LARG GEF and ARHGAP18 orchestrate RhoA activity to control mesenchymal stem cell lineage

dc.contributor.authorThompson, William R.
dc.contributor.authorYen, Sherwin S.
dc.contributor.authorUzer, Gunes
dc.contributor.authorXie, Zhihui
dc.contributor.authorSen, Buer
dc.contributor.authorStyner, Maya
dc.contributor.authorBurridge, Keith
dc.contributor.authorRubin, Janet
dc.contributor.departmentPhysical Therapy, School of Health and Rehabilitation Sciencesen_US
dc.date.accessioned2018-01-11T20:20:59Z
dc.date.available2018-01-11T20:20:59Z
dc.date.issued2018-02
dc.description.abstractThe quantity and quality of bone depends on osteoblastic differentiation of mesenchymal stem cells (MSCs), where adipogenic commitment depletes the available pool for osteogenesis. Cell architecture influences lineage decisions, where interfering with cytoskeletal structure promotes adipogenesis. Mechanical strain suppresses MSC adipogenesis partially through RhoA driven enhancement of cytoskeletal structure. To understand the basis of force-driven RhoA activation, we considered critical GEFs (activators) and GAPs (inactivators) on bone marrow MSC lineage fate. Knockdown of LARG accelerated adipogenesis and repressed basal RhoA activity. Importantly, mechanical activation of RhoA was almost entirely inhibited following LARG depletion, and the ability of strain to inhibit adipogenesis was impaired. Knockdown of ARHGAP18 increased basal RhoA activity and actin stress fiber formation, but did not enhance mechanical strain activation of RhoA. ARHGAP18 null MSCs exhibited suppressed adipogenesis assessed by Oil-Red-O staining and Western blot of adipogenic markers. Furthermore, ARHGAP18 knockdown enhanced osteogenic commitment, confirmed by alkaline phosphatase staining and qPCR of Sp7, Alpl, and Bglap genes. This suggests that ARHGAP18 conveys tonic inhibition of MSC cytoskeletal assembly, returning RhoA to an “off state” and affecting cell lineage in the static state. In contrast, LARG is recruited during dynamic mechanical strain, and is necessary for mechanical suppression of adipogenesis. In summary, mechanical activation of RhoA in mesenchymal progenitors is dependent on LARG, while ARHGAP18 limits RhoA delineated cytoskeletal structure in static cultures. Thus, on and off GTP exchangers work through RhoA to influence MSC fate and responses to static and dynamic physical factors in the microenvironment.en_US
dc.eprint.versionAuthor's manuscripten_US
dc.identifier.citationThompson, W. R., Yen, S. S., Uzer, G., Xie, Z., Sen, B., Styner, M., … Rubin, J. (2018). LARG GEF and ARHGAP18 orchestrate RhoA activity to control mesenchymal stem cell lineage. Bone, 107, 172-180. https://doi.org/10.1016/j.bone.2017.12.001en_US
dc.identifier.urihttps://hdl.handle.net/1805/15001
dc.language.isoenen_US
dc.publisherElsevieren_US
dc.relation.isversionof10.1016/j.bone.2017.12.001en_US
dc.relation.journalBoneen_US
dc.rightsPublisher Policyen_US
dc.sourceAuthoren_US
dc.subjectLARGen_US
dc.subjectARHGAP18en_US
dc.subjectRhoAen_US
dc.titleLARG GEF and ARHGAP18 orchestrate RhoA activity to control mesenchymal stem cell lineageen_US
dc.typeArticleen_US
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