Bone morphogenetic protein-2-induced signaling and osteogenesis is regulated by cell shape, RhoA/ROCK, and cytoskeletal tension

Yang Kao Wang, Xiang Yu, Daniel M. Cohen, Michele A. Wozniak, Michael T. Yang, Lin Gao, Jeroen Eyckmans, Christopher S. Chen

研究成果: Article

131 引文 (Scopus)

摘要

Osteogenic differentiation of human mesenchymal stem cells (hMSCs) is classically thought to be mediated by different cytokines such as the bone morphogenetic proteins (BMPs). Here, we report that cell adhesion to extracellular matrix (ECM), and its effects on cell shape and cytoskeletal mechanics, regulates BMP-induced signaling and osteogenic differentiation of hMSCs. Using micropatterned substrates to progressively restrict cell spreading and flattening against ECM, we demonstrated that BMP-induced osteogenesis is progressively antagonized with decreased cell spreading. BMP triggered rapid and sustained RhoA/Rho-associated protein kinase (ROCK) activity and contractile tension only in spread cells, and this signaling was required for BMP-induced osteogenesis. Exploring the molecular basis for this effect, we found that restricting cell spreading, reducing ROCK signaling, or inhibiting cytoskeletal tension prevented BMP-induced SMA/mothers against decapentaplegic (SMAD)1 c-terminal phosphorylation, SMAD1 dimerization with SMAD4, and SMAD1 translocation into the nucleus. Together, these findings demonstrate the direct involvement of cell spreading and RhoA/ROCK-mediated cytoskeletal tension generation in BMP-induced signaling and early stages of in vitro osteogenesis, and highlight the essential interplay between biochemical and mechanical cues in stem cell differentiation.

原文English
頁(從 - 到)1176-1186
頁數11
期刊Stem Cells and Development
21
發行號7
DOIs
出版狀態Published - 2012 五月 1

指紋

Bone Morphogenetic Protein 2
Bone Morphogenetic Proteins
Cell Shape
Osteogenesis
Mesenchymal Stromal Cells
Extracellular Matrix
rho-Associated Kinases
Dimerization
Mechanics
Cell Adhesion
Protein Kinases
Cues
Cell Differentiation
Stem Cells
Phosphorylation
Cytokines

All Science Journal Classification (ASJC) codes

  • Hematology
  • Developmental Biology
  • Cell Biology

引用此文

Wang, Yang Kao ; Yu, Xiang ; Cohen, Daniel M. ; Wozniak, Michele A. ; Yang, Michael T. ; Gao, Lin ; Eyckmans, Jeroen ; Chen, Christopher S. / Bone morphogenetic protein-2-induced signaling and osteogenesis is regulated by cell shape, RhoA/ROCK, and cytoskeletal tension. 於: Stem Cells and Development. 2012 ; 卷 21, 編號 7. 頁 1176-1186.
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abstract = "Osteogenic differentiation of human mesenchymal stem cells (hMSCs) is classically thought to be mediated by different cytokines such as the bone morphogenetic proteins (BMPs). Here, we report that cell adhesion to extracellular matrix (ECM), and its effects on cell shape and cytoskeletal mechanics, regulates BMP-induced signaling and osteogenic differentiation of hMSCs. Using micropatterned substrates to progressively restrict cell spreading and flattening against ECM, we demonstrated that BMP-induced osteogenesis is progressively antagonized with decreased cell spreading. BMP triggered rapid and sustained RhoA/Rho-associated protein kinase (ROCK) activity and contractile tension only in spread cells, and this signaling was required for BMP-induced osteogenesis. Exploring the molecular basis for this effect, we found that restricting cell spreading, reducing ROCK signaling, or inhibiting cytoskeletal tension prevented BMP-induced SMA/mothers against decapentaplegic (SMAD)1 c-terminal phosphorylation, SMAD1 dimerization with SMAD4, and SMAD1 translocation into the nucleus. Together, these findings demonstrate the direct involvement of cell spreading and RhoA/ROCK-mediated cytoskeletal tension generation in BMP-induced signaling and early stages of in vitro osteogenesis, and highlight the essential interplay between biochemical and mechanical cues in stem cell differentiation.",
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Bone morphogenetic protein-2-induced signaling and osteogenesis is regulated by cell shape, RhoA/ROCK, and cytoskeletal tension. / Wang, Yang Kao; Yu, Xiang; Cohen, Daniel M.; Wozniak, Michele A.; Yang, Michael T.; Gao, Lin; Eyckmans, Jeroen; Chen, Christopher S.

於: Stem Cells and Development, 卷 21, 編號 7, 01.05.2012, p. 1176-1186.

研究成果: Article

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