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Sustained subcutaneous delivery of secretome of human cardiac stem cells promotes cardiac repair following myocardial infarction

Version 2 2023-08-23, 06:42
Version 1 2021-03-12, 05:48
journal contribution
posted on 2023-08-23, 06:42 authored by Andrew R Kompa, David GreeningDavid Greening, Anne M Kong, Paul J McMillan, Hoayun Fang, Ritika Saxena, Raymond CB Wong, Jarmon G Lees, Priyadharshini Sivakumaran, Andrew E Newcomb, Bakhos A Tannous, Cameron Kos, Lina Mariana, Thomas Loudovaris, Derek J Hausenloy, Shiang Y Lim

Abstract: Aims - To establish pre-clinical proof of concept that sustained subcutaneous delivery of the secretome of human cardiac stem cells (CSCs) can be achieved in vivo to produce significant cardioreparative outcomes in the setting of myocardial infarction. Methods and results - Rats were subjected to permanent ligation of left anterior descending coronary artery and randomized to receive subcutaneous implantation of TheraCyte devices containing either culture media as control or 1 × 106 human W8B2+ CSCs, immediately following myocardial ischaemia. At 4 weeks following myocardial infarction, rats treated with W8B2+ CSCs encapsulated within the TheraCyte device showed preserved left ventricular ejection fraction. The preservation of cardiac function was accompanied by reduced fibrotic scar tissue, interstitial fibrosis, cardiomyocyte hypertrophy, as well as increased myocardial vascular density. Histological analysis of the TheraCyte devices harvested at 4 weeks post-implantation demonstrated survival of human W8B2+ CSCs within the devices, and the outer membrane was highly vascularized by host blood vessels. Using CSCs expressing plasma membrane reporters, extracellular vesicles of W8B2+ CSCs were found to be transferred to the heart and other organs at 4 weeks post-implantation. Furthermore, mass spectrometry-based proteomic profiling of extracellular vesicles of W8B2+ CSCs identified proteins implicated in inflammation, immunoregulation, cell survival, angiogenesis, as well as tissue remodelling and fibrosis that could mediate the cardioreparative effects of secretome of human W8B2+ CSCs. Conclusions - Subcutaneous implantation of TheraCyte devices encapsulating human W8B2+ CSCs attenuated adverse cardiac remodelling and preserved cardiac function following myocardial infarction. The TheraCyte device can be employed to deliver stem cells in a minimally invasive manner for effective secretome-based cardiac therapy.

Funding

This work was performed with support from the St Vincent’s Hospital (Melbourne) Research Endowment Fund and Stafford Fox Medical Research Foundation. Derek Hausenloy was supported by the British Heart Foundation (CS/14/3/31002); the National Institute for Health Research University College London Hospitals Biomedical Research Centre; Duke-National University Singapore Medical School; Singapore Ministry of Health’s National Medical Research Council under its Clinician Scientist-Senior Investigator scheme (NMRC/CSA-SI/ 0011/2017) and Collaborative Centre Grant scheme (NMRC/ CGAug16C006); and the Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2016-T2-2-021). This work was also funded in part by National Health and Medical Research Council project grants (#1057741 and #1139489 to D.W.G.), and Helen Amelia Hanis Fellowship (to D.W.G.). The O’Brien Institute Department of St Vincent’s Institute of Medical Research and the Centre for Eye Research Australia receive Operational Infrastructure Support from the Victorian State Government’s Department of Innovation, Industry and Regional Development. We thank Charles P. Lai and Bakhos A. Tannous for providing the CSCW-GlucB-IRES-GFP and CSCW-sshBirA-IRESmCherry plasmids, and Layal Wazen for the generation of the lentiviruses. This article is based upon work from COST Action EUCARDIOPROTECTION CA16225 supported by COST (European Cooperation in Science and Technology).

History

Publication Date

2021-03-01

Journal

Cardiovascular Research

Volume

117

Issue

3

Article Number

cvaa088

Pagination

12p. (p918-929)

Publisher

Oxford University Press

ISSN

0008-6363

Rights Statement

All rights reserved. The Author(s) 2020. For permissions, please email: journals.permissions@oup.com

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