title: Transforming growth factor β induces bone marrow mesenchymal stem cell migration via noncanonical signals and N-cadherin.
abstract: Transforming growth factor-beta (TGF-β) induces the migration and mobilization of bone marrow-derived mesenchymal stem cells (BM-MSCs) to maintain bone homeostasis during bone remodeling and facilitate the repair of peripheral tissues. Although many studies have reported the mechanisms through which TGF-β mediates the migration of various types of cells, including cancer cells, the intrinsic cellular mechanisms underlying cellular migration, and mobilization of BM-MSCs mediated by TGF-β are unclear. In this study, we showed that TGF-β activated noncanonical signaling molecules, such as Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), focal adhesion kinase (FAK), and p38, via TGF-β type I receptor in human BM-MSCs and murine BM-MSC-like ST2 cells. Inhibition of Rac1 by NSC23766 and Src by PP2 resulted in impaired TGF-β-mediated migration. These results suggested that the Smad-independent, noncanonical signals activated by TGF-β were necessary for migration. We also showed that N-cadherin-dependent intercellular interactions were required for TGF-β-mediated migration using functional inhibition of N-cadherin with EDTA treatment and a neutralizing antibody (GC-4 antibody) or siRNA-mediated knockdown of N-cadherin. However, N-cadherin knockdown did not affect the global activation of noncanonical signals in response to TGF-β. Therefore, these results suggested that the migration of BM-MSCs in response to TGF-β was mediated through N-cadherin and noncanonical TGF-β signals.
authors.affiliation: Graduate School of Biotechnology, Kyung Hee University, Yongin, Korea.
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Dubon
authors.affiliation: Graduate School of Biotechnology, Kyung Hee University, Yongin, Korea.
authors.forename: Jinyeong
authors.initials: J
authors.lastname: Yu
authors.affiliation: Graduate School of Biotechnology, Kyung Hee University, Yongin, Korea.
authors.forename: Sanghyuk
authors.initials: S
authors.lastname: Choi
authors.affiliation: East-West Medical Research Institute, Kyung Hee University, Seoul, Korea.|College of Medicine, Kyung Hee University, Seoul, Korea.
authors.forename: Ki-Sook
authors.identifier: http://orcid.org/0000-0002-3218-9405
authors.initials: KS
authors.lastname: Park
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009479:Neuropeptides / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C050361:CDH2 protein, human; D015820:Cadherins; C489083:Cdh2 protein, mouse; D009479:Neuropeptides; C107953:RAC1 protein, human; C484602:Rac1 protein, mouse; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse; D019061:src-Family Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D020830:rac1 GTP-Binding Protein
keywords: N-cadherin; mesenchymal stem cells; migration; transforming growth factor β