Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles Elicit Better Preservation of the Intra-Renal Microvasculature Than Renal Revascularization in Pigs with Renovascular Disease

• Published in: Cells (Basel, Switzerland) Vol. 10; no. 4; p. 763
• Main Authors: Ferguson, Christopher M, Farahani, Rahele A, Zhu, Xiang-Yang, Tang, Hui, Jordan, Kyra L, Saadiq, Ishran M, Lerman, Amir, Lerman, Lilach O, Eirin, Alfonso
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 31-03-2021; MDPI
• Subjects: Angiogenesis; Angioplasty; Antioxidants; Blood flow; Blood pressure; Catheters; Edema; Extracellular vesicles; Fibrosis; Glomerular filtration rate; Hemodynamics; Hogs; Hypertension; Inflammation; Kidneys; Localization; Medical imaging; mesenchymal stem/stromal cells; Mesenchyme; Microvasculature; Mortality; mRNA; Nutrition research; Oxidative stress; Preservation; Renal function; renovascular disease; revascularization; Stromal cells; Veins & arteries; United States > US; renovascular disease; revascularization; mesenchymal stem/stromal cells; extracellular vesicles; microvasculature
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells10040763

Percutaneous transluminal renal angioplasty (PTRA) confers clinical and mortality benefits in select 'high-risk' patients with renovascular disease (RVD). Intra-renal-delivered extracellular vesicles (EVs) released from mesenchymal stem/stromal cells (MSCs) protect the kidney in experimental RVD, but have not been compared side-by-side to clinically applied interventions, such as PTRA. We hypothesized that MSC-derived EVs can comparably protect the post-stenotic kidney via direct tissue effects.
Five groups of pigs (
= 6 each) were studied after 16 weeks of RVD, RVD treated 4 weeks earlier with either PTRA or MSC-derived EVs, and normal controls. Single-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were assessed in vivo with multi-detector CT, and renal microvascular architecture (3D micro CT) and injury pathways ex vivo.
Despite sustained hypertension, EVs conferred greater improvement of intra-renal microvascular and peritubular capillary density compared to PTRA, associated with attenuation of renal inflammation, oxidative stress, and tubulo-interstitial fibrosis. Nevertheless, stenotic kidney RBF and GFR similarly rose in both PTRA- and EV-treated pigs compared RVD + Sham. mRNA sequencing reveled that EVs were enriched with pro-angiogenic, anti-inflammatory, and antioxidants genes.
MSC-derived EVs elicit a better preservation of the stenotic kidney microvasculature and greater attenuation of renal injury and fibrosis compared to PTRA, possibly partly attributed to their cargo of vasculo-protective genes. Yet, both strategies similarly improve renal hemodynamics and function. These observations shed light on diverse mechanisms implicated in improvement of post-stenotic kidney function and position EVs as a promising therapeutic intervention in RVD.