Mesenchymal Stem Cell-Derived Extracellular Vesicles Improve the Renal Microvasculature in Metabolic Renovascular Disease in Swine

Alfonso Eirin, Xiang Yang Zhu, Sreela Jonnada, Amir Lerman, Andre J van Wijnen, Lilach O Lerman

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background: Extracellular vesicles (EVs) released from mesenchymal stem/stromal cells (MSCs) mediate their paracrine effect, but their efficacy to protect the microcirculation of the kidney is unknown. Using a novel swine model of unilateral renovascular disease (RVD) complicated by metabolic syndrome (MetS), we tested the hypothesis that EVs would attenuate renal microvascular loss. Methods: Four groups of pigs (n = 7 each) were studied after 16 weeks of diet-induced MetS and RVD (MetS+RVD), MetS+RVD treated 4 weeks earlier with a single intra-renal delivery of EVs harvested from autologous adipose tissue-derived MSCs, and Lean and MetS Sham controls. Stenotic-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were measured in-vivo (fast CT), whereas EV characteristics, renal microvascular architecture (micro-CT), and injury pathways were studied ex-vivo. Results: mRNA sequencing and proteomic analysis revealed that EVs are packed with several pro-angiogenic genes and proteins, such as vascular endothelial growth factor. Labeled EVs were detected in the stenotic kidney 4 weeks after injection internalized by tubular and endothelial cells. EVs restored renal expression of angiogenic factors and improved cortical microvascular and peritubular capillary density. Renal apoptosis, oxidative stress, tubular injury, and fibrosis were also attenuated in EV-treated pigs. RBF and GFR decreased in MetS+RVD compared with MetS, but normalized in MetS+RVD+EVs. Conclusions: Intra-renal delivery of MSC-derived EVs bearing pro-angiogenic properties restored the renal microcirculation and in turn hemodynamics and function in chronic experimental MetS+RVD. Our study suggests a novel therapeutic potential for MSC-derived EVs in restoring renal hemodynamics in experimental MetS+RVD.

Original languageEnglish (US)
Pages (from-to)1080-1095
Number of pages16
JournalCell Transplantation
Volume27
Issue number7
DOIs
StatePublished - Jul 1 2018

Fingerprint

Metabolic Diseases
Microvessels
Stem cells
Mesenchymal Stromal Cells
Swine
Kidney
Microcirculation
Hemodynamics
Renal Circulation
Blood
Bearings (structural)
Glomerular Filtration Rate
Oxidative stress
Extracellular Vesicles
Endothelial cells
Angiogenic Proteins
Cell death
Nutrition
Angiogenesis Inducing Agents
Wounds and Injuries

Keywords

  • extracellular vesicles
  • mesenchymal stem cells
  • metabolic syndrome
  • microcirculation
  • renovascular disease

ASJC Scopus subject areas

  • Biomedical Engineering
  • Cell Biology
  • Transplantation

Cite this

Mesenchymal Stem Cell-Derived Extracellular Vesicles Improve the Renal Microvasculature in Metabolic Renovascular Disease in Swine. / Eirin, Alfonso; Zhu, Xiang Yang; Jonnada, Sreela; Lerman, Amir; van Wijnen, Andre J; Lerman, Lilach O.

In: Cell Transplantation, Vol. 27, No. 7, 01.07.2018, p. 1080-1095.

Research output: Contribution to journalArticle

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abstract = "Background: Extracellular vesicles (EVs) released from mesenchymal stem/stromal cells (MSCs) mediate their paracrine effect, but their efficacy to protect the microcirculation of the kidney is unknown. Using a novel swine model of unilateral renovascular disease (RVD) complicated by metabolic syndrome (MetS), we tested the hypothesis that EVs would attenuate renal microvascular loss. Methods: Four groups of pigs (n = 7 each) were studied after 16 weeks of diet-induced MetS and RVD (MetS+RVD), MetS+RVD treated 4 weeks earlier with a single intra-renal delivery of EVs harvested from autologous adipose tissue-derived MSCs, and Lean and MetS Sham controls. Stenotic-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were measured in-vivo (fast CT), whereas EV characteristics, renal microvascular architecture (micro-CT), and injury pathways were studied ex-vivo. Results: mRNA sequencing and proteomic analysis revealed that EVs are packed with several pro-angiogenic genes and proteins, such as vascular endothelial growth factor. Labeled EVs were detected in the stenotic kidney 4 weeks after injection internalized by tubular and endothelial cells. EVs restored renal expression of angiogenic factors and improved cortical microvascular and peritubular capillary density. Renal apoptosis, oxidative stress, tubular injury, and fibrosis were also attenuated in EV-treated pigs. RBF and GFR decreased in MetS+RVD compared with MetS, but normalized in MetS+RVD+EVs. Conclusions: Intra-renal delivery of MSC-derived EVs bearing pro-angiogenic properties restored the renal microcirculation and in turn hemodynamics and function in chronic experimental MetS+RVD. Our study suggests a novel therapeutic potential for MSC-derived EVs in restoring renal hemodynamics in experimental MetS+RVD.",
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AU - van Wijnen, Andre J

AU - Lerman, Lilach O

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