Crohn's Disease Increases the Mesothelial Properties of Adipocyte Progenitors in the Creeping Fat.

Ana Madeira,María M Malagón,Sonia Fernández-Veledo,Margarita Menacho,Ana Megía,Rocío Guzmán-Ruiz,Marc Martí,Carolina Serena,Monica Millan,Miriam Ejarque,Eloy Espin,M Carmen Navarro-Ruiz,Elsa Maymó-Masip,Joan Vendrell

doi:10.3390/ijms22084292

Abstract

Our understanding of the interplay between human adipose tissue and the immune system is limited. The mesothelium, an immunologically active structure, emerged as a source of visceral adipose tissue. After investigating the mesothelial properties of human visceral and subcutaneous adipose tissue and their progenitors, we explored whether the dysfunctional obese and Crohn’s disease environments influence the mesothelial/mesenchymal properties of their adipocyte precursors, as well as their ability to mount an immune response. Using a tandem transcriptomic/proteomic approach, we evaluated the mesothelial and mesenchymal expression profiles in adipose tissue, both in subjects covering a wide range of body-mass indexes and in Crohn’s disease patients. We also isolated adipose tissue precursors (adipose-derived stem cells, ASCs) to assess their mesothelial/mesenchymal properties, as well as their antigen-presenting features. Human visceral tissue presented a mesothelial phenotype not detected in the subcutaneous fat. Only ASCs from mesenteric adipose tissue, named creeping fat, had a significantly higher expression of the hallmark mesothelial genes mesothelin (MSLN) and Wilms’ tumor suppressor gene 1 (WT1), supporting a mesothelial nature of these cells. Both lean and Crohn’s disease visceral ASCs expressed equivalent surface percentages of the antigen-presenting molecules human leucocyte antigen—DR isotype (HLA-DR) and CD86. However, lean-derived ASCs were predominantly HLA-DR dim, whereas in Crohn’s disease, the HLA-DR bright subpopulation was increased 3.2-fold. Importantly, the mesothelial-enriched Crohn’s disease precursors activated CD4+ T-lymphocytes. Our study evidences a mesothelial signature in the creeping fat of Crohn’s disease patients and its progenitor cells, the latter being able to present antigens and orchestrate an immune response.

Highlights

Excessive and dysfunctional adipose tissue is responsible for many of today’s health epidemics, especially obesity
We found that the expression of keratin 8 (KRT8), cadherin 1 (CDH1), mesothelin (MSLN), leucine rich repeat neuronal 4 (LRRN4), and Wilms’ tumor suppressor gene 1 (WT1) was significantly higher in VAT than in SAT (Figure 1A), which is consistent with the finding of a mesothelial gene expression pattern in omental fat in a previous microarray-based analysis (GEO accession number GSE20950; Supplementary Table S1) [34]
Results showed that the mesothelial proteins MSLN, tight junction protein 1 (TJP1), keratin 7 (KRT7), KRT8, and calponin 1 (CNN1) were detected in VAT but not in SAT

Summary

Introduction

Excessive and dysfunctional adipose tissue is responsible for many of today’s health epidemics, especially obesity. Fat accumulation and inflammation can be locally restricted. Such is the case in Crohn’s disease, a chronic inflammatory bowel disease characterized by the expansion of mesenteric adipose tissue, known as “creeping fat”, which correlates with the disease severity [2,3,4]. Recent findings indicate similarities between the complex pathological features of Crohn’s disease and obesity/T2D with respect to adipose tissue behavior [5], especially in terms of inflammation [5,6,7], and it is clear that adipose tissue holds yet unrealized functions in the setting of these diseases. A recent publication used a novel mesenteric creeping fat index based on computed tomography to characterize accurately the extent of mesenteric fat wrapping in surgical specimens, which correlated with intestinal fibrostenosis [8]

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