Effects of obesity on reparative function of human adipose tissue-derived mesenchymal stem cells on ischemic murine kidneys

• Published in: International Journal of Obesity Vol. 46; no. 6; pp. 1222 - 1233
• Main Authors: Klomjit, Nattawat, Conley, Sabena M., Zhu, Xiang Yang, Sadiq, Ishran M., Libai, Yaara, Krier, James D., Ferguson, Christopher M., Jordan, Kyra L., Tang, Hui, Lerman, Amir, Lerman, Lilach O.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-06-2022; Nature Publishing Group
• Subjects: 13/1; 13/100; 13/106; 13/51; 14/34; 14/63; 59; 59/36; 59/57; 631/443/319/1642/393; 631/80/458; 64; 64/60; 82/1; 96/21; Adipose tissue; Blood pressure; Body fat; Body mass index; Body size; Creatinine; Epidemiology; Fibrosis; Gastrointestinal surgery; Gene expression; Growth factors; Health Promotion and Disease Prevention; Hypoxia; Internal Medicine; Ischemia; Kidneys; Magnetic resonance imaging; Medicine; Medicine & Public Health; Mesenchymal stem cells; Metabolic Diseases; Obesity; Oxygenation; Patients; Perfusion; Public Health; Renal artery; Senescence; Stem cell transplantation; Stem cells; Stenosis; Stromal cells; Surgery; Vascular endothelial growth factor
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/s41366-022-01103-5

Introduction
Obesity is a health burden that impairs cellular processes. Mesenchymal stem/stromal cells (MSCs) are endowed with reparative properties and can ameliorate renal injury. Obesity impairs human MSC function in-vitro, but its effect on their in-vivo reparative potency remains unknown.
Subjects and methods
Abdominal adipose tissue-derived MSC were harvested from patients without (‘lean’) or with obesity (‘obese’) (body mass index <30 or ≥30 kg/m
2
, respectively) during kidney donation or bariatric surgery, respectively. MSC (5 × 10
5
/200 µL) or vehicle were then injected into 129S1 mice 2 weeks after renal artery stenosis (RAS) or sham surgery (
n
 = 8/group). Two weeks later, mice underwent magnetic resonance imaging to assess renal perfusion and oxygenation in-vivo, and kidneys then harvested for ex-vivo studies.
Results
Similar numbers of lean and obese-MSCs engrafted in stenotic mouse kidneys. Vehicle-treated RAS mice had reduced stenotic-kidney cortical and medullary perfusion and oxygenation. Lean (but not obese) MSC normalized ischemic kidney cortical perfusion, whereas both effectively mitigated renal hypoxia. Serum creatinine and blood pressure were elevated in RAS mice and lowered only by lean-MSC. Both types of MSCs alleviated stenotic-kidney fibrosis, but lean-MSC more effectively than obese-MSC. MSC senescence-associated beta-gal activity, and gene expression of p16, p21, and vascular endothelial growth factor correlated with recipient kidney perfusion and tissue injury, linking MSC characteristics with their in-vivo reparative capacity.
Discussion
Human obesity impairs the reparative properties of adipose-tissue-derived MSCs, possibly by inducing cellular senescence. Dysfunction and senescence of the endogenous MSC repair system in patients with obesity may warrant targeting interventions to restore MSC vitality.