TY - JOUR
T1 - Human Obesity Induces Dysfunction and Early Senescence in Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells
AU - Conley, Sabena M.
AU - Hickson, La Tonya J.
AU - Kellogg, Todd A.
AU - McKenzie, Travis
AU - Heimbach, Julie K.
AU - Taner, Timucin
AU - Tang, Hui
AU - Jordan, Kyra L.
AU - Saadiq, Ishran M.
AU - Woollard, John R.
AU - Isik, Busra
AU - Afarideh, Mohsen
AU - Tchkonia, Tamar
AU - Kirkland, James L.
AU - Lerman, Lilach O.
N1 - Publisher Copyright:
© Copyright © 2020 Conley, Hickson, Kellogg, McKenzie, Heimbach, Taner, Tang, Jordan, Saadiq, Woollard, Isik, Afarideh, Tchkonia, Kirkland and Lerman.
PY - 2020/3/26
Y1 - 2020/3/26
N2 - 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.
AB - 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.
KW - adipose tissue
KW - cellular dysfunction
KW - cellular senescence
KW - mesenchymal stem cells
KW - obesity
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U2 - 10.3389/fcell.2020.00197
DO - 10.3389/fcell.2020.00197
M3 - Article
AN - SCOPUS:85083093087
SN - 2296-634X
VL - 8
JO - Frontiers in Cell and Developmental Biology
JF - Frontiers in Cell and Developmental Biology
M1 - 197
ER -