AB43. Tuning stem cells with mechanobiological signaling

Abstract: For the stem cell activation, it has been demonstrated that biological signaling plays a critical role in regulating stem cell fate, such as the soluble stem cell niche signals (growth factors and cytokines), while recent evidence confirms that regulation of stem cell fate by these soluble factors is strongly influenced by the coexisting insoluble adhesive, mechanical, and topological cues inherently contained. These insoluble biophysical cues can be sensed and transduced into intracellular biochemical and functional responses by stem cells, a process known as mechanotransduction. Importantly, these mechanotransduction processes can couple with many other potent growth-factor-mediated signaling pathways to regulate mesenchymal stem cell (MSC) fate. Scientists have attempted to drive stem cell fate through the use of chemistry (traditional biological signaling) for decades. The results obtained on stem cell dynamics with Low energy shock wave add further evidence on the feasibility of using a physical energy to drive stem cell growth and fate, and may pave new way to regenerative treatments performed without the need of stem cell transplantation.

It has been reported that that mechanical force activated Wnt signaling and MyoD/Myf5 promoter were regulated by transcriptional factors from Wnt/Frizzled pathway. How the mechanical signals convert into biological signaling is not well understood now. The mechanical signals cellular transduction was consisted of two-phase procedures: cell membrane phase and nuclear phase. For the cell membrane phase, there are three components on cell membrane act as the mechanical-sensor, including the Stretch-activated ion channels (SACs), G-protein and receptor tyrosine kinases (RTK), and Integrin. Under the mechanical force, the cell membrane were stretched and compressed, where the three mechanical sensors were activated followed by series cellular signaling pathways activated. The nucleus phase is very quick response and almost occurred at the same time as cell membrane phase. The mechanical signals transduced into cell nucleus in five us through the linker of nucleoskeleton and cytoskeleton (LINC) in cell cytoplasm consisted by intergrin, laminin, dystrophin, talin, actin filaments, nesprin and SUN. The LINC connected to the Scaffold Matrix Attachment Region (SMAR) within DNA chromatin loops. It is reported that more than 97 genes were regulated by SMRA, including HSP70 (GRP78/BiP), one of the chaperone for unfolding protein response. Three major cellular signaling pathways were activated by mechanical signals directly, including Stretch-activated ion channels (SACs) cellular signaling pathway, G-protein and receptor tyrosine kinases (RTK) cellular signaling pathway, and Integrin/Focal adhesion kinase (FAK) cellular signaling pathway. The cross-talk among those cellular signaling pathways resulted the activation of PKC, Rho/ROCK, Ras, PIP3, MAPK, Akt pathways, and Wnt/Frizzled pathway. Importantly, the Wnt/ Frizzled pathway is the stem cell “Switch” for quiescent or activation.

Keywords: Tuning stem cells; mechanobiological signaling; Scaffold Matrix Attachment Region (SMAR)