and self-renew or differentiate. However, the cell-extrinsic signals inducing HSC cycling remain to be elucidated. Using in vivo high-resolution single HSC divisional tracking, we directly demonstrate that clinically applied thrombopoietin receptor but not granulocyte colony-stimulating factor (G-CSF) receptor agonists drive HSCs into self-renewing divisions leading to quantitative expansion of functional HSC as defined by their in vivo serial multilineage and long-term repopulating potential. These results suggest that thrombopoietin mimetics might be applicable to expand HSCs in vivo and to sensitize thrombopoietin receptor-expressing HSCs to cell cycle-dependent cytotoxic agents.
authors.affiliation: Division of Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland; and.
authors.forename: Larisa V
authors.initials: LV
authors.lastname: Kovtonyuk
authors.affiliation: Division of Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland; and.
authors.forename: Markus G
authors.initials: MG
authors.lastname: Manz
authors.affiliation: Division of Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland; and International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takizawa
mesh_terms: D000818:Animals; D001596:Benzylamines; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D000080027:Cyclams; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011961:Receptors, Fc; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000819:agonists*; D053628:Receptors, Thrombopoietin / Q000819:agonists*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013926:Thrombopoietin / Q000494:pharmacology*
chemical_list: D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D011961:Receptors, Fc; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins; D016179:Granulocyte Colony-Stimulating Factor; C082218:MPL protein, human; D013926:Thrombopoietin; C488777:romiplostim; C088327:plerixafor