title: COMP-angiopoietin 1 increases proliferation, differentiation, and migration of stem-like cells through Tie-2-mediated activation of p38 MAPK and PI3K/Akt signal transduction pathways.
abstract: Recombinant COMP-Ang1, a chimera of angiopoietin-1 (Ang1) and a short coiled-coil domain of cartilage oligomeric matrix protein (COMP), is under consideration as a therapeutic agent capable of inducing the homing of cells with increased angiogenesis. However, the potentials of COMP-Ang1 to stimulate migration of mesenchymal stem cells (MSCs) and the associated mechanisms are not completely understood. We examined the potential of COMP-Ang1 on bone marrow (BM)-MSCs, human periodontal ligament stem cells (PDLSCs), and calvarial osteoblasts. COMP-Ang1 augmented Tie-2 induction at protein and mRNA levels and increased proliferation and expression of runt-related transcription factor 2 (Runx2), osterix, and CXCR4 in BMMSCs, but not in osteoblasts. The COMP-Ang1-mediated increases were inhibited by Tie-2 knockdown and by treating inhibitors of phosphoinositide 3-kinase (PI3K), LY294002, or p38 mitogen-activated protein kinase (MAPK), SB203580. Phosphorylation of p38 MAPK and Akt was prevented by siRNA-mediated silencing of Tie-2. COMP-Ang1 also induced in vitro migration of BMMSCs and PDLSCs. The induced migration was suppressed by Tie-2 knockdown and by CXCR4-specific peptide antagonist or LY294002, but not by SB203580. Furthermore, COMP-Ang1 stimulated the migration of PDLSCs into calvarial defect site of rats. Collectively, our results demonstrate that COMP-Ang1-stimulated proliferation, differentiation, and migration of progenitor cells may involve the Tie-2-mediated activation of p38 MAPK and PI3K/Akt pathways.
authors.affiliation: Cluster for Craniofacial Development & Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Chonbuk National University, Jeonju, South Korea.
authors.forename: Sung-Ho
authors.initials: SH
authors.lastname: Kook
authors.affiliation: School of Dentistry and Dental Research Institute, Seoul National University, Seoul, South Korea.
authors.forename: Shin-Saeng
authors.initials: SS
authors.lastname: Lim
authors.affiliation: Cluster for Craniofacial Development & Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Chonbuk National University, Jeonju, South Korea.
authors.forename: Eui-Sic
authors.initials: ES
authors.lastname: Cho
authors.affiliation: Cluster for Craniofacial Development & Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Chonbuk National University, Jeonju, South Korea.
authors.forename: Young-Hoon
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Cluster for Craniofacial Development & Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Chonbuk National University, Jeonju, South Korea.
authors.forename: Seong-Kyu
authors.initials: SK
authors.lastname: Han
authors.affiliation: Cluster for Craniofacial Development & Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Chonbuk National University, Jeonju, South Korea.
authors.forename: Kyung-Yeol
authors.initials: KY
authors.lastname: Lee
authors.affiliation: College of Veterinary Medicine, Chonbuk National University, Jeonju, South Korea.
authors.forename: Jungkee
authors.initials: J
authors.lastname: Kwon
authors.affiliation: Cluster for Craniofacial Development & Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Chonbuk National University, Jeonju, South Korea.
authors.forename: Jae-Won
authors.initials: JW
authors.lastname: Hwang
authors.affiliation: Cluster for Craniofacial Development & Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Chonbuk National University, Jeonju, South Korea.
authors.forename: Cheol-Hyeon
authors.initials: CH
authors.lastname: Bae
authors.affiliation: Research Institute of Biotechnology, Dongguk University, Seoul, South Korea.
authors.forename: Young-Kwon
authors.initials: YK
authors.lastname: Seo
authors.affiliation: Cluster for Craniofacial Development & Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Chonbuk National University, Jeonju, South Korea. Electronic address: leejc88@jbnu.ac.kr.
authors.forename: Jeong-Chae
authors.initials: JC
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D000328:Adult; D042683:Angiopoietin-1 / Q000378:metabolism*; D000818:Animals; D064236:Cartilage Oligomeric Matrix Protein / Q000378:metabolism*; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D004791:Enzyme Inhibitors / Q000737:chemistry; D005269:Femur / Q000473:pathology; D020868:Gene Silencing; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D042787:Receptor, TIE-2 / Q000378:metabolism*; D015398:Signal Transduction; D013977:Tibia / Q000473:pathology; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D042683:Angiopoietin-1; D064236:Cartilage Oligomeric Matrix Protein; D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D042787:Receptor, TIE-2; D048051:p38 Mitogen-Activated Protein Kinases
keywords: COMP-Ang1; Mesenchymal stem cells; Migration; PI3K/Akt; Tie-2