title: Rantes/Ccl5 influences hematopoietic stem cell subtypes and causes myeloid skewing.
abstract: HSCs undergo dramatic changes with aging. An increase in absolute numbers of HSCs along with a functional deficit in reconstitution potential and a shift toward production of myeloid cells are the hallmarks of murine hematopoietic aging. Here, we show that high levels of the inflammatory cytokine Rantes are found in the aging stem cell milieu. Forced overproduction of Rantes by retroviral expression in BM progenitors resulted in a deficit of T-cell output, and brief ex vivo exposure of HSCs to Rantes resulted in a decrease in T-cell progeny concomitant with an increase in myeloid progenitors. In contrast, Rantes knockout (KO) animals exhibit a decrease in myeloid-biased HSCs and myeloid progenitors and an increase in T cells and lymphoid-biased HSCs. KO HSCs retained their HSC subtype distribution and they produced more lymphoid-biased HSCs in transplantations. Rantes deficiency also resulted in a decreased mammalian target of rapamycin (mTOR) activity in KLS cells. In a heterochronic transplantation setting, we further show that aged HSCs placed in a young environment generate less myeloid cells. These data establish a critical role for environmental factors in the establishment of the aged-associated myeloid skewing phenotype, which may contribute to age-associated immune deficiency.
authors.affiliation: Interdepartmental Program of Developmental Biology, Baylor College of Medicine, One Baylor Plaza, N1030, Houston, TX 77030, USA.
authors.forename: Aysegul V
authors.initials: AV
authors.lastname: Ergen
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Boles
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Goodell
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000502:physiology*; D018946:Chemokine CCL5 / Q000502:physiology*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023461:Myeloid Progenitor Cells / Q000166:cytology* / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D012333:RNA, Messenger; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases