As we have seen in previous blog posts in this mini-series of obesity and stem cells, there is a chronic low-grade systemic inflammation (metabolic inflammation) in obesity. The proinflammatory condition of obesity is considered the main factor in the pathogenesis of insulin resistance, leading to Type 2 diabetes; previous blog posts in this mini-series have discussed some of the association of obesity and Type 2 diabetes, but we haven’t yet discussed their impact on adipose tissue-derived stem cells (ADSCs). That is, the hostile environment of chronic inflammation, as we saw, alters the lymphoid and myeloid axis in haematopoiesis, but it also alters the functional immune properties of ADSCs. We have already seen that the inflammatory profile of ADSCs is increased in obesity. This blog posts will use the paper by Serena et al(1) to investigate how obesity and and Type 2 diabetes alter the immune properties of ADSCs. This increased inflammatory profile of ADSCs is “related to an activation of the inflammasome, higher migration, invasive, and phagocytosis capacities than those derived from lean donors” (p. 2559).
Therefore, today we will focus upon how metabolic inflammation (obesity) and Type 2 diabetes both impact the immune properties of ADSCs. Donors, in this study, were classified as lean or obese based upon body mass index (BMI) according to World Health Organization (WHO) criteria; Type 2 diabetes (T2D) was also diagnosed according to WHO criteria. Additionally, both subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were obtained and SAT and VAT were obtained from age- and gender-matched humans. In this way, cells from obese, T2D, and lean donors could be compared without having results skewed because of a mismatch in age or gender. In short, “…the data demonstrate that the hostile environment of AT [adipose tissue] in an obese state changes the functional characteristics of the different MSC populations present in this tissue” (p. 2571). I find it extremely exciting and helpful to have this manuscript that included investigations not just of cells, but also the cellular environment (often call the microenvironment, or niche) and the role it has upon cellular activities.
As has been described in several of the previous blog posts in the Obesity and Stem Cells mini-series, obesity is an inflammatory disease, and as such, the cytokine profile of ADSCs is different between obese and non-obese. While the inflammatory gene expression is higher in VAT than in SAT (in all subjects), Serena et al demonstrated that the inflammasome-mediated inflammatory response is elevated in both SAT and VAT in obesity and T2D compared with lean subjects. Additionally, there are differences between obesity and T2D; T2D ADSCs had higher mRNA expression of the inflammatory cytokine IL-1β than obese-derived ADSCs. Finally, in terms of gene expression levels of inflammasome components vary between obese-derived and T2D-derived ADSCs. NLRP1, NLRP3, and CASP-1 were highly expressed in VAT of T2D; CASP-1 was highly expressed from SAT and VAT of obese subjects. SAT depot ADSCs in T2D subjects had much higher expression of apoptosis (cell death) associated protein (ASC) compared to obese and lean subjects; ADSCs from VAT depot had increased expression of NLRP3, IL-1β, and ASC in T2D versus lean subjects and IL-1β and ASC expression were comparable between T2D and obese subjects; NLRP3 was higher in T2D than in obese subjects. While there is much overlap between obesity and T2D, it is also obvious, that the two impact cell inflammasome expression differently.
A “glycolytic phenotype” has been linked to NLRP3 inflammatory activation in macrophages. In obese and T2D-derived ADSCs, another pattern emerges when comparing obese, T2D, and lean-derived ADSCs. For lean-derived ADSCs, VAT has higher metabolic gene expression than SAT; however, in obese and T2D-derived ADSCs, both VAT and SAT displayed the glycolytic phenotype, “…suggesting that the obese environment might determine the basal metabolic capacity of these cells” (p. 2564). [As an aside, I continue to remind those to whom I lecture that the environment is more important than the cell. This is a demonstration of only a few negative impacts the environment can have upon cells.]
A second phenotype emerged in the study; ADSCs from obese and T2D subjects “…showed higher basal migration rates than those derived from lean subjects, in both SAT and VAT…” (p. 2565). Therefore, as we saw in Obesity, Stem Cells, and Cancer (Obesity and Stem Cells - Part V), the migration and invasion rates of obese and T2D-derived cells are increased compared with lean-derived cells; however, T2D-derived ADSCs from VAT were highest. “The cell-invasive phenotype is generally accompanied by changes in the expression of several MMP family proteins” (p. 2565). The obese-derived ADSCs from SAT showed higher MMP9 levels than from lean-derived ADSCs and from VAT, obese-derived ADSCs showed higher expression of MMP2 and MMP9 than lean-derived cells. MMP9 was also elevated in T2D-derived ADSCs from both VAT and SAT.
The increased cell migration and invasion are important steps in the process of phagocytosis. As increased cell migration and invasion were demonstrated, Serena et al also then demonstrated a phagocytic phenotype of obese-derived and T2D-derived ADSCs and that these cells act as “non-professional phagocytes.” In fact, the authors tested the ability of ADSCs from lean, obese, and T2D subjects to directly phagocytose the bacteria Escherichia coli. ADSCs from all donors could phagocytose the bacteria; however, the ADSCs from obese and T2D donors had a much higher capacity than the ADSCs from lean donors.
The immunomodulatory effects of MSCs have been the subject of numerous peer-reviewed papers.(2) Evidence suggests that ADSCs may affect the differentiation and functional properties of immunomodulatory cells. ADSCs from “healthy (lean) AT express various immunosuppressive molecules and growth factors that facilitate tissue repair and maintain immune homeostasis; among them, transforming growth factors beta 1 (TGF-β1) is the principal paracrine inhibitor of macrophage cytokine synthesis” (p. 2567). The expression of TGF-β1 then allowed the authors to determine immunosuppressive properties of ADSCs may depend upon the metabolic phenotype of the donor (i.e., lean, obese, T2D). ADSCs from obese and T2D donors has significantly lower expression of TGF-β1 than lean donors in both SAT and VAT. To determine whether the immunomodulatory response was altered, the ability of ADSCs from these three categories of donors to promote the M2 macrophage was also studied. While lean-derived ADSCs increased M2 markers, obese and T2D-derived ADSCs had decreased M2 markers. Finally, lean-derived ADSCs from SAT (not VAT) had suppressed T and B cell proliferation whereas obese and T2D-derived ADSCs from SAT had increased T and B cell proliferation. Therefore, ADSCs were implicated as “an immune cell type with significant phagocytic and immunosuppressive capacities, and these properties are weakened in cells taken from a compromised metabolic environment” (p. 2567). In a different study (3), it was found that obese-derived ADSCs had higher expression of human leukocyte antigen (HLA)-II and cluster of differentiation (CD) 106. It is clear that obesity (and T2D) alter the immunomodulatory elements of ADSCs.
While ADSCs are considered to be amongst several regenerative cells that can promote tissue repair and regeneration in vitro and in vivo, the loss of immunomodulatory capabilities is crucial in the practice of regenerative medicine where MSCs have a positive impact for their tropic effects. Loss of immunomodulatory capabilities demonstrates loss of the positive trophic effects. That is, the paracrine factors from emitted from cells appears to be the overwhelming driver of reestablishing function and remodeling tissue following injury and the metabolic phenotype of the donor alters these paracrine factors with obesity and T2D having a negative impact on paracrine factors.Therefore, serious thought should be placed on whether or not patients with obesity and/or T2D are candidates for adipose tissue cellular therapy. The increased proinflammatory cytokines in ADSCs from obese and T2D donors highlights the significance of the microenvironment from which cells are obtained. IL-1β seems to have been revealed in this study as a potential driver of dysfunctional immune behavior in obesity and T2D-derived ADSCs. The high metabolic demand of ADSCs in obese and T2D subjects demonstrates remarkable similarities in their proliferative, migratory, and invasive capacities to cancerous cells (the Warburg effect).
There are far more questions than there are answers; however, it is becoming clear that the dangers of obesity and T2D exist on a genetic and cellular level. Given that the cells and their behavior are altered, great care must be given as to whether or not patients with obesity and T2D are candidates for adipose tissue cellular therapy. Moreover, given the obesity-related changes already discussed within this mini-series in bone, bone marrow, and other stem cells, this point becomes even more concerning. “… [a]ll together the data demonstrate that the hostile environment of AT in an obese state changes the functional characteristics of the different MSC populations present in this tissue” (p. 2571). Additionally, with increased expression of HLA-II and CD106 (critical for T-cell activation and leukocyte recruitment), as well as the other changes discussed, it is clear that obesity and T2D significantly alter the cells and their functions.
1. Serena C, Keiran N, Ceperuelo-Mallafre V, et al. (2016). Obesity and Type 2 diabetes alters the immune properties of human adipose derived stem cells. Stem Cells; 34:2559-2573.
2. Caplan AI, and Dennis JE. (2008). Mesenchymal stem cells as trophic mediators. J Cell Biochem; 98:1076-84.
3. Pachón-Peña G, Serena C, Ejarque M, et al (2016). Obesity determines the immunophenotypic profile and functional characteristics of human mesenchymal stem cells from adipose tissue. Stem Cells Translational Medicine; 5:464-75.