title: Fibroblast activation protein (FAP) is essential for the migration of bone marrow mesenchymal stem cells through RhoA activation.
abstract: BACKGROUND
  The ability of human bone marrow mesenchymal stem cells (BM-MSCs) to migrate and localize specifically to injured tissues is central in developing therapeutic strategies for tissue repair and regeneration. Fibroblast activation protein (FAP) is a cell surface serine protease expressed at sites of tissue remodeling during embryonic development. It is also expressed in BM-MSCs, but not in normal tissues or cells. The function of FAP in BM-MSCs is not known.
  
  
  RESULTS
  We found that depletion of FAP proteins significantly inhibited the migration of BM-MSCs in a transwell chemotaxis assay. Such impaired migration ability of BM-MSCs could be rescued by re-expressing FAP in these cells. We then demonstrated that depletion of FAP activated intracellular RhoA GTPase. Consistently, inhibition of RhoA activity using a RhoA inhibitor rescued its migration ability. Inhibition of FAP activity with an FAP-specific inhibitor did not affect the activation of RhoA or the migration of BM-MSCs. Furthermore, the inflammatory cytokines interleukin-1beta (IL-1β) and transforming growth factor-beta (TGF-β) upregulated FAP expression, which coincided with better BM-MSC migration.
  
  
  CONCLUSIONS
  Our results indicate FAP plays an important role in the migration of BM-MSCs through modulation of RhoA GTPase activity. The peptidase activity of FAP is not essential for such migration. Cytokines IL-1β and TGF-β upregulate the expression level of FAP and thus enhance BM-MSC migration.
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan, Republic of China.
authors.forename: Kuei-Min
authors.initials: KM
authors.lastname: Chung
authors.affiliation: Vaccine Research and Development Center, National Health Research Institutes, Miaoli, Taiwan, Republic of China.
authors.forename: Shu-Ching
authors.initials: SC
authors.lastname: Hsu
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan, Republic of China.
authors.forename: Yue-Ru
authors.initials: YR
authors.lastname: Chu
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan, Republic of China.
authors.forename: Mei-Yao
authors.initials: MY
authors.lastname: Lin
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan, Republic of China.
authors.forename: Weir-Tong
authors.initials: WT
authors.lastname: Jiaang
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan, Republic of China.
authors.forename: Ruey-Hwa
authors.initials: RH
authors.lastname: Chen
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan, Republic of China ; Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
mesh_terms: D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002633:Chemotaxis; D010450:Endopeptidases; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018093:Gelatinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D005786:Gene Expression Regulation; D005816:Genetic Complementation Test; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D061251:Primary Cell Culture; D012697:Serine Endopeptidases / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D010450:Endopeptidases; D004791:Enzyme Inhibitors; D018093:Gelatinases; D053583:Interleukin-1beta; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D016212:Transforming Growth Factor beta; D020742:rhoA GTP-Binding Protein; D000099167:Fibroblast Activation Protein Alpha; C066737:RHOA protein, human