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

Sabena M Conley; LaTonya J Hickson; Todd A Kellogg; Travis McKenzie; Julie K Heimbach; Timucin Taner; Hui Tang; Kyra L Jordan; Ishran M Saadiq; John R Woollard; Busra Isik; Mohsen Afarideh; Tamar Tchkonia; James L Kirkland; Lilach O Lerman

doi:10.3389/fcell.2020.00197

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

Front Cell Dev Biol. 2020 Mar 26:8:197. doi: 10.3389/fcell.2020.00197. eCollection 2020.

Authors

Sabena M Conley¹, LaTonya J Hickson^{1

2}, Todd A Kellogg³, Travis McKenzie³, Julie K Heimbach³, Timucin Taner^{2

4}, Hui Tang¹, Kyra L Jordan¹, Ishran M Saadiq¹, John R Woollard¹, Busra Isik¹, Mohsen Afarideh¹, Tamar Tchkonia⁵, James L Kirkland^{2

5}, Lilach O Lerman¹

Affiliations

¹ Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, United States.
² Division of Geriatric Medicine and Gerontology, Department of Medicine, Mayo Clinic, Rochester, MN, United States.
³ Department of Surgery, Mayo Clinic, Rochester, MN, United States.
⁴ Department of Immunology, Mayo Clinic, Rochester, MN, United States.
⁵ Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, United States.

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.

Keywords: adipose tissue; cellular dysfunction; cellular senescence; mesenchymal stem cells; obesity.

Abstract

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