The effects of high fat diet‐induced obesity and exercise training on hematopoietic stem and progenitor cells following sub‐lethal radiation

Abstract

Of the 14 million cancer survivors in the United States, approximately 2/3 have received radiation therapy. Hematopoietic stem and progenitor cells (HSPCs) are among the most sensitive cells to radiation damage resulting in anemia and immunosuppression acutely following radiation exposure, and decreased hematopoiesis in the long‐term. Increased adiposity and physical inactivity are common among cancer survivors and both have negative effects on hematopoiesis. However, the impacts of obesity and exercise on the late effects of radiation exposure on HSPCs are unknown. The purpose of the present investigation was to evaluate the impact of obesity and exercise on HSPCs following sub‐lethal radiation exposure. A total of 40 CBA mice were divided into 4 groups (CON+SED n=10, CON+EX n=10, HF+SED n=10, HF+EX n=10). Mice were put onto a control (CON) or high fat diet (HFD) to induce obesity for 4 weeks before being placed into a progressive treadmill exercise (EX) program for 9 weeks or remained sedentary (SED). Four weeks into the training program, all mice were exposed to a 3 Gy dose of gamma radiation and completed their respective exercise and diet programs. At the conclusion of the 9 week intervention, bone marrow cells were collected and lineage negative cells were separated and analyzed for total HSPCs (LSK, SCA+cKit+), and HSPC subpopulations: long‐term (LT‐HSC, LSK CD150+CD48−), short‐term hematopoietic stem cell (ST‐HSC, LSK CD150+, CD48+), and multi‐potent progenitors (MPP, LSK CD150−,48+). HFD‐induced obesity reduced bone marrow cellularity compared to control mice (p<0.01). EX attenuated these changes to bone marrow cellularity (p<0.01). A decrease in the total number of LSK resulted from consuming HFD (p<0.01) that was attenuated with EX (p<0.01). Similar HFD‐induced decreases were seen in LT‐HSC (p<0.01), ST‐HSC (p<0.01), and MPPs (p<0.01) which were attenuated with EX (LT‐HSC, p<0.01, ST‐HSCs, p<0.05) and strongly trended in MPPs (p=0.067).ConclusionHere we show that HFD‐induce obesity decreases bone marrow cellularity and HSPC content following radiation exposure which is rescued by EX. As such, exercise training may serve as a promising therapy to preserve HSPCs following radiation therapy.Support or Funding InformationFunded by the UIUC Research Board Grant, ACSM Student Research Grant, and ACSM Foundation Grant