Mechanosensitive TRPM7 mediates shear stress and modulates osteogenic differentiation of mesenchymal stromal cells through Osterix pathway

Abstract

Microenvironments that modulate fate commitments of mesenchymal stromal cells (MSCs) are composed of chemical and physical cues, but the latter ones are much less investigated. Here we demonstrate that intermittent fluid shear stress (IFSS), a potent and physiologically relevant mechanical stimulus, regulates osteogenic differentiation of MSCs through Transient receptor potential melastatin 7 (TRPM7)-Osterix axis. Immunostaining showed the localization of TRPM7 near or at cell membrane upon IFSS, and calcium imaging analysis demonstrated the transient increase of cytosolic free calcium. Expressions of osteogenic marker genes including Osterix, but not Runx2, were upregulated after three-hour IFSS. Phosphorylation of p38 and Smad1/5 was promoted by IFSS as well. TRPM7 gene knockdown abolished the promotion of bone-related gene expressions and phosphorylation. We illustrate that TRPM7 is mechanosensitive to shear force of 1.2 Pa, which is much lower than 98 Pa pressure loading reported recently, and mediates distinct mechanotransduction pathways. Additionally, our results suggest the differential roles of TRPM7 in endochondral and intramembranous ossification. Together, this study elucidates the mechanotransduction in MSCs fate commitments and displays an efficient mechano-modulation for MSCs osteogenic differentiation. Such findings should be taken into consideration when designing relevant scaffolds and microfluidic devices for osteogenic induction in the future.

TheDrosophilaTrpm channel mediates calcium influx during egg activation

“…Both Drosophila Trpm and mouse TRPM7 are reported to be constitutively active and permeable to a wide range of divalent cations (23,31). Mouse TRPM7 is known to respond to mechanical pressure (32,33), but further study will be needed to determine whether Drosophila Trpm is similarly responsive to mechanical triggers, such as those that occur during ovulation.…”

Biomimetic fetal rotation bioreactor for engineering bone tissues—Effect of cyclic strains on upregulation of osteogenic gene expression

“…The stem cells are known to sense and respond by the activation of downstream signalling pathways that control MSC lineage commitment such as bone morphogenic protein signalling, G‐protein signalling, wingless‐related integration site signalling, and fibroblast growth factors (Q. Chen et al, ) finally culminating in osteogenic gene expression that has been observed in our study (Figure b). Although the fluid shear stress mediated activation of extracellular signal‐regulated kinase1/2 by the phosphorylation of focal adhesion kinases has been shown to cause the leading to upregulation of Runx2 and osteogenic genes (L. Liu et al, ), both mechanical strains and fluid shear stresses have been shown to activate mechanosensitive ion channels that in turn enable influx of calcium ions (Y. S. Liu et al, ). Although elucidation of the specific signalling pathways induced under different modes of the bioreactor (static, compression, biaxial rotation, and multimodal) is beyond the scope of our current study, nevertheless, we believe that ultimately, the combined effects in our multimodal platform have proven to be beneficial for increased osteogenic differentiation of stem cells on 3D scaffolds.…”

DrosophilaTrpm mediates calcium influx during egg activation

“…Both Drosophila Trpm and its mouse ortholog TRPM7 are reported to be constitutively active and permeable to a wide range of divalent cations (21,29). Mouse TRPM7 is known to respond to mechanical pressure (30,31), but further study will be needed to determine whether Drosophila Trpm is similarly responsive to mechanical triggers, such as those that occur during ovulation.…”