YAP MECHANOSENSOR AS A CRUCIAL DETERMINANT IN THE DIFFERENTIATION OF ADIPOSE TISSUE-DERIVED MESENCHYMAL STEM CELLS
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| Rok publikování | 2015 |
| Druh | Konferenční abstrakty |
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| Popis | Extracellular matrix (ECM) provides a dynamic environment acting as critical regulator of cell behavior and stem cell fate decision. ECM composition and mechanics are known to contribute to organ development, tissue remodeling, while participating in the onset and progression of degenerative diseases. Yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1 or TAZ), the key effectors of the Hippo Pathway, have been proposed as cell mechanosensors converting the mechanical cues arising from the ECM into biochemical intracellular signals. This pathway is also known to play a crucial role in contact inhibition, by mediating the cadherin-catenin activity in vitro and in vivo. Additionally, YAP/TAZ proteins have been indicated as regulators of adult mesodermal progenitor differentiation, through the direct interaction with the transcription factors RUNX-2 and PPAR Here, we establish a direct correlation between the signals arising from the ECM and YAP activity in determining adipose mesenchymal stem cell (AD-MSC) fate decision. By taking advantage of micropatterned surfaces coated with different components of ECM or proteins involved in cell-cell communication, we mimic cell-matrix and cell-cell interaction at the single cell level and highlight the crucial role of YAP in determining AD-MSC shape, polarity and fate in response to ECM composition and mechanics. We demonstrate that YAP activity is directly dependent upon the availability of cell-ECM or cell-cell binding sites and determines the mechanical pertinence of AD-MSCs and their fate. In turn, we unveil the role of the cadherin/catenin axis as a positive regulator of the Hippo pathway in AD-MSCs, inhibiting YAP nuclear localization, preventing cell spreading and shaping, while modulating focal adhesion maturation, cytoskeletal assembly, and force distribution. Taken together, our results show that molecular and mechanical signals concur to a selective modulation of the Hippo pathway to regulate the fate of AD-MSCs and shape a central role of YAP/TAZ proteins in bridging between the extracellular milieu and cell function. |