title: Asymmetry in skeletal distribution of mouse hematopoietic stem cell clones and their equilibration by mobilizing cytokines.
abstract: Hematopoietic stem cells (HSCs) are able to migrate through the blood stream and engraft bone marrow (BM) niches. These features are key factors for successful stem cell transplantations that are used in cancer patients and in gene therapy protocols. It is unknown to what extent transplanted HSCs distribute throughout different anatomical niches in the BM and whether this changes with age. Here we determine the degree of hematopoietic migration at a clonal level by transplanting individual young and aged mouse HSCs labeled with barcoded viral vector, followed by assessing the skeletal distribution of hundreds of HSC clones. We detected highly skewed representation of individual clones in different bones at least 11 mo after transplantation. Importantly, a single challenge with the clinically relevant mobilizing agent granulocyte colony-stimulating factor (G-CSF) caused rapid redistribution of HSCs across the skeletal compartments. Old and young HSC clones showed a similar level of migratory behavior. Clonal make-up of blood of secondary recipients recapitulates the barcode composition of HSCs in the bone of origin. These data demonstrate a previously unanticipated high skeletal disequilibrium of the clonal composition of HSC pool long-term after transplantation. Our findings have important implications for experimental and clinical and stem cell transplantation protocols.
authors.affiliation: Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, Netherlands.
authors.forename: Evgenia
authors.initials: E
authors.lastname: Verovskaya
authors.forename: Mathilde J C
authors.initials: MJ
authors.lastname: Broekhuis
authors.forename: Erik
authors.initials: E
authors.lastname: Zwart
authors.forename: Ellen
authors.initials: E
authors.lastname: Weersing
authors.forename: Martha
authors.initials: M
authors.lastname: Ritsema
authors.forename: Lisette J
authors.initials: LJ
authors.lastname: Bosman
authors.forename: Theo
authors.initials: T
authors.lastname: van Poele
authors.forename: Gerald
authors.initials: G
authors.lastname: de Haan
authors.forename: Leonid V
authors.initials: LV
authors.lastname: Bystrykh
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D003114:Colony-Forming Units Assay; D016207:Cytokines / Q000378:metabolism*; D058893:DNA Barcoding, Taxonomic; D005822:Genetic Vectors; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000502:physiology; D016014:Linear Models; D051379:Mice; D008810:Mice, Inbred C57BL; D018709:Statistics, Nonparametric
chemical_list: D016207:Cytokines; D016179:Granulocyte Colony-Stimulating Factor