Focal adhesion kinase signaling regulates anti-inflammatory function of bone marrow mesenchymal stromal cells induced by biomechanical force

Abstract

Mesenchymal stromal cells (MSCs) have tremendous potential for use in regenerative medicine due to their multipotency and immune cell regulatory functions. Biomimetic physical forces have been shown to direct differentiation and maturation of MSCs in tissue engineering applications; however, the effect of force on immunomodulatory activity of MSCs has been largely overlooked. Here we show in human bone marrow-derived MSCs that wall shear stress (WSS) equivalent to the fluid frictional force present in the adult arterial vasculature significantly enhances expression of four genes that mediate MSC immune regulatory function, PTGS2, HMOX1, IL1RN, and TNFAIP6. Several mechanotransduction pathways are stimulated by WSS, including calcium ion (Ca2+) flux and activation of Akt, MAPK, and focal adhesion kinase (FAK). Inhibition of PI3K-Akt by LY294002 or Ca2+ signaling with chelators, ion channel inhibitors, or Ca2+ free culture conditions failed to attenuate WSS-induced COX2 expression. In contrast, the FAK inhibitor PF-562271 blocked COX2 induction, implicating focal adhesions as critical sensory components upstream of this key immunomodulatory factor. In co-culture assays, WSS preconditioning stimulates MSC anti-inflammatory activity to more potently suppress TNF-α production by activated immune cells, and this improved potency depended upon the ability of FAK to stimulate COX2 induction. Taken together, our data demonstrate that biomechanical force potentiates the reparative and regenerative properties of MSCs through a FAK signaling cascade and highlights the potential for innovative force-based approaches for enhancement in MSC therapeutic efficacy.

Preconditioning Human Adipose-Derived Stromal Cells on Decellularized Adipose Tissue Scaffolds Within a Perfusion Bioreactor Modulates Cell Phenotype and Promotes a Pro-regenerative Host Response

“…Similarly, Becquart et al (2016) demonstrated that intermittent shear stress stimulated the production of nitric oxide (NO) and enhanced mRNA expression of VEGFA , FGF2 , and IGF1 in cultured human bone marrow-derived MSCs. In addition, Lee et al (2017) recently demonstrated that human bone marrow-derived MSCs cultured under physiological shear stress within a microfluidic system showed enhanced anti-inflammatory function, with the effects regulated through focal adhesion kinase (FAK) signaling.…”

ZINC40099027 Promotes Gastric Mucosal Repair in Ongoing Aspirin-Associated Gastric Injury by Activating Focal Adhesion Kinase

“…The involvement of FAK in the inflammatory response is controversial. Some studies suggest that FAK mediates the release of proinflammatory cytokines, such as TNF-α and IL-1β [ 49 ], and may contribute to the worsening of inflammation. However, others suggest that nuclear FAK regulates the expression of some inflammatory genes, such as IL-33 and GATA4, resulting in reduced inflammatory responses by inducing regulatory T cells (T reg ) and, thus, enhancing repair [ 50 , 51 ].…”

Membrane fluidity regulates high shear stress-induced FAK activation at different subcellular compartments

“…A fluorescence resonance energy transfer (FRET) study found that the degree of FAK activation in lipid rafts is higher than in non-rafts domain during cell adhesion and platelet-derived growth factor (PDGF) stimulation (Guan, 2004;Seong et al, 2011a;Seong et al, 2011b). The fluid shear stress can also regulate the localization and activity of FAK in endothelial cells, thereby regulating different processes (Li et al, 2002;Andersen et al, 2017;Lee et al, 2017). For example, lipid rafts targeted FAK has a higher activity at the upstream of the endothelial cells in response to 65 dyn/cm 2 of shear stress) (Liu et al, 2014).…”