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.

Bone marrow adipose tissue-derived stem cell factor mediates metabolic regulation of hematopoiesis

“…Compared to the standard housing temperature (22°C), thermoneutrality (30°C) suppresses the SNS, promotes HSPC apoptosis, and increases the radiosensitivity of mice. 53 Consistent to the previous finding, 53 we did not observe any difference in BM cellularity ( Online Supplementary Figure S9A ) or the frequency of LSK, MP, and CLP (Online Supplementary Figure S9B) between mice housed at 22°C and 30°C. However, thermoneutrality increased the ratio of MEP to GMP and the ratio of CLP to CMP ( Online Supplementary Figure S9C and D ).…”

Thermoneutrality, Mice, and Cancer: A Heated Opinion

“…The key to reproducibility is accurate reporting of these seemingly mundane details, which potentially have large effects ' [87]. Although housing temperature was not included as a factor in these analyses, studies are accumulating in which experimental outcomes differ depending on the ambient temperature; these are summarized in Figure 1 [7,10,11,19,27,28,40,42,44,46,48,63,66,67,70,79,84,[88][89][90][91][92][93][94] biomedical applications, and how this condition may influence decisions for translation to the clinic (see Outstanding Questions). It is likely that many, if not all, of the metabolic abnormalities noted previously in mouse models stem largely from chronic mild cold stress and the increase in adaptive thermogenesis.…”

Manipulation of Ambient Housing Temperature To Study the Impact of Chronic Stress on Immunity and Cancer in Mice

“…Thus, the role for UCP1 in adaptive adrenergic thermogenesis, which had been questioned on the basis of negative results obtained in mice housed at 22˚C, was confirmed when chronic cold stress was alleviated by housing at 30˚C, clearly demonstrating the significance of considering ambient housing temperatures when planning and interpreting experiments. To our knowledge, our group first reported that mouse models of cancer and antitumor immunity (39)(40)(41), immune responses in graft versus host disease (42), dendritic cell biology (43), and radiosensitivity of hematopoietic stem cells (44) are each significantly influenced by room temperature. These are representative of a growing number of papers reporting how choice of housing temperature impacts experimental outcomes and reproducibility in several mouse models of disease and we have recently reviewed this topic (45)(46)(47).…”