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Adipose Tissue and Immunomodulation: It’s not what you do, it’s where you do it!

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Review of “Adipogenic Differentiation of Mesenchymal Stem Cells Alters Their Immunomodulatory Properties in a Tissue-Specific Manner” from STEM CELLS by Stuart P. Atkinson

Mesenchymal stem cells (MSC) are tissue-resident precursors with potent immunomodulatory capabilities that aid homeostatic control in a range of tissues [1]. However, studies have suggested that lineage-specific differentiation of MSCs may alter these capabilities [2].

The laboratory of Helen M. McGettrick (University of Birmingham, UK) has focused their studies on the adipogenic differentiation of MSCs, given that a number of inflammatory disorders (including Duchenne muscular dystrophy, myocardial infarction, and type II diabetes) are associated with ectopic fat deposits and/or alterations in local adipose tissue. Specifically, the lab’s new STEM CELLS study aimed to discover if the adipogenic differentiation of MSCs in inflamed tissues led to the loss of immunomodulatory activity and the aggravation of inflammatory disorders [3]. 

Their exciting new study now suggests that for adipose tissue and immunomodulation, it’s not what you do, it’s where you do it!

Initial coculture experiments assessed how MSCs affected neutrophil recruitment towards TNFα-treated endothelial cells (ECs), which models an inflammatory milieu. The study discovered that while MSCs blocked neutrophil recruitment and hence exhibited immunosuppressive activity, MSCs that underwent adipogenic differentiation lost this ability. This deficit correlated with alterations in TGFβ1 and IL-6 signaling in ECs and a switch in their function from immunosuppressive to pro-inflammatory signaling [4-6]. Indeed, further analysis indicated that adipogenic differentiation of MSCs altered the composition and bioactivity of the coculture protein-secretion pattern (See figure) to promote further modulation of IL-6 and TGFβ1 responses.

Data collected so far implied that adipogenic differentiation under inflammatory conditions led to the loss of immunomodulatory capabilities in MSCs. However, adipocytes derived from adipose stem cells (ASCs) as well as mature adipocytes extracted from the same native fat tissue demonstrated that both cell types exhibited potent immunosuppressive effects in coculture experiments. Therefore, the authors of the study propose that only adipose tissue derived from aberrant/ectopic differentiating MSCs displays deficits in their immunomodulatory capabilities. 

The authors hypothesize that adipocytes exist in two functional states: immunoprotective in healthy adipose tissue and non-immunoprotective when formed in ectopic sites of fat deposition associated with chronic inflammation. Therefore, for adipose tissue and immunomodulation, it’s not what you do, it’s where you do it!

Stay tuned to the Stem Cells Portal to keep up to date with all the new findings in the exciting area!

References

  1. Munir H, Luu NT, Clarke LS, et al. Comparative Ability of Mesenchymal Stromal Cells from Different Tissues to Limit Neutrophil Recruitment to Inflamed Endothelium. PLoS One 2016;11:e0155161.
  2. Hulot JS, Stillitano F, Salem JE, et al. Considerations for pre-clinical models and clinical trials of pluripotent stem cell-derived cardiomyocytes. Stem Cell Res Ther 2014;5:1.
  3. Munir H, Ward LSC, Sheriff L, et al. Adipogenic Differentiation of Mesenchymal Stem Cells Alters Their Immunomodulatory Properties in a Tissue-Specific Manner. Stem Cells 2017;35:1636-1646.
  4. Lally F, Smith E, Filer A, et al. A novel mechanism of neutrophil recruitment in a coculture model of the rheumatoid synovium. Arthritis Rheum 2005;52:3460-3469.
  5. McGettrick HM, Smith E, Filer A, et al. Fibroblasts from different sites may promote or inhibit recruitment of flowing lymphocytes by endothelial cells. Eur J Immunol 2009;39:113-125.
  6. Tull SP, Anderson SI, Hughan SC, et al. Cellular pathology of atherosclerosis: smooth muscle cells promote adhesion of platelets to cocultured endothelial cells. Circ Res 2006;98:98-104.