In vitro stretch modulates mitochondrial dynamics andenergy metabolism to induce smooth muscle differentiationin mesenchymal stem cells

Authors:

Yu Liu, Zhijie Yang, Jing Na, Xinyuan Chen, Ziyi Wang, Lisha Zheng, Yubo Fan

Keywords:

cyclic stretch; energy metabolism; mesenchymal stem cells; mitochondrial dynamics; smooth muscle cells

Abstract:

The smooth muscle cells (SMCs) located in the vascular media layer are continuously subjected to cyclic stretching perpendicular to the vessel wall and play a crucial role in vascular wall remodeling and blood pressure regulation. Mesenchymal stem cells (MSCs) are promising tools to differentiate into SMCs. Mechanical stretch loading offers an opportunity to guide the MSC-SMC differentiation and mechanical adaption for function regeneration of blood vessels. This study shows that cyclic stretch induces the expression of SMC markers α- SMA and SM22 in MSCs. These cells exhibit contractile ability in vitro and facilitate angiogenesis in the Matrigel plug assay in vivo. The contraction of SMCs requires remodeling of their energy metabolism. However, the underlying mechanismin the differentiation of MSCs into SMCs remains to be revealed. Cyclic stretchtraining promotes glycolysis, oxidative phosphorylation, and mitochondrial fusion and modulates mitochondrial dynamics-related proteins (MFN1, MFN2,DRP1) expression, thereby contributing to MSCs differentiation. Yes-associated protein (YAP) affects mitochondrial dynamics, oxidative phosphorylation, and glycolysis to regulate stretch-mediated differentiation into SMCs. Additionally, Piezo-type mechanosensitive ion channel component 1 (Piezo1) impacts energy metabolism and MSCs differentiation by regulating intracellular Ca 2+ levels and YAP nuclear localization. It indicates that YAP can integrate stretch force andenergy metabolism signals to regulate the differentiation of MSCs into SMCs.

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