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 (TGFβ 1 ) 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 TGFβ 1 induced 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 TGFβ 1 or 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.

DPSCs treated by TGF-β1 regulate angiogenic sprouting of three-dimensionally co-cultured HUVECs and DPSCs through VEGF-Ang-Tie2 signaling

“…The secreted VEGF assessed by ELISA had a similar trend, which was highest at day 3, and decreased at days 5 and 7. Consistently, it was reported that mesenchymal stem cells (MSCs), such as ASCs, following their differentiation into smooth muscle cells downregulated VEGF expression while upregulating α-SMA, SM22α expression [ 15 , 16 ].…”

“…It was found that VEGF secretion is precisely orchestrated parallel to the different stages of the angiogenic process [ 11 , 12 ]. Other MSCs, such as bone marrow mesenchymal stem cells (BMMSCs) and adipose stem cells (ASCs), interact with ECs similarly, shifting their paracrine activity from being pro-angiogenic to angiostatic and phenotypes from stem cells to mural cells following the developmental progress of the vessel formation [ 13 – 16 ].…”

“…Transforming growth factor beta 1 (TGF-β1) protein is the most effective soluble growth factor regularly utilized for inducing stem cell differentiation into SMCs [ 5 , 16 , 23 ]. TGF-β1/Smad signaling pathway is critical for differentiation of mesenchymal stem cell/progenitors into SMCs [ 24 ].…”

Preparation and evaluation of anti‐renal fibrosis activity of novel truncated TGF‐β receptor type II

“…A carefully controlled balance of TGF‐β1‐dependent signaling pathways regulates cell differentiation , proliferation , migration , metastasis, and ECM production . Inappropriate alteration of this balance often occurs in the pathogenesis and progression of fibrosis‐related diseases .…”

Adipose-derived stem cells contribute to cardiovascular remodeling

“…Activin A was indispensable in the early stages of ADSCs differentiation into vascular SMCs when cultured with ECs [50]. However, induction of activin A secretion after stimulating ADSCs towards SMCs diminished ADSCs’ vasculogenic activity [51]. The summary of mechanisms of ADSCs differentiation into SMCs is displayed in Figure 1.…”