Human Obesity Induces Dysfunction and Early Senescence in Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells

Abstract

Background: Chronic inflammatory conditions like obesity may adversely impact the biological functions underlying the regenerative potential of mesenchymal stromal/stem cells (MSC). Obesity can impair MSC function by inducing cellular senescence, a growth-arrest program that transitions cells to a pro-inflammatory state. However, the effect of obesity on adipose tissue-derived MSC in human subjects remains unclear. We tested the hypothesis that obesity induces senescence and dysfunction in human MSC. Methods: MSC were harvested from abdominal subcutaneous fat collected from obese and age-matched non-obese subjects (n = 40) during bariatric or kidney donation surgeries, respectively. MSC were characterized, their migration and proliferation assessed, and cellular senescence evaluated by gene expression of cell-cycle arrest and senescence-associated secretory phenotype markers. In vitro studies tested MSC effect on injured human umbilical vein endothelial cells (HUVEC) function. Results: Mean age was 59 ± 8 years, 66% were females. Obese subjects had higher body-mass index (BMI) than non-obese. MSC from obese subjects exhibited lower proliferative capacities than non-obese-MSC, suggesting decreased function, whereas their migration remained unchanged. Senescent cell burden and phenotype, manifested as p16, p53, IL-6, and MCP-1 gene expression, were significantly upregulated in obese subjects' MSC. BMI correlated directly with expression of p16, p21, and IL-6. Furthermore, co-incubation with non-obese, but not with obese-MSC, restored VEGF expression and tube formation that were blunted in injured HUVEC. Conclusion: Human obesity triggers an early senescence program in adipose tissue-derived MSC. Thus, obesity-induced cellular injury may alter efficacy of this endogenous repair system and hamper the feasibility of autologous transplantation in obese individuals.

Suppressed anti-inflammatory heat shock response in high-risk COVID-19 patients: lessons from basic research (inclusive bats), light on conceivable therapies

“…In rodents, even a relatively small number of senescent cells can cause long-lasting cellular dysfunction and spread to other tissues [ 118 ]. In humans, obesity triggers an early senescence program in adipose tissue-derived mesenchymal stromal/stem cells [ 119 ]. Moreover, both aging and diabetes mellitus share ER-stress-dependent senescence-associated dysfunctions such as atherosclerosis, coronary artery disease, insulin resistance and related metabolic anomalies, NAFLD, neurodegenerative diseases, osteoporosis, chronic kidney disease, peripheral vascular disease, periodontitis, impaired immune responses, frailty and sarcopenia [ 87 , 113 , 120 , 121 ].…”

A Rapid and Highly Predictive in vitro Screening Platform for Osteogenic Natural Compounds Using Human Runx2 Transcriptional Activity in Mesenchymal Stem Cells

“…Such challenges are further compounded in screening for osteogenic effects by the long process required for both in vitro and in vivo functional assays—which range from several days for the ALP assay to several weeks and even months for mineralization assays—with the additional requirement of using primary cells with the capacity for osteogenesis. Indeed, one major reason for the conflicting reports of agonistic/antagonistic osteogenic properties of many compounds may be due to the quality of the primary MSCs used, since it is well documented that MSC senescence is related to a loss of osteogenic differentiation capacity while increasing adipogenic capacity ( Nuttall and Gimble, 2000 ; Moerman et al, 2004 ; Ho et al, 2013 ; Conley et al, 2020 ). We therefore sought to develop a rapid and robust in vitro platform for drug screening of osteogenic compounds based on our previous work on the proximal human Runx2 promoter, the master osteogenesis transcription factor, introduced into an immortalized, non-cancerous MSC cell line.…”

Differentiation potential and mRNA profiles of human dedifferentiated adipose cells and adipose‑derived stem cells from young donors

“…However, the existing data indicated that there were significant individual differences between the two types of cells. In addition, most studies have reported that obesity and age can significantly affect the differentiation ability of adipose derived stem cells, and whether there is an opposite effect for DAs has only been the subject of relatively few studies ( 41 , 42 ). As suggested in the present study, obesity may enhance the proliferation of DAs.…”