TY - JOUR
T1 - Mesenchymal Stem/Stromal Cells and their Extracellular Vesicle Progeny Decrease Injury in Poststenotic Swine Kidney through Different Mechanisms
AU - Zhao, Yu
AU - Zhu, Xiangyang
AU - Zhang, Lei
AU - Ferguson, Christopher M.
AU - Song, Turun
AU - Jiang, Kai
AU - Conley, Sabena M.
AU - Krier, James D.
AU - Tang, Hui
AU - Saadiq, Ishran
AU - Jordan, Kyra L.
AU - Lerman, Amir
AU - Lerman, Lilach O.
N1 - Funding Information:
This research was partly supported by National Institutes of Health grants DK122734, DK120292, DK104273, and DK102325. The other authors declare no conflicts of interest.
Funding Information:
Dr. L.O.L. is a consultant for AstraZeneca and Weijian Technologies and receives research funding from Novo Nordisk. The other authors declare no conflicts of interest.
Funding Information:
The authors thank the China Scholarship Council for support.
Publisher Copyright:
© 2020, Mary Ann Liebert, Inc., publishers.
PY - 2020/9/15
Y1 - 2020/9/15
N2 - Novel therapies are needed to address the increasing prevalence of chronic kidney disease. Mesenchymal stem/stromal cells (MSCs) and MSC-derived extracellular vesicles (EVs) augment tissue repair. We tested the hypothesis that EVs are as effective as MSCs in protecting the stenotic kidney, but target different injury pathways. Pigs were studied after 16 weeks of renal injury achieved by diet-induced metabolic syndrome (MetS) and renal artery stenosis (RAS). Pigs were untreated or treated 4 weeks earlier with intrarenal delivery of autologous adipose tissue-derived MSCs (107) or their EVs (1011). Lean pigs and sham RAS served as controls (n = 6 each). Stenotic-kidney function was studied in vivo using computed tomography and magnetic resonance imaging. Histopathology and expression of necroptosis markers [receptor-interacting protein kinase (RIPK)-1 and RIPK-3], inflammatory, and growth factors (angiopoietin-1 and vascular endothelial growth factor) were studied ex vivo. Stenotic-kidney glomerular filtration rate and blood flow in MetS + RAS were both lower than Lean and increased in both MetS + RAS + MSC and MetS + RAS + EV. Both MSCs and EV improved renal function and decreased renal hypoxia, fibrosis, and apoptosis. MSCs were slightly more effective in preserving microvascular (0.02-0.2 mm diameters) density and prominently attenuated renal inflammation. However, EV more significantly upregulated growth factor expression and decreased necroptosis. In conclusion, adipose tissue-derived MSCs and their EV both improve stenotic kidney function and decrease tissue injury in MetS + RAS by slightly different mechanisms. MSCs more effectively preserved the microcirculation, while EV bestowed better preservation of renal cellular integrity. These findings encourage further exploration of this novel approach to attenuate renal injury.
AB - Novel therapies are needed to address the increasing prevalence of chronic kidney disease. Mesenchymal stem/stromal cells (MSCs) and MSC-derived extracellular vesicles (EVs) augment tissue repair. We tested the hypothesis that EVs are as effective as MSCs in protecting the stenotic kidney, but target different injury pathways. Pigs were studied after 16 weeks of renal injury achieved by diet-induced metabolic syndrome (MetS) and renal artery stenosis (RAS). Pigs were untreated or treated 4 weeks earlier with intrarenal delivery of autologous adipose tissue-derived MSCs (107) or their EVs (1011). Lean pigs and sham RAS served as controls (n = 6 each). Stenotic-kidney function was studied in vivo using computed tomography and magnetic resonance imaging. Histopathology and expression of necroptosis markers [receptor-interacting protein kinase (RIPK)-1 and RIPK-3], inflammatory, and growth factors (angiopoietin-1 and vascular endothelial growth factor) were studied ex vivo. Stenotic-kidney glomerular filtration rate and blood flow in MetS + RAS were both lower than Lean and increased in both MetS + RAS + MSC and MetS + RAS + EV. Both MSCs and EV improved renal function and decreased renal hypoxia, fibrosis, and apoptosis. MSCs were slightly more effective in preserving microvascular (0.02-0.2 mm diameters) density and prominently attenuated renal inflammation. However, EV more significantly upregulated growth factor expression and decreased necroptosis. In conclusion, adipose tissue-derived MSCs and their EV both improve stenotic kidney function and decrease tissue injury in MetS + RAS by slightly different mechanisms. MSCs more effectively preserved the microcirculation, while EV bestowed better preservation of renal cellular integrity. These findings encourage further exploration of this novel approach to attenuate renal injury.
KW - extracellular vesicles
KW - mesenchymal stem cells
KW - renal artery stenosis
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U2 - 10.1089/scd.2020.0030
DO - 10.1089/scd.2020.0030
M3 - Article
C2 - 32657229
AN - SCOPUS:85091126917
SN - 1547-3287
VL - 29
SP - 1190
EP - 1200
JO - Stem Cells and Development
JF - Stem Cells and Development
IS - 18
ER -