title: Adipose stromal cells differentiation toward smooth muscle cell phenotype diminishes their vasculogenic activity due to induction of activin A secretion.
abstract: Adipose stromal cells (ASCs) support endothelial cell (EC) vasculogenesis through paracrine and cell-contact communications. In addition, ASCs differentiate towards the smooth muscle cell (SMC) phenotype under different stimuli, which prompted their use as a source of mural cells in fabricating small calibre vessels. How ASCs' SMC-lineage commitment affects their subsequent communication with ECs is unknown. The vasculogenic characteristics of human ASCs in progenitor stage and after differentiation towards SMC phenotype were analysed in the present study. Exposure to transforming growth factor β1 (TGFβ1) or activin A has induced expression of SMC markers in ASCs. Analysis performed after treatment withdrawal revealed that secretome of pre-differentiated ASCs had a reduced potency to support EC survival and these ASCs had diminished ability to support EC vasculogenesis in vitro. Vascularization of subcutaneous implants carrying a mixture of ECs and ASCs was 50% lower when, instead of control, pre-differentiated ASCs were used. Pre-differentiated ASCs had an inferior mitogenic response to EC-produced factors. Differentiation of ASCs was accompanied by upregulation of vascular endothelial growth factor and a decrease in hepatocyte growth factor (HGF) production; however, addition of HGF to the co-culture incubation media did not improve vasculogenesis. In parallel, ASC treatment with TGFβ1induced secretion of activin A. Augmenting co-culture incubation media with anti-activin A IgG restored the ability of pre-differentiated ASCs to support vasculogenesis to the same degree as control ASCs. The present study suggests that TGFβ1or activin A-induced ASC commitment to SMC phenotype negatively affects the ability of ASCs to support EC vasculogenesis in applications based on EC and ASC co-injection into target tissues. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Department of Medicine, Indiana Center for Vascular Biology and Medicine.|Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.|VA Center for Regenerative Medicine, R.L. Roudebush VA Medical Center, Indianapolis, IN, 46202, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Merfeld-Clauss
authors.affiliation: VA Center for Regenerative Medicine, R.L. Roudebush VA Medical Center, Indianapolis, IN, 46202, USA.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Lease
authors.affiliation: Department of Medicine, Indiana Center for Vascular Biology and Medicine.|Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.|VA Center for Regenerative Medicine, R.L. Roudebush VA Medical Center, Indianapolis, IN, 46202, 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, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.|VA Center for Regenerative Medicine, R.L. Roudebush VA Medical Center, Indianapolis, IN, 46202, USA.|Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN, 46202, 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, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.|VA Center for Regenerative Medicine, R.L. Roudebush VA Medical Center, Indianapolis, IN, 46202, USA.
authors.forename: Dmitry O
authors.initials: DO
authors.lastname: Traktuev
mesh_terms: D028341:Activins / Q000378:metabolism*; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism
chemical_list: C422405:activin A; D028341:Activins
keywords: activin A; adipose stromal cells; co-culture; endothelial cells; mural cells; vasculogenesis