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 - Funding Information:
We thank our study coordinators: Marcia K. Mahlman CCRP, Donna K. Lawson CCRP, LPN, and Tamara K. Evans. We would also like to thank Dr. Ye Zheng for assistance with the IncuCyte® Live Cell Analysis System. Funding. This study was partly supported by NIH grants DK120292 (LL), DK102325 (LL), DK122734 (LL), T32-DK07013 (SC), K23-DK109134 (LH), R37-AG013925 (JK), and P01 AG062413 (JK), the Burroughs Wellcome Fund (SC), the Connor Fund (JK), Robert J. and Theresa W. Ryan (JK), and the Noaber Foundation (JK).
Funding Information:
SC, LH, TTc, JK, and LL contributed conception and design of the study. SC, LH, HT, KJ, IS, JW, BI, MA, TTc, JK, and LL collected the data, and contributed to data analysis and interpretation. LH, TK, TM, JH, TTa, JK, and LL acquired the study sample and or research materials. SC, LH, JK, and LL provided financial support. SC wrote the first draft of the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.
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 -