title: Microenvironmental Interaction Between Hypoxia and Endothelial Cells Controls the Migration Ability of Placenta-Derived Mesenchymal Stem Cells via α4 Integrin and Rho Signaling.
abstract: Mesenchymal stem cells (MSCs) are a powerful source for cell therapy in degenerative diseases. The migration ability of MSCs is an important factor that enhances the therapeutic effect of the cells when they are transplanted into target tissues or organs. Hypoxia and the endothelial barrier, which are representative migration microenvironmental factors, are known to be regulated by the integrin-mediated pathway in several cancers. However, their regulatory mechanisms in MSCs remain unclear. Here, the objectives of the study were to compare the expression of markers related to integrin-mediated signaling in placenta-derived MSCs (PDMSCs) dependent on hypoxia and co-cultured with human umbilical vein endothelial cells (HUVECs) and to evaluate their correlations between migration ability and microenvironmetal factors including hypoxia and endothelial cells. The migration abilities of PDMSCs exposed to hypoxic conditions were significantly increased compared with normal fibroblasts (WI-38) and control (P < 0.05). Interestingly, decreased integrin α4 in PDMSCs under hypoxia induce to increase migration abilities of PDMSCs. Also, Rho family-related markers were significantly increased in PDMSCs under hypoxic conditions compared with normoxia (P < 0.05). Furthermore, the migration ability of PDMSCs was decreased by Rho kinase inhibitor treatment (Y-27632) and co-culturing with HUVECs in an ex vivo system. ROCK activity was increased by inhibiting integrin α4 with HUVECs and hypoxia compared with the absence of HUVECs and under normoxia. The findings suggest microenvironment event by hypoxia and the interaction with endothelial cells may be useful as a regulator of MSC migration and provide insight into the migratory mechanism of MSCs in stem cell-based therapy.
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam-si, Republic of Korea.
authors.forename: Jong Ho
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam-si, Republic of Korea.
authors.forename: Seung Mook
authors.initials: SM
authors.lastname: Lim
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam-si, Republic of Korea.
authors.forename: Yong In
authors.initials: YI
authors.lastname: Yoo
authors.affiliation: Department of Nanobiomedical Science, Dankook University, Cheonan-si, Republic of Korea.
authors.forename: Jieun
authors.initials: J
authors.lastname: Jung
authors.affiliation: Department of Biomedical Sciences and Pharmacology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jong-Won
authors.initials: JW
authors.lastname: Park
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam-si, Republic of Korea.
authors.forename: Gi Jin
authors.initials: GJ
authors.lastname: Kim
mesh_terms: D000577:Amides / Q000494:pharmacology; D015153:Blotting, Western; D015687:Cell Hypoxia; D002460:Cell Line; D002465:Cell Movement; D002478:Cells, Cultured; D060833:Cellular Microenvironment; D018920:Coculture Techniques; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D039441:Integrin alpha4 / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D010920:Placenta / Q000166:cytology; D011247:Pregnancy; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D011725:Pyridines; C108830:Y 27632; D039441:Integrin alpha4; D054460:rho-Associated Kinases; D020778:Matrix Metalloproteinase 2
keywords: HOMING; HUMAN UMBILICAL VEIN ENDOTHELIAL CELL (HUVEC); HYPOXIA; INTEGRIN α4; PLACENTA-DERIVED MESENCHYMAL STEM CELLS; RHO FAMILY