The Effects of Obesity on Stem Cell Function and the Development of Osteoarthritis

<p>Obesity due to a high-fat diet is characterized by accumulation of inflammatory macrophages in tissues, leading to chronic low-grade systemic inflammation. Obese individuals also exhibit impaired tissue healing. With a high-fat feeding, cells are exposed to the elevated levels of dietary fatty acids (FAs), and such a change of microenvironment may alter their properties. Stem cells are cells capable of multipotent differentiation, and this potential allows them to play a promising role in healing and regenerative medicine. However, the effect of obesity, particularly various types of dietary FAs, on the function of stem cells remains largely unknown. Furthermore, obesity is a primary risk factor of osteoarthritis (OA), a disease of entire of joint involving degradation of cartilage, synovitis, and subchondral bone changes. Yet, the mechanisms linking obesity and OA are not fully understood. Furthermore, although macrophages are well recognized for their inflammatory role in obesity, little is known regarding functionality of these cells in regulating the effect of obesity on OA. This dissertation develops fundamental stem cell isolation and culture techniques, and utilizes animal models to investigate (1) the influences of high-fat diet induced-obesity on function of adult stem cells, (2) examine the effect of obesity and dietary FAs on OA, and (3) evaluate the role of macrophages in obesity-associated OA by depleting macrophages using a transgenic mouse model.</p><p>A variety of adult stem cell populations including bone marrow-derived mesenchymal stem cells (MSCs), subcutaneous adipose-derived stem cells (sqASCs), and infrapatellar-derived stem cells (IFP cells) were successfully isolated from lean and obese mice and expanded in vitro. Obese stem cells demonstrated altered multilineage differentiation potential and distinct immunophenotypes as compared to lean stem cells. Furthermore, FA treatment of lean stem cells significantly changed their multipotency but did not completely recapitulate the properties of obese stem cells.</p><p>Supplementation of &#969;-3 polyunsaturated fatty acids (PUFAs) in a high-fat diet was capable to mitigate injury-induced OA and decrease serum inflammatory cytokine levels. &#969;-3 PUFAs also significantly enhanced wound repair, while saturated FAs and &#969;-6 PUFAs act as a detrimental factor in OA, synovitis, and wound healing. Spontaneous locomotion of the mice was independent of OA development. Furthermore, using mathematical models and weight-matched mice, we found that OA was significantly associated with dietary FA content but not with body weight and mouse activity. These results suggest that metabolic factor plays a more significant role in obesity-associated OA than mechanical factor. </p><p>Despite their temporary improved metabolic parameters and reduced osteophyte formation, obese mice receiving short-term, systemic macrophage depletion did not mitigate cartilage degeneration following joint injury. Instead, macrophage depletion significantly enhanced joint synovitis in the surgery-operated joint. Macrophage-depleted mice also exhibited up-regulated expression of inflammatory cytokines in synovial fluid. These findings indicate that despite their recognized pro-inflammatory role, macrophages are vital in regulating the homeostasis of immune cells in the joint following injury. </p><p>Taken together, this research further elucidates the relationships among obesity, stem cells, and OA. The results from our study may provide a framework to develop stem cell therapy for obese patients and intervention program for obese OA patients in the future.</p>Dissertatio