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

International Journal of Obesity volume 46, pages 1222–1233 (2022)Cite this article

Subjects

Abstract

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/m2, respectively) during kidney donation or bariatric surgery, respectively. MSC (5 × 105/200 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.

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Fig. 1: Lean-MSC improves blood pressure and kidney function.
Fig. 2: Lean-MSC improves stenotic kidney (STK) cortical perfusion more than obese-MSC.
Fig. 3: Tissue changes in STKs.
Fig. 4: Peritubular capillary loss and vascular wall remodeling in the stenotic kidneys.
Fig. 5: Oxidative stress in the stenotic kidneys.
Fig. 6: Correlation between MSC senescence, inflammatory and proangiogenic gene expression with renal perfusion and histological changes.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA

    Nattawat Klomjit, Sabena M. Conley, Xiang Yang Zhu, Ishran M. Sadiq, Yaara Libai, James D. Krier, Christopher M. Ferguson, Kyra L. Jordan, Hui Tang & Lilach O. Lerman

  2. Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA

    Amir Lerman

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Contributions

NK: conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; SMC: provision of study material, collection and assembly of data; XZ: conception and design, provision of study material, collection and assembly of data; IMS: provisional of study material, collection and assembly of data, YL: collection and assembly of data, data analysis an interpretation; JDK: administrative support, provisional of study material, collection and assembly of data; CMF: administrative support, provisional of study material, collection and assembly of data; KLJ: provisional of study material, collection and assembly of data; HT: provisional of study material, collection and assembly of data; AL: data interpretation, manuscript writing; LOL: conception and design, financial support, administrative support, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript

Corresponding author

Correspondence to Lilach O. Lerman.

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Competing interests

This study was partly supported by NIH grant numbers DK120292, DK122734, and AG062104. LOL is an advisor to AstraZeneca, CureSpec, and Butterfly Biosciences. All authors declare no conflict of interest.

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Klomjit, N., Conley, S.M., Zhu, X.Y. et al. Effects of obesity on reparative function of human adipose tissue-derived mesenchymal stem cells on ischemic murine kidneys. Int J Obes 46, 1222–1233 (2022). https://doi.org/10.1038/s41366-022-01103-5

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