TY - JOUR
T1 - Mesenchymal stem cell–derived extracellular vesicles attenuate kidney inflammation
AU - Eirin, Alfonso
AU - Zhu, Xiang Yang
AU - Puranik, Amrutesh S.
AU - Tang, Hui
AU - McGurren, Kelly A.
AU - van Wijnen, Andre J.
AU - Lerman, Amir
AU - Lerman, Lilach O.
N1 - Publisher Copyright:
© 2017 International Society of Nephrology
PY - 2017/7
Y1 - 2017/7
N2 - Mesenchymal stem/stromal cells (MSCs) have distinct capability for renal repair, but may have safety concerns. MSC-derived extracellular vesicles emerged as a novel noncellular alternative. Using a porcine model of metabolic syndrome and renal artery stenosis we tested whether extracellular vesicles attenuate renal inflammation, and if this capacity is mediated by their cargo of the anti-inflammatory cytokine interleukin (IL) 10. Pigs with metabolic syndrome were studied after 16 weeks of renal artery stenosis untreated or treated four weeks earlier with a single intrarenal delivery of extracellular vesicles harvested from adipose tissue–derived autologous MSCs. Lean and sham metabolic syndrome animals served as controls (seven each). Five additional pigs with metabolic syndrome and renal artery stenosis received extracellular vesicles with pre-silenced IL10 (IL10 knock-down). Single-kidney renal blood flow, glomerular filtration rate, and oxygenation were studied in vivo and renal injury pathways ex vivo. Retention of extracellular vesicles in the stenotic kidney peaked two days after delivery and decreased thereafter. Four weeks after injection, extracellular vesicle fragments colocalized with stenotic-kidney tubular cells and macrophages, indicating internalization or fusion. Extracellular vesicle delivery attenuated renal inflammation, and improved medullary oxygenation and fibrosis. Renal blood flow and glomerular filtration rate fell in metabolic syndrome and renal artery stenosis compared to metabolic syndrome, but was restored in pigs treated with extracellular vesicles. These renoprotective effects were blunted in pigs treated with IL10-depleted extracellular vesicles. Thus, extracellular vesicle–based regenerative strategies might be useful for patients with metabolic syndrome and renal artery stenosis.
AB - Mesenchymal stem/stromal cells (MSCs) have distinct capability for renal repair, but may have safety concerns. MSC-derived extracellular vesicles emerged as a novel noncellular alternative. Using a porcine model of metabolic syndrome and renal artery stenosis we tested whether extracellular vesicles attenuate renal inflammation, and if this capacity is mediated by their cargo of the anti-inflammatory cytokine interleukin (IL) 10. Pigs with metabolic syndrome were studied after 16 weeks of renal artery stenosis untreated or treated four weeks earlier with a single intrarenal delivery of extracellular vesicles harvested from adipose tissue–derived autologous MSCs. Lean and sham metabolic syndrome animals served as controls (seven each). Five additional pigs with metabolic syndrome and renal artery stenosis received extracellular vesicles with pre-silenced IL10 (IL10 knock-down). Single-kidney renal blood flow, glomerular filtration rate, and oxygenation were studied in vivo and renal injury pathways ex vivo. Retention of extracellular vesicles in the stenotic kidney peaked two days after delivery and decreased thereafter. Four weeks after injection, extracellular vesicle fragments colocalized with stenotic-kidney tubular cells and macrophages, indicating internalization or fusion. Extracellular vesicle delivery attenuated renal inflammation, and improved medullary oxygenation and fibrosis. Renal blood flow and glomerular filtration rate fell in metabolic syndrome and renal artery stenosis compared to metabolic syndrome, but was restored in pigs treated with extracellular vesicles. These renoprotective effects were blunted in pigs treated with IL10-depleted extracellular vesicles. Thus, extracellular vesicle–based regenerative strategies might be useful for patients with metabolic syndrome and renal artery stenosis.
KW - extracellular vesicles
KW - interleukin-10
KW - mesenchymal stem cells
KW - metabolic syndrome
KW - renal artery stenosis
UR - http://www.scopus.com/inward/record.url?scp=85013646107&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85013646107&partnerID=8YFLogxK
U2 - 10.1016/j.kint.2016.12.023
DO - 10.1016/j.kint.2016.12.023
M3 - Article
C2 - 28242034
AN - SCOPUS:85013646107
SN - 0085-2538
VL - 92
SP - 114
EP - 124
JO - Kidney international
JF - Kidney international
IS - 1
ER -