title: Standard sub-thermoneutral caging temperature influences radiosensitivity of hematopoietic stem and progenitor cells.
abstract: The production of new blood cells relies on a hierarchical network of hematopoietic stem and progenitor cells (HSPCs). To maintain lifelong hematopoiesis, HSPCs must be protected from ionizing radiation or other cytotoxic agents. For many years, murine models have been a valuable source of information regarding factors that either enhance or reduce the survival of HSPCs after exposure of marrow to ionizing radiation. In a recent series of studies, however, it has become clear that housing-related factors such as the cool room temperature required for laboratory mice can exert a surprising influence on the outcome of experiments. Here we report that the mild, but chronic cold-stress endured by mice housed under these conditions exerts a protective effect on HSPCs after both non-lethal and lethal doses of total body irradiation (TBI). Alleviation of this cold-stress by housing mice at a thermoneutral temperature (30°C) resulted in significantly greater baseline radiosensitivity to a lethal dose of TBI with more HSPCs from mice housed at thermoneutral temperature undergoing apoptosis following non-lethal TBI. Cold-stressed mice have elevated levels of norepinephrine, a key molecule of the sympathetic nervous system that binds to β-adrenergic receptors. We show that blocking this signaling pathway in vivo through use of the β-blocker propanolol completely mitigates the protective effect of cold-stress on HSPC apoptosis. Collectively this study demonstrates that chronic stress endured by the standard housing conditions of laboratory mice increases the resistance of HSPCs to TBI-induced apoptosis through a mechanism that depends upon β-adrenergic signaling. Since β-blockers are commonly prescribed to a wide variety of patients, this information could be important when predicting the clinical impact of HSPC sensitivity to TBI.
authors: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, United States of America.
authors: Benjamin J
authors: BJ
authors: Povinelli
authors: Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, United States of America.
authors: Kathleen M
authors: KM
authors: Kokolus
authors: Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, United States of America.
authors: Jason W-L
authors: JW
authors: Eng
authors: Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, United States of America.
authors: Christopher W
authors: CW
authors: Dougher
authors: Department of Laboratory Animal Resources, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, United States of America.
authors: Leslie
authors: L
authors: Curtin
authors: Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, United States of America.
authors: Maegan L
authors: ML
authors: Capitano
authors: Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, United States of America.
authors: Christi T
authors: CT
authors: Sailsbury-Ruf
authors: Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, United States of America.
authors: Elizabeth A
authors: EA
authors: Repasky
authors: Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, United States of America; Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, United States of America.
authors: Michael J
authors: MJ
authors: Nemeth
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D058639:Cold-Shock Response; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects*; D006799:Housing, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D011433:Propranolol / Q000494:pharmacology; D011836:Radiation Tolerance; D015398:Signal Transduction; D014916:Whole-Body Irradiation
chemical_list: D000319:Adrenergic beta-Antagonists; D011433:Propranolol