The Impact of Obesity on Bone Marrow Hematopoietic Stem Cell Function and Acute Immune Response

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Abstract

Obesity is associated with immune dysfunction due to impaired wound healing and response to infection. In obesity the accumulation of adiposity extends beyond the visceral depots and into the bone marrow (BM) niche where the immune system is regulated by hematopoietic stem cells (HSC). In this dissertation we evaluate how excess adiposity and changes to the bone marrow microenvironment impact hematopoiesis and HSC function. Using a mouse model of diet-induced obesity (DIO), we found that engraftment and repopulating capabilities of healthy HSCs is not hindered when they are introduced into an obese condition with excess fat following bone marrow transplantation (BMT). DIO mice exhibit increased BM engraftment of donor cells with a greater dependence on donor stem cell repopulation compared to lean mice. Long-term repopulation led to enhanced BM hematopoiesis in DIO indicated by increased B, T and myeloid cells with increased recruitment to extra-medullary visceral fat pads, suggesting that BM cells are partially fueling adipose tissue inflammation. Following acute radiation exposure DIO mice presented higher susceptibly to BM damage evidenced by greater suppression of BM lymphocytes, trabecular bone volume fraction (BV/TV) and greater numbers of apoptotic cells compared to lean mice. This damage to the marrow is partially to blame for the greater dependence on donor cell engraftment in obesity. We also investigated the use of low intensity vibrations (LIV) as a countermeasure to the effects of obesity. LIV has been shown to suppress adiposity through its influence on BM mesenchymal stem cells. The application of LIV in an estrogen deficient model of obesity suppressed the encroachment of marrow adipose tissue (MAT) but was not effective at normalizing immune populations in the absence of estrogen. Additionally, LIV application for 7w during the development of obesity partially protected DIO mice from acute radiation exposure by preserving trabecular BV/TV and suppressing MAT. While implications of the enhanced HSC functionality in obese mice warrants further investigation, this study demonstrates that obesity induced inflammation likely drives BM HSC behavior and that subtle mechanical signals have the potential to protect the marrow niche and could possibly influence HSC activity in obesity.

Cited Works (12)

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