Abstract
ObjectiveThe present study was undertaken to characterize the remodeling phenotype of human adipose tissue (AT) macrophages (ATM) and to analyze their paracrine effects on AT progenitor cells.Research Design and MethodsThe phenotype of ATM, immunoselected from subcutaneous (Sc) AT originating from subjects with wide range of body mass index and from paired biopsies of Sc and omental (Om) AT from obese subjects, was studied by gene expression analysis in the native and activated states. The paracrine effects of ScATM on the phenotype of human ScAT progenitor cells (CD34+CD31−) were investigated.ResultsTwo main ATM phenotypes were distinguished based on gene expression profiles. For ScAT-derived ATM, obesity and adipocyte-derived factors favored a pro-fibrotic/remodeling phenotype whereas the OmAT location and hypoxic culture conditions favored a pro-angiogenic phenotype. Treatment of native human ScAT progenitor cells with ScATM-conditioned media induced the appearance of myofibroblast-like cells as shown by expression of both α-SMA and the transcription factor SNAIL, an effect mimicked by TGFβ1 and activinA. Immunohistochemical analyses showed the presence of double positive α-SMA and CD34 cells in the stroma of human ScAT. Moreover, the mRNA levels of SNAIL and SLUG in ScAT progenitor cells were higher in obese compared with lean subjects.ConclusionsHuman ATM exhibit distinct pro-angiogenic and matrix remodeling/fibrotic phenotypes according to the adiposity and the location of AT, that may be related to AT microenvironment including hypoxia and adipokines. Moreover, human ScAT progenitor cells have been identified as target cells for ScATM-derived TGFβ and as a potential source of fibrosis through their induction of myofibroblast-like cells.
Highlights
Excessive development of adipose tissue (AT) in obesity is characterized by an accumulation of immune cells [1,2,3,4]
The expression of several genes involved in angiogenesis and matrix remodeling/fibrosis (IL-10, interleukin 6 (IL-6), TGFb1, monocyte chemotactic protein 1 (MCP-1), matrix metalloproteinase 2 (MMP-2) and -9, vascular endothelial growth factor (VEGFA) and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1)) were analyzed by real-time PCR in human native Adipose tissue macrophages (ATM) (CD342/CD14+) immunoselected from the ScAT of non-obese and obese individuals
The levels of expression of TGFb1 as well as MCP-1, MMP-2, LYVE1 and VEGFA were markedly higher whereas matrix metalloproteinase 9 (MMP-9) transcript levels were lower in the ATM isolated from the obese compared to the non-obese group
Summary
Excessive development of adipose tissue (AT) in obesity is characterized by an accumulation of immune cells [1,2,3,4]. Adipose tissue macrophages (ATM) originating from these newly recruited monocytes showed a marked inflammatory phenotype in comparison to resident ATM Such a subset has been involved in the establishment of the systemic low grade inflammation seen in obesity and insulin resistance [1,2,4,5,6]. Large scale transcriptomic analyses of AT from obese humans, together with immunohistochemical analysis and in vitro approaches, have shown that inflammatory (i.e, LPS-stimulated) monocyte-derived macrophages induced phenotypic alterations of human AT progenitor cells that resulted in excessive synthesis of extracellular matrix components [21,22]. We and others have shown that factors secreted by hATM inhibited the adipogenesis of human AT progenitor cells either directly or through the enhanced expression of a TGFb family member, INBHA/activinA [8,23,24]. The fate of these AT progenitor cells arrested by hATM-derived factors remains to be established
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