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Autologous Extracellular Vesicles Attenuate Cardiac Injury in Experimental Atherosclerotic Renovascular Disease More Effectively Than Their Parent Mesenchymal Stem/Stromal Cells

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Abstract

Atherosclerotic renovascular disease (RVD) leads to hypertension, chronic kidney disease (CKD), and heart disease. Intrarenal delivery of mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (EVs) attenuate renal injury and suppress release of inflammatory cytokines in porcine RVD. We hypothesized that this strategy would also be useful for cardioprotection. Pigs with renovascular hypertension and metabolic syndrome were studied 4 weeks after treatment with a single intrarenal infusion of autologous MSCs, EVs, or vehicle. Cardiac structure and function were assessed in vivo, and myocardial remodeling and expression of the pro-fibrotic factor growth factor receptor-bound protein-2 (Grb2) were measured ex-vivo. Inflammatory cytokine levels were measured in the systemic circulation and myocardial tissue. Blood pressure was elevated in all RVD groups, but serum creatinine increased in RVD and decreased in both RVD + MSCs and RVD + EVs. RVD-induced diastolic dysfunction (lower E/A ratio) was normalized in both MSCs- and EVs- treated pigs. Intrarenal delivery of MSCs and EVs also attenuated RVD-induced myocardial fibrosis, collagen deposition, and Grb2 expression, yet EVs restored capillary density and inflammation more effectively than MSCs. These observations suggest that autologous EVs attenuate cardiac injury in experimental RVD more effectively than their parent MSCs.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This study was partly supported by NIH grant numbers DK120292, DK122734, HL158691, and AG062104.

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Authors and Affiliations

  1. Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Siting Hong, Xiang-Yang Zhu, Yamei Jiang, Lei Zhang, Hui Tang, Kyra L. Jordan, Ishran M. Saadiq, Weijun Huang, Alfonso Eirin & Lilach O. Lerman

  2. Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People’s Republic of China

    Siting Hong

  3. Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, 55905, USA

    Amir Lerman

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  1. Siting Hong
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Contributions

S.H.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; X.-Y.Z.: conception and design, methodology and supervision, final approval of manuscript; Y.J.: methodology, data analysis and interpretation, final approval of manuscript; L.Z.: methodology, data analysis and interpretation, final approval of manuscript; H.T.: methodology, collection and assembly of data, final approval of manuscript; K.L.J.: methodology, collection and assembly of data, final approval of manuscript; I.M.S.: methodology, collection and assembly of data, final approval of manuscript; W.H.: methodology, final approval of manuscript; A.L.: resources and supervision, final approval of manuscript; A.E.: financial support and resources, final approval of manuscript; L.O.L.: conception and design, financial support, manuscript writing, final approval of manuscript.

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Correspondence to Lilach O. Lerman.

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The study was approved by the Mayo Clinical Animal Care and Use Committee (A65014-15).

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LOL is an advisor to AstraZeneca, Butterfly Biosciences, CureSpec, Beren Therapeutics, and Ribocure Pharmaceuticals. The other authors indicated no potential conflicts of interest.

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Hong, S., Zhu, XY., Jiang, Y. et al. Autologous Extracellular Vesicles Attenuate Cardiac Injury in Experimental Atherosclerotic Renovascular Disease More Effectively Than Their Parent Mesenchymal Stem/Stromal Cells. Stem Cell Rev and Rep 19, 700–712 (2023). https://doi.org/10.1007/s12015-022-10473-2

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