title: Mechanosensitive TRPM7 mediates shear stress and modulates osteogenic differentiation of mesenchymal stromal cells through Osterix pathway.
abstract: Microenvironments that modulate fate commitments of mesenchymal stromal cells (MSCs) are composed of chemical and physical cues, but the latter ones are much less investigated. Here we demonstrate that intermittent fluid shear stress (IFSS), a potent and physiologically relevant mechanical stimulus, regulates osteogenic differentiation of MSCs through Transient receptor potential melastatin 7 (TRPM7)-Osterix axis. Immunostaining showed the localization of TRPM7 near or at cell membrane upon IFSS, and calcium imaging analysis demonstrated the transient increase of cytosolic free calcium. Expressions of osteogenic marker genes including Osterix, but not Runx2, were upregulated after three-hour IFSS. Phosphorylation of p38 and Smad1/5 was promoted by IFSS as well. TRPM7 gene knockdown abolished the promotion of bone-related gene expressions and phosphorylation. We illustrate that TRPM7 is mechanosensitive to shear force of 1.2 Pa, which is much lower than 98 Pa pressure loading reported recently, and mediates distinct mechanotransduction pathways. Additionally, our results suggest the differential roles of TRPM7 in endochondral and intramembranous ossification. Together, this study elucidates the mechanotransduction in MSCs fate commitments and displays an efficient mechano-modulation for MSCs osteogenic differentiation. Such findings should be taken into consideration when designing relevant scaffolds and microfluidic devices for osteogenic induction in the future.
authors.affiliation: Stem Cell Research Center, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Yi-Shiuan
authors.initials: YS
authors.lastname: Liu
authors.affiliation: Stem Cell Research Center, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Yu-An
authors.initials: YA
authors.lastname: Liu
authors.affiliation: Stem Cell Research Center, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Chin-Jing
authors.initials: CJ
authors.lastname: Huang
authors.affiliation: Stem Cell Research Center, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Meng-Hua
authors.initials: MH
authors.lastname: Yen
authors.affiliation: Stem Cell Research Center, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Chien-Tzu
authors.initials: CT
authors.lastname: Tseng
authors.affiliation: Institute of Engineering in Medicine, University of California at San Diego, La Jolla, CA 92093, USA.|Departments of Bioengineering and Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Shu
authors.initials: S
authors.lastname: Chien
authors.affiliation: Taipei City Hospital, Taipei 10341, Taiwan.|Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan.|Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
authors.forename: Oscar K
authors.initials: OK
authors.lastname: Lee
mesh_terms: D000818:Animals; D015415:Biomarkers; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D003599:Cytoskeleton / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D040542:Mechanotransduction, Cellular / Q000235:genetics; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D010012:Osteogenesis / Q000235:genetics; D010766:Phosphorylation; D021381:Protein Transport; D051898:Smad1 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D013314:Stress, Mechanical; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015415:Biomarkers; D051898:Smad1 Protein; D051902:Smad5 Protein; D050053:TRPM Cation Channels; C421903:Trpm7 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium