Immune-modulatory properties of adipose tissue-derived mesenchymal stem/stromal cells (MSCs) might be susceptible to metabolic disturbances. We hypothesized that the immune-modulatory function of MSCs might be blunted in obese human subjects. MSCs were collected from abdominal subcutaneous fat of obese and lean subjects during bariatric or kidney donation surgeries, respectively. MSCs were co-cultured in vitro for 24 h with M1 macrophages, which were determined as M1or M2 phenotypes by flow cytometry, and cytokines measured in conditioned media. In vivo, lean or obese MSCs (5 × 105), or PBS, were injected into mice two weeks after unilateral renal artery stenosis (RAS) or sham surgeries (n = 6 each). Fourteen days later, kidneys were harvested and stained with M1 or M2 markers. Lean MSCs decreased macrophages M1 marker intensity, which remained elevated in macrophages co-cultured with obese MSCs. TNF-α levels were four-fold higher in conditioned media collected from obese than from lean MSCs. RAS mouse kidneys were shrunk and showed increased M1 macrophage numbers and inflammatory cytokine expression compared with normal kidneys. Lean MSCs decreased M1 macrophages, M1/M2 ratio and inflammation in RAS kidneys, whereas obese MSCs did not. MSCs isolated from lean human subjects decrease inflammatory M1 macrophages both in vivo and in vitro, an immune-modulatory function which is blunted in MSCs isolated from obese subjects.
Bibliographical noteFunding Information:
The adipose tissue represents a complex endocrine organ containing several different cellular populations, including adipocytes, MSCs and immune cells like macrophages and lymphocytes. We have previously demonstrated in obese pigs a shift towards amplified numbers of pro‐inflammatory macrophages and levels of the inflammatory cytokine TNF‐α in subcutaneous adipose tissue. This alteration promotes a chronic low‐grade inflammation and may negatively affect MSC progenitor function, hindering the ability of MSCs to support immunomodulatory function. This notion was supported by the current study showing impaired immunomodulatory capability in adipose tissue‐derived MSCs isolated from obese human subjects. These subjects not only had increased BMI but also increased circulating levels of triglycerides and haemoglobin A1c, indicating systemic metabolic alterations that may affect MSC function. Furthermore, obese MSCs exhibited significantly elevated release of the inflammatory cytokine TNF‐α into conditioned media, reflecting this pro‐inflammatory shift. 17
© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
- mesenchymal stem cells
- renal artery stenosis
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural