Mechanical Stimulation on Mesenchymal Stem Cells and Surrounding Microenvironments in Bone Regeneration: Regulations and Applications

Abstract

Treatment of bone defects remains a challenge in the clinic. Artificial bone grafts are the most promising alternative to autologous bone grafting. However, one of the limiting factors of artificial bone grafts is the limited means of regulating stem cell differentiation during bone regeneration. As a weight-bearing organ, bone is in a continuous mechanical environment. External mechanical force, a type of biophysical stimulation, plays an essential role in bone regeneration. It is generally accepted that osteocytes are mechanosensitive cells in bone. However, recent studies have shown that mesenchymal stem cells (MSCs) can also respond to mechanical signals. This article reviews the mechanotransduction mechanisms of MSCs, the regulation of mechanical stimulation on microenvironments surrounding MSCs by modulating the immune response, angiogenesis and osteogenesis, and the application of mechanical stimulation of MSCs in bone regeneration. The review provides a deep and extensive understanding of mechanical stimulation mechanisms, and prospects feasible designs of biomaterials for bone regeneration and the potential clinical applications of mechanical stimulation.

Effects of cell seeding technique and cell density on BMP‐2 production in transduced human mesenchymal stem cells

“…This suggests that the addition of orbital shaking significantly enhances transgene expression and BMP‐2 production, potentially allowing us to achieve equivalent BMP‐2 levels with significantly fewer cells. This finding is consistent with prior studies which demonstrate an important role for mechanostimulation in the form of fluid shear stresses in the osteogenic differentiation of MSCs, and supports the use of dynamic cell seeding methods for transduced cells in ex vivo regional gene therapy for bone repair 23,24 …”

“…This finding is consistent with prior studies which demonstrate an important role for mechanostimulation in the form of fluid shear stresses in the osteogenic differentiation of MSCs, and supports the use of dynamic cell seeding methods for transduced cells in ex vivo regional gene therapy for bone repair. 23,24 Additionally, there was a significantly greater increase in BMP-2 production from 2 to 7 days after seeding of 1 M cells when compared to higher cell density suspensions. With all three seeding techniques, the scaffolds loaded with 1 M cells demonstrated significantly greater increases in BMP-2 production from 2 to 7 days, when compared with scaffolds loaded with either 3 or 5 M cells.…”

Adipose tissue in bone regeneration - stem cell source and beyond

“…Numerous reports exist regarding the in vitro osteogenic potential of ADSCs under defined differentiation media, and osteogenic conversion is assessed based on specific gene expression (OC, core-binding factor subunit alpha-1, also known as RUNX2, AP, osteonectin, osteopontin, BMP-2, ALP activity and mineralized ECM deposition)[ 106 ]. Mechanical stimulation by dynamic compression or magnetic nanoparticle-induced remote actuation has also been reported to increase in vitro osteogenesis[ 107 , 108 ].…”

Characterization of Mechanics Driven Heterogeneity in Mesenchymal Stromal Cells

“…The substrate or the extracellular matrix mechanics of the cell affect the structure and mechanics of the cytoskeleton and the nucleus [15], which can have far-reaching impacts through gene expression and cell function, as shown in many cell types including MSC. Cells exert contractile forces on their culture substrate and the substrate elasticity can alter the migration behavior of endothelial cells, promoting the formation of cell-cell interactions [16] through integrins that transmit these mechanical signals via actin stress fibers and associated pathways [17]. Mechanical signal from the substrate elasticity can be relayed through the LINC (Link of Nucleoskeleton and Cytoskeleton) complex to the nucleus to trigger differential gene regulation pathways through epigenetic regulations [18] or through the engagement of transcriptional coactivators such as YAP (Yes-associated protein) and Transcriptional Co-Activator TAZ [17,19].…”

“…Cells exert contractile forces on their culture substrate and the substrate elasticity can alter the migration behavior of endothelial cells, promoting the formation of cell-cell interactions [16] through integrins that transmit these mechanical signals via actin stress fibers and associated pathways [17]. Mechanical signal from the substrate elasticity can be relayed through the LINC (Link of Nucleoskeleton and Cytoskeleton) complex to the nucleus to trigger differential gene regulation pathways through epigenetic regulations [18] or through the engagement of transcriptional coactivators such as YAP (Yes-associated protein) and Transcriptional Co-Activator TAZ [17,19]. YAP/TAZ regulate key biological processes such as cell proliferation and migration, differentiation, and cell morphology [20] requiring Rho GTPase activity and tension exerted by the actomyosin contraction [21].…”