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<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 ω-3 polyunsaturated fatty acids (PUFAs) in a
high-fat diet was capable to mitigate injury-induced OA and decrease serum inflammatory
cytokine levels. ω-3 PUFAs also significantly enhanced wound repair, while saturated
FAs and ω-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>
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