title: Simulated microgravity inhibits osteogenic differentiation of mesenchymal stem cells via depolymerizing F-actin to impede TAZ nuclear translocation.
abstract: Microgravity induces observed bone loss in space flight, and reduced osteogenesis of bone mesenchymal stem cells (BMSCs) partly contributes to this phenomenon. Abnormal regulation or functioning of the actin cytoskeleton induced by microgravity may cause the inhibited osteogenesis of BMSCs, but the underlying mechanism remains obscure. In this study, we demonstrated that actin cytoskeletal changes regulate nuclear aggregation of the transcriptional coactivator with PDZ-binding motif (TAZ), which is indispensable for osteogenesis of bone mesenchymal stem cells (BMSCs). Moreover, we utilized a clinostat to model simulated microgravity (SMG) and demonstrated that SMG obviously depolymerized F-actin and hindered TAZ nuclear translocation. Interestingly, stabilizing the actin cytoskeleton induced by Jasplakinolide (Jasp) significantly rescued TAZ nuclear translocation and recovered the osteogenic differentiation of BMSCs in SMG, independently of large tumor suppressor 1(LATS1, an upstream kinase of TAZ). Furthermore, lysophosphatidic acid (LPA) also significantly recovered the osteogenic differentiation of BMSCs in SMG through the F-actin-TAZ pathway. Taken together, we propose that the depolymerized actin cytoskeleton inhibits osteogenic differentiation of BMSCs through impeding nuclear aggregation of TAZ, which provides a novel connection between F-actin cytoskeleton and osteogenesis of BMSCs and has important implications in bone loss caused by microgravity.
authors.affiliation: Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Luo
authors.affiliation: Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
authors.forename: Chuanchuan
authors.initials: C
authors.lastname: Lin
authors.affiliation: Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Kuang
authors.affiliation: Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
authors.forename: Guanbin
authors.initials: G
authors.lastname: Song
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus; D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002470:Cell Survival; D047630:Depsipeptides / Q000494:pharmacology; D005434:Flow Cytometry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008246:Lysophospholipids / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D010012:Osteogenesis / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D018474:Weightlessness Simulation
chemical_list: D000199:Actins; D047630:Depsipeptides; D047908:Intracellular Signaling Peptides and Proteins; D008246:Lysophospholipids; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C000612286:WWTR1 protein, rat; C057531:jasplakinolide; C032881:lysophosphatidic acid