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

被引:96
作者
Conley, Sabena M. [1 ]
Hickson, La Tanya J. [1 ,2 ]
Kellogg, Todd A. [3 ]
McKenzie, Travis [3 ]
Heimbach, Julie K. [3 ]
Taner, Timucin [2 ,4 ]
Tang, Hui [1 ]
Jordan, Kyra L. [1 ]
Saadiq, Ishran M. [1 ]
Woollard, John R. [1 ]
Isik, Busra [1 ]
Afarideh, Mohsen [1 ]
Tchkonia, Tamar [5 ]
Kirkland, James L. [2 ,5 ]
Lerman, Lilach O. [1 ]
机构
[1] Mayo Clin, DiV Nephrol & Hypertens, Dept Med, Rochester, MN 55905 USA
[2] Mayo Clin, Div Geriatr Med & Gerontol, Dept Med, Rochester, MN USA
[3] Mayo Clin, Dept Surg, Rochester, MN USA
[4] Mayo Clin, Dept Immunol, Rochester, MN USA
[5] Mayo Clin, Robed & Arlene Kogod Ctr Aging, Rochester, MN USA
关键词
obesity; mesenchymal stem cells; cellular senescence; adipose tissue; cellular dysfunction; STEM-CELLS; EXTRACELLULAR VESICLES; CELLULAR SENESCENCE; SWINE; EXPRESSION; GENES;
D O I
10.3389/fcell.2020.00197
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
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页数:11
相关论文
共 47 条
[1]   Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders [J].
Baker, Darren J. ;
Wijshake, Tobias ;
Tchkonia, Tamar ;
LeBrasseur, Nathan K. ;
Childs, Bennett G. ;
van de Sluis, Bart ;
Kirkland, James L. ;
van Deursen, Jan M. .
NATURE, 2011, 479 (7372) :232-U112
[2]   Mesenchymal Stromal Cells A Novel Treatment Modality for Tissue Repair [J].
Bernardo, Maria Ester ;
Locatelli, Franco ;
Fibbe, Willem E. .
HEMATOPOIETIC STEM CELLS VII, 2009, 1176 :101-117
[3]   Melatonin restricts the viability and angiogenesis of vascular endothelial cells by suppressing HIF-1/ROS/VEGF [J].
Cheng, Jiao ;
Yang, Hui-Li ;
Gu, Chun-Jie ;
Liu, Yu-Kai ;
Shao, Jun ;
Zhu, Rui ;
He, Yin-Yan ;
Zhu, Xiao-Yong ;
Li, Ming-Qing .
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, 2019, 43 (02) :945-955
[4]   Senescent intimal foam cells are deleterious at all stages of atherosclerosis [J].
Childs, Bennett G. ;
Baker, Darren J. ;
Wijshake, Tobias ;
Conover, Cheryl A. ;
Campisi, Judith ;
van Deursen, Jan M. .
SCIENCE, 2016, 354 (6311) :472-477
[5]   The spectrum of kidney biopsy findings in patients with morbid obesity [J].
Choung, Hae-Yoon Grace ;
Bomback, Andrew S. ;
Stokes, M. Barry ;
Santoriello, Dominick ;
Campenot, Eric S. ;
Batal, Ibrahim ;
Markowitz, Glen S. ;
D'Agati, Vivette D. .
KIDNEY INTERNATIONAL, 2019, 95 (03) :647-654
[6]   Metabolic syndrome alters expression of insulin signaling-related genes in swine mesenchymal stem cells [J].
Conley, Sabena M. ;
Zhu, Xiang-Yang ;
Eirin, Alfonso ;
Tang, Hui ;
Lerman, Amir ;
van Wijnen, Andre J. ;
Lerman, Lilach O. .
GENE, 2018, 644 :101-106
[7]   A BIOMARKER THAT IDENTIFIES SENESCENT HUMAN-CELLS IN CULTURE AND IN AGING SKIN IN-VIVO [J].
DIMRI, GP ;
LEE, XH ;
BASILE, G ;
ACOSTA, M ;
SCOTT, C ;
ROSKELLEY, C ;
MEDRANO, EE ;
LINSKENS, M ;
RUBELJ, I ;
PEREIRASMITH, O ;
PEACOCKE, M ;
CAMPISI, J .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (20) :9363-9367
[8]   Decreased expression of adipogenic genes in obese subjects with type 2 diabetes [J].
Dubois, Severine G. ;
Heilbronn, Leonie K. ;
Smith, Steven R. ;
Albu, Jeanine B. ;
Kelley, David E. ;
Ravussin, Eric .
OBESITY, 2006, 14 (09) :1543-1552
[9]   Mesenchymal Stem Cells Improve Medullary Inflammation and Fibrosis after Revascularization of Swine Atherosclerotic Renal Artery Stenosis [J].
Ebrahimi, Behzad ;
Eirin, Alfonso ;
Li, Zilun ;
Zhu, Xiang-Yang ;
Zhang, Xin ;
Lerman, Amir ;
Textor, Stephen C. ;
Lerman, Lilach O. .
PLOS ONE, 2013, 8 (07)
[10]   Integrated transcriptomic and proteomic analysis of the molecular cargo of extracellular vesicles derived from porcine adipose tissue-derived mesenchymal stem cells [J].
Eirin, Alfonso ;
Zhu, Xiang-Yang ;
Puranik, Amrutesh S. ;
Woollard, John R. ;
Tang, Hui ;
Dasari, Surendra ;
Lerman, Amir ;
van Wijnen, Andre J. ;
Lerman, Lilach O. .
PLOS ONE, 2017, 12 (03)