Stem cell impairment associated with type 2 diabetes mellitus : investigating the effects of obesity-associated inflammation on mesenchymal stem cell function

[摘要] ENGLISH ABSTRACT : Background: South Africa has the highest prevalence of obesity in sub-Saharan Africa, particularly in Black women. This population is thus at a higher risk of developing obesity-associated type 2 diabetes mellitus (T2DM) and its associated co-morbidities such as non-healing wounds. Adipose tissue-derived mesenchymal stem cells (ADSCs) have been widely utilized in the treatment of chronic wounds, however, autologous stem cell therapies using endogenous ADSCs from T2DM patients have proven unsuccessful. Metabolic disorders such as T2DM are thus thought to compromise the functional capacity of mesenchymal stem cells. The underlying molecular mechanisms that contribute to the functional decline of mesenchymal stem cells is still unclear and it is not yet known at which stage of disease progression ADSCs become compromised. In this research study, it was hypothesised that the progressive worsening of chronic systemic inflammation during disease progression from obesity towards T2DM, contributes to the decline of ADSCs' multifunctional properties.Methods: A total of forty-seven (n=47) reproductive aged (18-45 years) Black Xhosa women from peri-urban areas surrounding the Tygerberg hospital, were included in this study. Participants were subdivided into: a) healthy lean (n=10) (BMI ≤ 25 kg/m2); b) healthy obese (n=11) (BMI ≥ 30 kg/m2); c) obese metabolic syndrome (n=19) and d) previously diagnosed T2DM (n=7) groups. Health, lifestyle and dietary questionnaires were completed by participants. Anthropometric measurements and a dual energy x-ray absorptiometry (DXA) scan were performed in order to assess body composition. Blood samples were collected in order to assess each participant's metabolic- (fasting blood glucose, total cholesterol, HDL, LDL, triglycerides) and inflammatory (CRP, SDF-1α, IL-6, IL-8, IL-10, TNF-α, IFN-γ) profiles. To establish whether a relationship exists between systemic inflammation at different stages of disease progression and stem cell impairment, in vitro experiments were performed in which ADSCs (Poietics cell line) were exposed to participant-derived serum for a period of 48h. Changes in cellular viability (MTT-based assay), proliferation (BrdU) and migration (wound healing assay) were assessed using standard tissue culture techniques.Results: Systemic inflammation was evident in the healthy obese (CRP 29.8 ± 8 pg/mL) and obese metabolic syndrome (CRP 50.8 ± 24 pg/mL) participants. Additionally, circulating levels of the anti-inflammatory cytokine IL-10, were significantly reduced in T2DM participants (0.42 ± 0.63 pg/mL) (p < 0.05) compared to the healthy lean and obese groups. Due to individual variability within the different groups, there were no significant differences observed in circulating levels of IL-6, IL-8, TNF-α and IFN-γ.However, there was a significant correlation between circulating levels of IL-6 and the proliferation of ADSCs, particularly in the healthy lean (p < 0.01) and metabolic syndrome (p < 0.01) groups. Furthermore, serum levels of IL-8 significantly correlated with the migration of ADSCs (p < 0.01). Healthy lean participant serum had a mitogenic effect on ADSCs, which was not observed in the obese groups.Conclusion: This study demonstrated for the first time, that the disruption in the delicate systemic inflammatory balance as a result of obesity, regardless of metabolic syndrome, may have an adverse effect on the functional capacity of ADSCs.

[发布机构] Stellenbosch University