Abstract
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.
Highlights
Mesenchymal stem/stromal cells (MSCs) are derived from different adult and neonatal tissues
The weight ratio of stenotic/contralateral kidneys in RAS was significantly decreased in RAS+ vehicle, confirming renal and CD3+ T lymphocytes in the stenotic mouse kidney. (C) The ratio of the stenotic and contralateral kidney weights was decreased in mice with renal artery stenosis (RAS) compared to sham and improved in mice injected with lean MSCs, but not with obese MSCs. *p < 0.05 vs. sham, #p < 0.05 vs. RAS
Renal artery stenosis kidneys showed an increase in both M1 (F4/80+/iNOS+) and M2 (F4/80+/mannose receptor-1+) macrophage numbers and the M1/M2 ratio compared with normal mouse kidneys (Figure 2)
Summary
Mesenchymal stem/stromal cells (MSCs) are derived from different adult (adipose tissue, peripheral blood, bone marrow) and neonatal tissues. The mechanisms involved in their immunomodulatory effects have not been fully elucidated and may depend on both cell contact-dependent mechanisms and paracrine effects through production of cytokines and various soluble factors that regulate immune cell functions.7–9 Previous studies[10,11] demonstrated in vitro that healthy MSCs inhibit adhesion and invasion of inflammatory cells and promote polarization of macrophages from an inflammatory (M1) to anti-inflammatory (M2) phenotype. Adipose tissue-derived MSCs exhibit advantageous capabilities in polarization of M1 macrophages and anti-inflammatory effects compared to bone marrow-derived MSCs.[12]
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