Biomechanical promotion of mesenchymal stem cell proliferation as a countermeasure to the development of obesity and osteoporosis

Abstract

Pluripotent mesenchymal stem cells (MSCs) are considered ideal therapeutic targets in regenerative medicine, as they hold the capacity to differentiate into osteoblasts, adipocytes, fibroblasts, chondrocytes, and myocytes. The potential to harness MSCs as a means of prevention and treatment of disease is dependent on an improved understanding of the means by which exogenous signals regulate their activity, and the ability of these stimuli to influence either/both proliferation and differentiation This work addressed the hypothesis that MSCs represent a common mechano-responsive element upstream of osteoblast and adipocyte differentiation that could potentially be targeted for the control and treatment of both obesity and osteoporosis. We proposed that low magnitude mechanical signals (LMMS) could non-pharmacologically and non-invasively promote stem cell proliferation, and thus an organism’s healing and regenerative potential.

In light of the increased health complications experienced by obese individuals, we assessed the impact of a high fat diet on the resident stem cell population, as a possible contributing factor in the pathophysiology of obesity. We show that the MSC population was significantly diminished in animals fed a high fat diet for six weeks. Data from flow cytometry and real-time PCR provided clear indication that while the high fat diet decreased the MSC population, LMMS increased the proliferation of MSC’s and was able to recover the diet-induced decrease in cell numbers. In addition, the marrow environment in LMMS animals had shifted towards osteogenesis both in cell number and gene expression, providing a mechanism of LMMS action based on the selective differentiation of MSC’s into osteoprogenitors.

To characterize the phenotypic effects of twelve weeks of LMMS stimulation on a young adult animal, we developed a methodology for in vivo micro-computed tomography (microCT) for the precise determination of fat quantity, and more importantly fat distribution in the body. We applied these in vivo imaging methods to a complete characterization of the phenotypic fat suppression under normal dietary conditions, and several models of dietary induced obesity. Finally, data from a long term study (36 week of LMMS treatment) provided preliminary evidence of the benefit of LMMS in mitigating some the deleterious effects of dietary induced obesity and aging.

The experiments and results presented herein indicate that MSCs respond to LMMS by increasing proliferation. A developmentally mediated mechanism by which fat was suppressed and bone was enhanced, was implicated and was linked to the mechanically-based biasing of the mesenchymal stem cells to preferentially differentiate towards osteoblasts over adipocytes. The mechanical promotion of the number of progenitor cells, as well as driving commitment choices, suggests a means to enhance an organism’s regenerative capacity as achieved by exploiting stem cell sensitivity to physical signals.