Enhancement of Immuno-Modulatory Capacity by Shear Stress in Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) possess tremendous therapeutic potentials due to their self-renewal, multi-lineage differentiation and paracine capabilities. More importantly, MSCs also possess immuno-modulatory ability, which has substantially contributed to the therapeutic effects of MSCs transplantation in many clinical trials. MSCs achieve immuno-modulatory effects through the production of critical soluble factors and direct regulation of surface molecules expression. In our previously published works, immuno-modulatory capacity of MSCs has been demonstrated in various disease-based animal models. From the results of these pre-clinical studies, it has become clear that the next generation of MSCs therapy should focus on rapid enhancement of the immuno-modulatory ability of MSCs before transplantation ex vivo, in order to increase their therapeutic efficacy and clinical success after transplantation. Shear stress, which is exerted by mechanical flow, can rapidly regulate cell physiology. Shear force activates kinase-associated signaling pathway through menchanosensors on the membrane to regulate genetic expression; shear-induced mechanotransduction can also be propagated within microseconds through physical interactions with the extracellular matrix, actin filaments and nuclear membrane. The actions of shear stress stimuli on cell functions depends on shear patterns, magnitude and duration, cell types, and environmental conditions. It is known that the differentiation ability of stem cells can be promoted under long-term, high-magnitude laminar shear stress. Recently, short-term, intermittent low shear stress has been found to increase the MSC proliferation and cytokine secretion. The relationship between shear stress and MSCs immuno-modulatory ability has not yet been well established. We found that oscillatory shear stress rapidly activates ERK and alters gene expressions in MSCs. The up-regulated genes include those associated with differentiation, proliferation and anti-inflammation. The aim of this study is to investigate whether immuno-modulation ability of MSCs can be enhanced by short-term oscillatory shear (OS) stimuli and the relevant molecular mechanisms involved. In the first year, the optimal oscillatory shear condition for enhancement of immuno-modulatory ability in MSCs will be defined and validated. In the second year, the mechanosensors, molecular mechanism as well as the genes most responsive to OS stimuli will be elucidated. In the third year, two animal models of disease (diabetes mellitus and acute lung injury) will be used to investigate the immuno-modulatory and therapeutic effects of MSCs after oscillatory shear stimulation. The originality of the study is high as no similar studies have been reported in the literature. The significance of the research achievements of this study is that, besides the elucidation of shear stress-induced immuno-modulatory regulation in MSCs, it will offer a novel platform technology and therapeutic strategy for functional enhancement of MSCs via an effective and time-saving way to increase their therapeutic efficacy.