Mesenchymal stem cell secretions improve donor heart function following ex vivo cold storage.

Abstract

OBJECTIVES:

Heart transplantation is the gold standard of treatments for end-stage heart failure, but its use is limited by extreme shortage of donor organs. The time "window" between procurement and transplantation sets the stage for myocardial ischemia/reperfusion injury, which constrains the maximal storage time and lowers use of donor organs. Given mesenchymal stem cell (MSC)-derived paracrine protection, we aimed to evaluate the efficacy of MSC-conditioned medium (CM) and extracellular vesicles (EVs) when added to ex vivo preservation solution on ameliorating ischemia/reperfusion-induced myocardial damage in donor hearts.

METHODS:

Mouse donor hearts were stored at 0°C-4°C of <1-hour cold ischemia (<1hr-I), 6hr-I + vehicle, 6hr-I + MSC-CM, 6hr-I + MSC-EVs, and 6hr-I + MSC-CM from MSCs treated with exosome release inhibitor. The hearts were then heterotopically implanted into recipient mice. At 24 hours postsurgery, myocardial function was evaluated. Heart tissue was collected for analysis of histology, apoptotic cell death, microRNA (miR)-199a-3p expression, and myocardial cytokine production.

RESULTS:

Six-hour cold ischemia significantly impaired myocardial function, increased cell death, and reduced miR-199a-3p in implanted hearts versus <1hr-I. MSC-CM or MSC-EVs in preservation solution reversed the detrimental effects of prolong cold ischemia on donor hearts. Exosome-depleted MSC-CM partially abolished MSC secretome-mediated cardioprotection in implanted hearts. MiR-199a-3p was highly enriched in MSC-EVs. MSC-CM and MSC-EVs increased cold ischemia-downregulated miR-199a-3p in donor hearts, whereas exosome-depletion neutralized this effect.

CONCLUSIONS:

MSC-CM and MSC-EVs confer improved myocardial preservation in donor hearts during prolonged cold static storage and MSC-EVs can be used for intercellular transport of miRNAs in heart transplantation.

• Authors: Meijing Wang, Liangliang Yan, Qianzhen Li, Yang Yang, Mark Turrentine, Keith March, I-Wen Wang
• Journal: The Journal of thoracic and cardiovascular surgery (J Thorac Cardiovasc Surg) Vol. 163 Issue 4 Pg. e277-e292 (04 2022) ISSN: 1097-685X [Electronic] United States
• PMID: 32981709 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Chemical References

• Culture Media, Conditioned
• MicroRNAs
• Mirn199 microRNA, mouse
• Organ Preservation Solutions

Topics

• Animals
• Cold Ischemia
• Cryopreservation
• Culture Media, Conditioned
• Down-Regulation
• Extracellular Vesicles (metabolism)
• Heart Transplantation
• Mesenchymal Stem Cells
• Mice, Inbred C57BL
• MicroRNAs (metabolism)
• Myocardial Reperfusion Injury (prevention & control)
• Organ Preservation Solutions
• Tissue Donors
• Mice