title: Hematopoietic stem cells lacking Ott1 display aspects associated with aging and are unable to maintain quiescence during proliferative stress.
abstract: Aging degrades hematopoietic stem cell (HSC) functions, including stress response; however, the involved molecular pathways are incompletely defined. Murine BM conditionally deleted for One-Twenty-Two-1 (Ott1), is able to maintain lifelong hematopoiesis and has preserved numbers of long-term HSCs, yet cannot repopulate nor sustain itself after transplantation against a competitor even when Ott1 is excised after engraftment. We show, specifically under replicative stress, that Ott1-deleted HSCs have a significant reduction of the G(0) cell-cycle fraction associated with self-renewal and undergo early failure. Therefore, Ott1 is required to preserve HSC quiescence during stress but not steady-state hematopoiesis. Reduced tolerance of replicative stress, increased myeloid potential, and greater absolute numbers are mutual characteristics of both Ott1-deleted and aged HSCs, and comparison of their gene expression profiles reveals a shared signature. Ott1-deleted HSCs share multiple aging-associated physiologic changes, including increases in NF-κB activation and DNA damage. Loss of Ott1 causes increased reactive oxygen species; however, antioxidant treatment does not rescue the competitive defect, indicating the existence of additional essential Ott1-dependent HSC pathways. In conclusion, our data establish a requirement for Ott1 in stress hematopoiesis and suggest that Ott1-dependent processes may converge with those affected by aging.
authors.affiliation: Division of Hematology/Oncology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Xiao
authors.forename: Kaushal
authors.initials: K
authors.lastname: Jani
authors.forename: Kelly
authors.initials: K
authors.lastname: Morgan
authors.forename: Rachel
authors.initials: R
authors.lastname: Okabe
authors.forename: Dana E
authors.initials: DE
authors.lastname: Cullen
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Jesneck
authors.forename: Glen D
authors.initials: GD
authors.lastname: Raffel
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics* / Q000502:physiology; D055786:Gene Knockout Techniques; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016192:Resting Phase, Cell Cycle / Q000235:genetics* / Q000502:physiology; D013312:Stress, Physiological / Q000235:genetics / Q000502:physiology
chemical_list: D016601:RNA-Binding Proteins; C519408:Rbm15 protein, mouse