title: RhoA determines lineage fate of mesenchymal stem cells by modulating CTGF-VEGF complex in extracellular matrix.
abstract: Mesenchymal stem cells (MSCs) participate in the repair/remodelling of many tissues, where MSCs commit to different lineages dependent on the cues in the local microenvironment. Here we show that TGFβ-activated RhoA/ROCK signalling functions as a molecular switch regarding the fate of MSCs in arterial repair/remodelling after injury. MSCs differentiate into myofibroblasts when RhoA/ROCK is turned on, endothelial cells when turned off. The former is pathophysiologic resulting in intimal hyperplasia, whereas the latter is physiological leading to endothelial repair. Further analysis revealed that MSC RhoA activation promotes formation of an extracellular matrix (ECM) complex consisting of connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF). Inactivation of RhoA/ROCK in MSCs induces matrix metalloproteinase-3-mediated CTGF cleavage, resulting in VEGF release and MSC endothelial differentiation. Our findings uncover a novel mechanism by which cell-ECM interactions determine stem cell lineage specificity and offer additional molecular targets to manipulate MSC-involved tissue repair/regeneration.
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.|Department of Endocrinology, Institute of Endocrinology and Metabolism, Second Xiangya Hospital of Central South University, Changsha 410011, China.
authors.forename: Changjun
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Gehua
authors.initials: G
authors.lastname: Zhen
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chai
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Xie
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Crane
authors.affiliation: Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Farber
authors.affiliation: Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Farber
authors.affiliation: Department of Endocrinology, Institute of Endocrinology and Metabolism, Second Xiangya Hospital of Central South University, Changsha 410011, China.
authors.forename: Xianghang
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Medicine, Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA.
authors.forename: Peisong
authors.initials: P
authors.lastname: Gao
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Wan
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism*; D005263:Femoral Artery / Q000293:injuries / Q000378:metabolism; D005786:Gene Expression Regulation; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration / Q000235:genetics; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing / Q000235:genetics*; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: C526318:CCN2 protein, mouse; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D055513:Connective Tissue Growth Factor; D054460:rho-Associated Kinases; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein