5 PicoNewtons - The Difference Between Osteogenic and Adipogenic Fate Choice in Human Mesenchymal Stem Cells.
ACS nano(2019)
摘要
The ability of mesenchymal stem cells to sense nanoscale variations in extracellular matrix (ECM) compositions in their local microenvironment is crucial to their survival and their fate, however the underlying molecular mechanisms defining how such fates are temporally modulated remains poorly understood. In this work we have utilised self-assembled, block copolymer surfaces to present nanodomains of an adhesive peptide found in many ECM proteins at different lateral spacings (from 30 to 60nm) and studied the temporal response (2 hours to 14 days) of hMSCs using a panel of real-time localization and activity biosensors. Our findings revealed that within the first four to 24 hours post adhesion and spreading, hMSCs on smaller nanodomain spacings recruit more activated FAK and Src proteins to produce larger, longer-lived and increased numbers of focal adhesions (FAs). The adhesions formed on smaller nanospacings rapidly recruit higher amounts of non-muscle myosin IIA and vinculin, and experience significantly higher tension forces (by > 5 pN/FA) than those observed on larger nanodomain spacings. The transmission of higher levels of tension into the cytoskeleton at short times was accompanied by higher Rac1, cytosolic beta-catenin and nuclear localisation of YAP/TAZ and RUNX2, which together biased the commitment of hMSCs to an osteogenic fate. This investigation provides mechanistic insights to confirm that smaller lateral spacings of adhesive nanodomains alter hMSCs mechanosensing and biases mechanotransduction at short times via differential coupling of FAK/Src/Rac1/myosinIIA/YAP/TAZ signaling pathways to support longer-term changes in stem cell differentiation and state.
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关键词
lateral ligand spacing stem cell fate,focal adhesions,mechanosensing,mechanotransduction
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