Human pluripotent stem cell-derived cardiomyocytes as a target
platform for paracrine protection by cardiac mesenchymal stromal
cells
platform for paracrine protection by cardiac mesenchymal stromal
cells
File(s)
Published version
Author(s)
Constantinou, Chrystalla
Miranda Almeida, Antonio
Chaves Guerrero, Patricia
Bellahcene, Mohamed
Massaia, Andrea
Type
Journal Article
Abstract
Ischemic heart disease remains the foremost cause of death globally, with survivors at risk for subsequent heart failure. Paradoxically, cell therapies to offset cardiomyocyte loss after ischemic injury improve long-term cardiac function despite a lack of durable engraftment. An evolving consensus, inferred preponderantly from non-human models, is that transplanted cells benefit the heart via early paracrinesignals. Here, we tested the impact of paracrine signals on human cardiomyocytes, using human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) as the target of mouse and human cardiac mesenchymal stromal cells (cMSC) with progenitor-like features. In co-culture and conditioned medium studies, cMSCs markedly inhibited human cardiomyocyte death. Little or no protection was conferred by mouse tail tip or human skin fibroblasts. Consistent with the results of transcriptomic profiling, functional analyses showed that the cMSC secretome suppressed apoptosis and and preserved cardiac mitochondrial transmembrane potential. Protection was independent of exosomes under the conditions tested. In mice, injecting cMSC-conditioned media into the infarct border zone reduced apoptotic cardiomyocytes >70% locally. Thus, hPSC-CMs provide an auspicious, relevant human platform to investigate extracellular signals for cardiac muscle survival, substantiating human cardioprotection by cMSCs, and suggesting the cMSC secretome or its components as potential cell-free therapeutic products.
Date Issued
2020-08-03
Date Acceptance
2020-05-22
Citation
Scientific Reports, 2020, 10
ISSN
2045-2322
Publisher
Nature Publishing Group
Journal / Book Title
Scientific Reports
Volume
10
Copyright Statement
© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creat iveco mmons .org/licen ses/by/4.0/.
License URL
Sponsor
British Heart Foundation
British Heart Foundation
British Heart Foundation
British Heart Foundation
British Heart Foundation
Grant Number
RM/13/1/30157
RG/15/1/31165
CH/08/002/25297
PG/16/47/32156
RM/17/1/33377
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
GENE-EXPRESSION
ISCHEMIC-INJURY
HUMAN HEART
REGENERATION
MECHANISMS
ROLES
EXOSOMES
MYOSIN
DEATH
MYOCARDIUM
Publication Status
Published
Article Number
ARTN 13016