title: Inhibition of Rho-Associated Protein Kinase Increases the Angiogenic Potential of Mesenchymal Stem Cell Aggregates via Paracrine Effects.
abstract: The aggregation of multiple cells, such as mesenchymal condensation, is an important biological process in skeletal muscle development, osteogenesis, and adipogenesis. Due to limited in vivo study model systems, a simple and effective in vitro three-dimensional (3D) aggregation system is required to study the mechanisms of multicellular aggregation and its applications. We first generated controlled mesenchymal stem cell (MSC) aggregates using a bioprinting technique to monitor their aggregation and sprouting. We induced the angiogenic potential of the MSCs through chemical inhibition of the Rho/Rho-associated protein kinase (ROCK) pathway, which led to hairy sprouting in the aggregates. The angiogenic potential of this 3D construct was then tested by subcutaneously implanting the Matrigel with 3D MSC aggregates in a rat. Treatment of 3D MSCs with the ROCK inhibitor, Y27632, increased their angiogenic activity in vivo. The gene expressions and histological staining indicated that angiogenesis and neovascularization were mainly regulated by the paracrine factors secreted from human 3D MSC constructs. Our results demonstrate the enhancement of the angiogenic potential of the MSC constructs through the secretion of vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) by the inhibition of the Rho/ROCK pathway.
authors.affiliation: 1 Department of Biomedical Engineering, College of Medicine, Korea University , Seoul, Korea.|2 Biomedical Engineering Research Center, Asan Medical Center , Seoul, Korea.
authors.forename: Soyoung
authors.initials: S
authors.lastname: Hong
authors.affiliation: 1 Department of Biomedical Engineering, College of Medicine, Korea University , Seoul, Korea.
authors.forename: Jae Yeon
authors.initials: JY
authors.lastname: Lee
authors.affiliation: 2 Biomedical Engineering Research Center, Asan Medical Center , Seoul, Korea.
authors.forename: Changmo
authors.initials: C
authors.lastname: Hwang
authors.affiliation: 3 Department of Mechanical Engineering, Graduate School of Medical Science and Engineering , KAIST, Daejeon, Korea.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Shin
authors.affiliation: 1 Department of Biomedical Engineering, College of Medicine, Korea University , Seoul, Korea.
authors.forename: Yongdoo
authors.initials: Y
authors.lastname: Park
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D004815:Epidermal Growth Factor / Q000096:biosynthesis; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D019899:Paracrine Communication / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000577:Amides; D011725:Pyridines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; C108830:Y 27632; D004815:Epidermal Growth Factor; D054460:rho-Associated Kinases