title: Mesenchymal stem cell-derived extracellular vesicles attenuate kidney inflammation.
abstract: 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.
authors.affiliation: Divisions of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Eirin
authors.affiliation: Divisions of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Zhu
authors.affiliation: Divisions of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Amrutesh S
authors.initials: AS
authors.lastname: Puranik
authors.affiliation: Divisions of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Tang
authors.affiliation: Divisions of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: McGurren
authors.affiliation: Division of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
authors.affiliation: Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Amir
authors.initials: A
authors.lastname: Lerman
authors.affiliation: Divisions of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA; Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA. Electronic address: Lerman.Lilach@Mayo.Edu.
authors.forename: Lilach O
authors.initials: LO
authors.lastname: Lerman
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000067128:Extracellular Vesicles / Q000378:metabolism / Q000637:transplantation*; D005260:Female; D005355:Fibrosis; D005919:Glomerular Filtration Rate; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D024821:Metabolic Syndrome / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000601:surgery*; D009393:Nephritis / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D010100:Oxygen / Q000097:blood; D034622:RNA Interference; D012078:Renal Artery Obstruction / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000601:surgery*; D012079:Renal Circulation; D034421:Sus scrofa; D013997:Time Factors; D014182:Transplantation, Autologous
chemical_list: D016753:Interleukin-10; D010100:Oxygen
keywords: extracellular vesicles; interleukin-10; mesenchymal stem cells; metabolic syndrome; renal artery stenosis