Obesity is a systemic disorder that simultaneously compromises the glucose metabolism, immune system, bone marrow microenvironment, and bone health. Current treatments for obesity are mainly in the form of lifestyle changes, such as diet and exercise. However, these treatment approaches face poor patient compliance and exercise might not even be a possibility for severely obese or disabled patients. Previous studies have demonstrated the efficacy of low magnitude mechanical stimulation, delivered in the form of low intensity vibration (LIV) signals, to bias mesenchymal and hematopoietic stem cell fate, having potential implications for obesity and osteoimmunology. This dissertation aims to build on the existing data and investigate whether refractory period incorporated LIV can be used as a treatment for obesity-induced systemic metabolic disruptions (in the form of impaired glucose metabolism and chronic inflammation) and deteriorated bone and marrow health in adults. We also explore potential mechanisms through which cells may respond to LIV signals in vitro and examine whether changing different parameters of LIV (frequency, magnitude, bout duration, number of bouts, and refractory period duration) can aid in elevating cell proliferation and protein production for bioprocessing applications.
To examine the efficacy of LIV signals in combating obesity-induced metabolic, bone, and marrow disruptions, a murine model of diet-induced obesity with intention-to-treat design was employed. Following 2 weeks of high fat diet to establish an obese phenotype, mice were subjected to 6 weeks of LIV treatment while continuing on the high fat diet. LIV treatment delivered in two bouts of 15 minutes with a 5-hour refractory period (2x15 LIV), but not one bout of 30 minutes (1x30 LIV), mitigated high-fat diet induced visceral adiposity, adipocyte hypertrophy, immune cell infiltration in adipose tissue, chronic inflammation of adipose tissue, glucose intolerance, insulin resistance, and bone marrow microenvironment. On the other hand, 1x30 LIV, but not 2x15 LIV, led to improved trabecular and cortical bone quantity and bone remodeling rate, indicating that body’s response to LIV is not homogenous.
Experimenting with adipocytes at different developmental stages (preadipocytes vs. mature adipocytes), outside of a complex whole body environment, demonstrated that adipocytes respond to LIV by increasing the F-actin level in their cytoskeleton and that the increase in Factin level fluctuates at different time points following the LIV treatment, prompting the need to optimize the refractory period duration in different cell types to achieve the greatest cellular response to LIV. This was evident by observing how different adherent and suspension cells respond differently to the same parameters of LIV, where while one might show increased cell proliferation, the other showed a decrease in cell proliferation. A combination of different parameters of LIV led to elevated cell proliferation and protein production in CHO-Adherent and CHO-Suspension cells to potentially reduce cost of production for bioprocessing.
|2011||Appiah-Nkansah K. Integration of Refractory Periods in the Administration of Low-Magnitude Mechanical Signals Increases Mesenchymal Stem Cell Numbers in the Bone Marrow [Master's thesis]. Stony Brook, NY: Stony Brook University; May 2011.|
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