Macrophages are multifunctional immune system cells that are essential for the mechanical stimulation‐induced control of metabolism. Piezo1 is a non‐selective calcium channel expressed in multifarious tissues to convey mechanical signals. Here, a cellular model of tension was used to study the effect of mechanical stretch on the phenotypic transformation of macrophages and its mechanism. An indirect co‐culture system was used to explore the effect of macrophage activation on bone marrow mesenchymal stem cells (BMSCs), and a treadmill running model was used to validate the mechanism in vivo for in vitro studies. p53 was acetylated and deacetylated by macrophages as a result of mechanical strain being detected by Piezo1. This process is able to polarize macrophages towards M2 and secretes transforming growth factor‐beta (TGF‐β1), which subsequently stimulates BMSCs migration, proliferation and osteogenic differentiation. Knockdown of Piezo1 inhibits the conversion of macrophages to the reparative phenotype, thereby affecting bone remodelling. Blockade of TGF‐β I, II receptors and Piezo1 significantly reduced exercise‐increased bone mass in mice. In conclusion, we showed that mechanical tension causes calcium influx, p53 deacetylation, macrophage polarization towards M2 and TGF‐β1 release through Piezo1. These events support BMSC osteogenesis.
Human adipose-derived stem cells (hASCs) have multi-directional differentiation potential including osteogenic differentiation. Mechanical stimulation is thought to be a key regulator of bone remodeling and has been proved to promote osteogenic differentiation of mesenchymal stem cells. However, the mechanism how mechanical tension-induced osteogenesis of hASCs still remains poor understood. Polycystin-2 (PC2), a member of the transient receptor potential polycystic (TRPP) family, is involved in cilia-mediated mechanical transduction. To understand the role of PC2 in osteogenic differentiation under mechanical stimuli in hASCs, PKD2 gene was stably silenced by using lentivirus-mediated shRNA technology. The results showed that mechanical tension sufficiently enhanced osteogenic differentiation but hardly affected proliferation of hASCs. Silencing PKD2 gene caused hASCs to lose the ability of sensing mechanical stimuli and subsequently promoting osteogenesis. PC2 knock-out also reduced the cilia population frequency and cilia length in hASCs. TAZ (transcriptional coactivator with PDZ-binding motif, also known as Wwtr1) could mediate the genes regulation and biological functions of mechanotransduction signal pathway. Here, mechanical tension also enhanced TAZ nuclear translocation of hASCs. PC2 knock-out blocked tension-induced upregulation of nuclear TAZ and suppress tension-induced osteogenesis. TAZ could directly interact with Runx2, and inhibiting TAZ could suppress tension-induced upregulation of Runx2 expression. In summary, our findings demonstrated that PC2 mediate mechanical tension-induced osteogenic differentiation of hASCs by activating TAZ.
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