title: Adipose Stromal Cell Contact with Endothelial Cells Results in Loss of Complementary Vasculogenic Activity Mediated by Induction of Activin A.
abstract: Adipose stem/stromal cells (ASCs) after isolation produce numerous angiogenic growth factors. This justifies their use to promote angiogenesis per transplantation. In parallel, local coimplantation of ASC with endothelial cells (ECs) leading to formation of functional vessels by the donor cells suggests the existence of a mechanism responsible for fine-tuning ASC paracrine activity essential for vasculogenesis. As expected, conditioned media (CM) from ASC promoted ECs survival, proliferation, migration, and vasculogenesis. In contrast, media from EC-ASC cocultures had neutral effects upon EC responses. Media from cocultures exhibited lower levels of vascular endothelial growth factor (VEGF), hepatic growth factor, angiopoietin-1, and stromal cell-derived factor-1 compared with those in ASC CM. Activin A was induced in ASC in response to EC exposure and was responsible for overall antivasculogenic activity of EC-ASC CM. Except for VEGF, activin A diminished secretion of all tested factors by ASC. Activin A mediated induction of VEGF expression in ASC, but also upregulated expression of VEGF scavenger receptor FLT-1 in EC in EC-ASC cocultures. Blocking the FLT-1 expression in EC led to an increase in VEGF concentration in CM. In vitro pre-exposure of ASC to low number of EC before subcutaneous coimplantation with EC resulted in decrease in vessel density in the implants. In vitro tests suggested that activin A was partially responsible for this diminished ASC activity. This study shows that neovessel formation is associated with induction of activin A expression in ASC; this factor, by affecting the bioactivity of both ASC and EC, directs the crosstalk between these complementary cell types to establish stable vessels.
authors.affiliation: Department of Medicine, Indiana Center for Vascular Biology and Medicine, Krannert Institute of Cardiology, Indianapolis, Indiana, USA.|Department of Medicine, Indiana Center for Vascular Biology and Medicine, Krannert Institute of Cardiology, Indianapolis, Indiana, USA.|VA Center for Regenerative Medicine, R.L. Roudebush VA Medical Center, Indianapolis, Indiana, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Merfeld-Clauss
authors.affiliation: Department of Medicine, Indiana Center for Vascular Biology and Medicine, Krannert Institute of Cardiology, Indianapolis, Indiana, USA.|Department of Medicine, Indiana Center for Vascular Biology and Medicine, Krannert Institute of Cardiology, Indianapolis, Indiana, USA.|VA Center for Regenerative Medicine, R.L. Roudebush VA Medical Center, Indianapolis, Indiana, USA.
authors.forename: Ivan P
authors.initials: IP
authors.lastname: Lupov
authors.affiliation: Department of Medicine, Indiana Center for Vascular Biology and Medicine, Krannert Institute of Cardiology, Indianapolis, Indiana, USA.|Department of Medicine, Indiana Center for Vascular Biology and Medicine, Krannert Institute of Cardiology, Indianapolis, Indiana, USA.|VA Center for Regenerative Medicine, R.L. Roudebush VA Medical Center, Indianapolis, Indiana, USA.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Lu
authors.affiliation: Department of Medicine, Indiana Center for Vascular Biology and Medicine, Krannert Institute of Cardiology, Indianapolis, Indiana, USA.|Department of Medicine, Indiana Center for Vascular Biology and Medicine, Krannert Institute of Cardiology, Indianapolis, Indiana, USA.|VA Center for Regenerative Medicine, R.L. Roudebush VA Medical Center, Indianapolis, Indiana, USA.|Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Keith L
authors.initials: KL
authors.lastname: March
authors.affiliation: Department of Medicine, Indiana Center for Vascular Biology and Medicine, Krannert Institute of Cardiology, Indianapolis, Indiana, USA.|Department of Medicine, Indiana Center for Vascular Biology and Medicine, Krannert Institute of Cardiology, Indianapolis, Indiana, USA.|VA Center for Regenerative Medicine, R.L. Roudebush VA Medical Center, Indianapolis, Indiana, USA.
authors.forename: Dmitry O
authors.initials: DO
authors.lastname: Traktuev
mesh_terms: D028341:Activins / Q000096:biosynthesis* / Q000378:metabolism; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D017154:Stromal Cells / Q000166:cytology* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis
chemical_list: D017077:Culture Media, Conditioned; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C422405:activin A; D028341:Activins; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: Activin A; Adipose stem/stromal cells; Coculture; Endothelial cells; FLT-1; Vascular endothelial growth factor; Vasculogenesis