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Expression profile of human preadipocytes cultured with activated macrophages medium

ABSTRACT: Extracellular matrix (ECM) remodelling occurs during tissue repair and inflammation-related pathologies with deposition of specific proteins. White adipose tissue (WAT) was recently shown to be the site of substantial interstitial fibrosis. ECM components, such as fibronectin, and their receptors integrins control cell migration, proliferation and differentiation. Adipocyte differentiation which is under the control of a specific transcriptional network is associated with decrease of fibronectin-rich matrix. Considering macrophage accumulation in white adipose tissues from obese subjects, we recently demonstrated that macrophage-secreted factors provoke an inhibition of differentiation with a proinflammatory state of human preadipocytes. The functional analysis of gene expression measurements obtained from cDNA microarray experiments reveals that themes related to the “extracellular matrix” are among the most significantly enriched in overexpressed genes in inflammatory preadipocytes. ECM remodelling, characterized by high deposition of fibronectin, collagen I and tenascin-C and important clustering of ECM receptors integrin alpha-5, is associated with increased proliferation and migration of preadipocytes. siRNA deletion of NF-kappaB in inflammatory preadipocytes decreased fibronectin network formation and their proliferation. Cyclin D1 and FAK constitute pivotal molecular targets in the synergistic promotion of migration and proliferation of the inflammatory preadipocytes. Importantly, interactions between preadipocytes and macrophages are favoured in 3D collagen I, a microenvironment mimicking fibrosis context of obese WATs. These data suggest that inflammatory preadipocytes could contribute to the production of fibrosis components and, in the context of WAT repair, these altered properties of preadipocytes could further lead to reconstitution of new fat clusters. Keywords: cell type comparison

ORGANISM(S): Homo sapiens

PROVIDER: GSE9017 | GEO | 2007/09/24

SECONDARY ACCESSION(S): PRJNA105305

REPOSITORIES: GEO

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Project description:This SuperSeries is related to a manuscript published in Genome Biology. The abstract of this manuscript follows here: Background Investigations performed in mice and humans have acknowledged obesity as a low-grade inflammatory disease. Several molecular mechanisms have been convincingly involved in activating inflammatory processes and altering cell composition in white adipose tissue (WAT); however, the overall importance of these alterations, and their long-term impact on the metabolic functions of the WAT and on its morphology, remain unclear. Results Here, we analyzed the transcriptomic signature of the WAT in obese human subjects, in stable weight conditions and after weight loss following bariatric surgery. An original integrative functional genomic approach was applied to quantify relations between relevant structural and functional themes annotating differentially expressed genes, to construct a comprehensive map of transcriptional interactions defining the obese WAT. These analyses highlighted a significant up-regulation of genes and biological themes related to extracellular matrix (ECM) constituents, including members of integrins family, and suggested that these elements could play a major mediating role in a chain of interactions which connects local inflammatory phenomena to the alteration of WAT metabolic functions in obese subjects. Tissue and cellular investigations, driven by the analysis of transcriptional interactions, revealed an increased amount of interstitial fibrosis in obese WAT, associated with an infiltration of different types of inflammatory cells, and suggested that phenotypic alterations of human preadipocytes, induced by a proinflammatory environment, may lead to an excessive synthesis of ECM components. Conclusions This study opens new perspectives in understanding the biology of human WAT and its pathologic changes indicative of tissue deterioration, associated with the development of obesity. This SuperSeries is composed of the SubSeries listed below.

Project description:Dupuytren's disease (DD) is a classic example of pathological fibrosis which results in a debilitating disorder affecting a large sector of the human population. It is characterized by excessive local proliferation of fibroblasts and over-production of collagen and other components of the extracellular matrix (ECM) in the palmar fascia. The fibrosis progressively results in contracture of elements between the palmar fascia and skin causing flexion deformity or clawing of the fingers and a severe reduction in hand function. While much is known about the pathogenesis and surgical treatment of DD, little is known about the factors that cause its onset and progression, despite many years of research. Gene expression patterns in DD patients now offers the potential to identify genes that direct the pathogenesis of DD. In this study, we used primary cultures of fibroblasts derived from excisional biopsies of fibrotic tissue from DD patients to compare the gene expression profiles on a genome-wide basis with normal control fibroblasts. Our investigations have identified genes that may be involved with DD pathogenesis including some which are directly relevant to fibrosis. In particular, these include significantly reduced expression levels of three matrix metallopeptidases (MMP1, MMP3, MMP16), follistatin, and STAT1, and significantly increased expression levels of fibroblast growth factors (FGF9, FGF11), a number of collagen genes and other ECM genes in DD patient samples. Many of these gene products are known to be involved in fibrosis, tumour formation and in the normal processes of tissue remodelling. In addition, alternative splicing was identified in some DD-associated genes. These highly sensitive genomic investigations provide new insight into the molecular mechanisms that may underpin the development and progression of DD. Four exon arrays of DD primary fibroblasts derived from fibrotic tissue were compared to fibroblasts derived from skin punch biopsies from individuals who did not show DD symptoms.

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Expression profile of human preadipocytes cultured with activated macrophages medium

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