TY - JOUR
T1 - Mesenchymal stem cells protect renal tubular cells via TSG-6 regulating macrophage function and phenotype switching
AU - Zhao, Yu
AU - Zhu, Xiang Yang
AU - Song, Turun
AU - Zhang, Lei
AU - Eirin, Alfonso
AU - Conley, Sabena
AU - Tang, Hui
AU - Saadiq, Ishran
AU - Jordan, Kyra
AU - Lerman, Amir
AU - Lerman, Lilach O.
N1 - Funding Information:
We thank the China Scholarship Council for support.
Funding Information:
This work was partly supported by National Institutes of Health Grants DK122734, DK104273, DK120292, AG062104, and DK102325.
Publisher Copyright:
© 2021 the American Physiological Society
PY - 2021
Y1 - 2021
N2 - Tumor necrosis factor (TNF)-a-induced gene/protein (TSG)-6 regulates the immunomodulatory properties of mesenchymal stem cells (MSCs), but its ability to protect the ischemic kidney is unknown. In a swine model of renal artery stenosis (RAS) and metabolic syndrome (MetS), we assessed the contribution of TSG-6 produced by MSCs to their immunomodulatory properties. Pigs were studied after 16 wk of diet-induced MetS and unilateral RAS and were either untreated or treated 4 wk earlier with intrarenal autologous adipose tissue-derived MSCs (n = 6 each). Lean, MetS, and RAS sham animals served as controls. We studied renal function in vivo (using computed tomography) and kidney histopathology and macrophage phenotype ex vivo. In vitro, TSG-6 levels were also measured in conditioned media of human MSCs incubated with TNF-a and levels of the tubular injury marker lactate dehydrogenase in conditioned media after coculturing macrophages with injured human kidney 2 (HK-2) cells with or without TSG-6. The effects of TSG-6 on macrophage phenotype (M1/M2), adhesion, and migration were also determined. MetS þ RAS showed increased M1 macrophages and renal vein TNF-a levels. After MSC delivery, renal vein TSG-6 increased and TNF-a decreased, the M1-to-M2 ratio decreased, renal function improved, and fibrosis was alleviated. In vitro, TNF-a increased TSG-6 secretion by human MSCs. TSG-6 decreased lactate dehydrogenase release from injured HK-2 cells, increased expression of macrophage M2 markers, and reduced M1 macrophage adhesion and migration. Therefore, TSG-6 released from MSCs may decrease renal tubular cell injury, which is associated with regulating macrophage function and phenotype. These observations suggest that TSG-6 is endowed with renoprotective properties. NEW & NOTEWORTHY Tumor necrosis factor-a-induced gene/protein (TSG)-6 regulates the immunomodulatory properties of MSCs, but its ability to protect the ischemic kidney is unknown. In pigs with renal artery stenosis, we show that MSC delivery increased renal vein TSG-6, decreased kidney inflammatory macrophages, and improved renal function. In vitro, TSG-6 decreased inflammatory macrophages and tubular cell injury. Therefore, TSG-6 released from MSCs may decrease renal tubular cell injury, which is associated with regulating macrophage function and phenotype.
AB - Tumor necrosis factor (TNF)-a-induced gene/protein (TSG)-6 regulates the immunomodulatory properties of mesenchymal stem cells (MSCs), but its ability to protect the ischemic kidney is unknown. In a swine model of renal artery stenosis (RAS) and metabolic syndrome (MetS), we assessed the contribution of TSG-6 produced by MSCs to their immunomodulatory properties. Pigs were studied after 16 wk of diet-induced MetS and unilateral RAS and were either untreated or treated 4 wk earlier with intrarenal autologous adipose tissue-derived MSCs (n = 6 each). Lean, MetS, and RAS sham animals served as controls. We studied renal function in vivo (using computed tomography) and kidney histopathology and macrophage phenotype ex vivo. In vitro, TSG-6 levels were also measured in conditioned media of human MSCs incubated with TNF-a and levels of the tubular injury marker lactate dehydrogenase in conditioned media after coculturing macrophages with injured human kidney 2 (HK-2) cells with or without TSG-6. The effects of TSG-6 on macrophage phenotype (M1/M2), adhesion, and migration were also determined. MetS þ RAS showed increased M1 macrophages and renal vein TNF-a levels. After MSC delivery, renal vein TSG-6 increased and TNF-a decreased, the M1-to-M2 ratio decreased, renal function improved, and fibrosis was alleviated. In vitro, TNF-a increased TSG-6 secretion by human MSCs. TSG-6 decreased lactate dehydrogenase release from injured HK-2 cells, increased expression of macrophage M2 markers, and reduced M1 macrophage adhesion and migration. Therefore, TSG-6 released from MSCs may decrease renal tubular cell injury, which is associated with regulating macrophage function and phenotype. These observations suggest that TSG-6 is endowed with renoprotective properties. NEW & NOTEWORTHY Tumor necrosis factor-a-induced gene/protein (TSG)-6 regulates the immunomodulatory properties of MSCs, but its ability to protect the ischemic kidney is unknown. In pigs with renal artery stenosis, we show that MSC delivery increased renal vein TSG-6, decreased kidney inflammatory macrophages, and improved renal function. In vitro, TSG-6 decreased inflammatory macrophages and tubular cell injury. Therefore, TSG-6 released from MSCs may decrease renal tubular cell injury, which is associated with regulating macrophage function and phenotype.
KW - Macrophage
KW - Mesenchymal stem cells
KW - Metabolic syndrome
KW - Renal artery stenosis
KW - Tumor necrosis factor-a-induced gene/ protein-6
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U2 - 10.1152/AJPRENAL.00426.2020
DO - 10.1152/AJPRENAL.00426.2020
M3 - Article
C2 - 33554782
AN - SCOPUS:85102964088
SN - 0363-6127
VL - 320
SP - F454-F463
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 3
ER -