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

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.

Pygopus2 ameliorates mesenteric adipocyte poor differentiation to alleviate Crohn's disease ‐like colitis via the Axin2/GSK3β pathway

“…Previous studies have suggested that adipocyte dysfunction and poor differentiation could aggravate CD colitis. 24 Considering the inhibitory effect of Pygo2 on adipocyte differentiation, we examined whether the absence of Pygo2 attenuated inflammation in the intestine and MAT by promoting the differentiation of adipocytes in CD. We found that Pygo2 KD Il‐10 −/− mice showed increased expression of perilipin, a marker of mature adipocytes (Figure 4A,B ).…”

“…3.4 | Pygo2 knockdown improved mesenteric adipocyte differentiation in Il-10 À/À mice Previous studies have suggested that adipocyte dysfunction and poor differentiation could aggravate CD colitis. 24 Considering the inhibitory effect of Pygo2 on adipocyte differentiation, we examined whether the absence of Pygo2 attenuated inflammation in the intestine and MAT by promoting the differentiation of adipocytes in CD. We found that Pygo2 KD Il-10 À/À mice showed increased expression of perilipin, a marker of mature adipocytes (Figure 4A,B).…”

Anti-TNF Therapies Suppress Adipose Tissue Inflammation in Crohn’s Disease

“…As mentioned earlier, creeping fat hyperplasia in patients with CD is triggered by the enhanced recruitment of ASC precursors neighboring damaged intestinal areas. We previously demonstrated that ASCs from patients with CD have a bolstered pro-inflammatory and antigen-presentation capacity [ 21 , 22 ]. We studied whether anti-TNF treatments improved the pro-inflammatory profile in ASCs by examining the relative gene expression of typical pro-inflammatory markers ( TNFA , IL6 , IL1B , and CCL2 ) in ASCs isolated from the creeping fat of patients treated or not with anti-TNF therapy.…”

“…Of note, our proteomics results showed a decline in IL6 abundance in ASCs isolated from patients receiving anti-TNF treatment, which is consistent with a decline in IL-6 levels in the patients’ serum. We previously demonstrated that CD disturbs the immune properties of ASCs isolated from the creeping fat, which show enhanced inflammatory, phagocytic, and invasive capacities as compared with ASCs isolated from healthy individuals [ 21 ] and bolstered the antigen-presenting capacity [ 22 ]. In this study, we demonstrate that anti-TNF therapies revert these immunomodulatory capacities in the ASCs isolated from anti-TNF-treated patients as we observed lower gene expression levels of antigen-presentation markers and co-stimulatory molecules in these cells.…”

“…After isolation, the minimal functional and quantitative criteria, established by the International Society of Cell Therapy and the International Federation for Adipose Therapeutics and Science, were confirmed by flow cytometry using the FacsAriaIII (BD, Biosciences, San Jose, CA, USA). Data analysis was performed using the FACSDiva software (BD Biosciences, San Jose, CA, USA) [ 22 , 51 ].…”