title: Mechanically induced focal adhesion assembly amplifies anti-adipogenic pathways in mesenchymal stem cells.
abstract: The fate of pluripotent mesenchymal stem cells (MSC) is determined through integration of chemical, spatial, and physical signals. The suppression of MSC adipogenesis by mechanical stimuli, which requires Akt-induced inhibition of glycogen synthase kinase 3β (GSK3β) with β-catenin activation, can be enhanced by repetitive dosing within a single day. Here, we demonstrate that reapplication of cyclic strain within a 24-hour period leads to amplification of both Akt activation and its subsequent inhibition of GSK3β, such that total cycle number can be reduced while still inhibiting adipogenesis. Amplification of Akt signaling is facilitated by a dynamic restructuring of the cell in response to mechanical signals, as evidenced by a transient increase in focal adhesion (FA) number and increased RhoA activity. Preventing FA assembly or development of tension blocks activation of Akt by mechanical signals, but not by insulin. This indicates that the FA infrastructure is essential to the physical, but not necessarily the chemical, sensitivity, and responsiveness of the cell. Exploiting the transient nature of cytoskeletal remodeling may represent a process to enhance cell responsiveness to mechanical input and ultimately define the fate of MSCs with a minimal input.
authors: Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors: Buer
authors: B
authors: Sen
authors: Christophe
authors: C
authors: Guilluy
authors: Zhihui
authors: Z
authors: Xie
authors: Natasha
authors: N
authors: Case
authors: Maya
authors: M
authors: Styner
authors: Jacob
authors: J
authors: Thomas
authors: Ipek
authors: I
authors: Oguz
authors: Clinton
authors: C
authors: Rubin
authors: Keith
authors: K
authors: Burridge
authors: Janet
authors: J
authors: Rubin
mesh_terms: D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D022001:Focal Adhesions / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013314:Stress, Mechanical
chemical_list: D051057:Proto-Oncogene Proteins c-akt