AUTHOR=Spiroski Ana-Mishel , McCracken Ian R. , Thomson Adrian , Magalhaes-Pinto Marlene , Lalwani Mukesh K. , Newton Kathryn J. , Miller Eileen , Bénézech Cecile , Hadoke Patrick , Brittan Mairi , Mountford Joanne C. , Beqqali Abdelaziz , Gray Gillian A. , Baker Andrew H. 

TITLE=Human embryonic stem cell-derived endothelial cell product injection attenuates cardiac remodeling in myocardial infarction

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2022.953211

DOI=10.3389/fcvm.2022.953211

ISSN=2297-055X

ABSTRACT=<sec><title>Background</title><p>Mechanisms contributing to tissue remodeling of the infarcted heart following cell-based therapy remain elusive. While cell-based interventions have the potential to influence the cardiac healing process, there is little direct evidence of preservation of functional myocardium.</p></sec><sec><title>Aim</title><p>The aim of the study was to investigate tissue remodeling in the infarcted heart following human embryonic stem cell-derived endothelial cell product (hESC-ECP) therapy.</p></sec><sec><title>Materials and methods</title><p>Following coronary artery ligation (CAL) to induce cardiac ischemia, we investigated infarct size at 1 day post-injection in media-injected controls (CALM, <italic>n</italic> = 11), hESC-ECP-injected mice (CALC, <italic>n</italic> = 10), and dead hESC-ECP-injected mice (CALD, <italic>n</italic> = 6); echocardiography-based functional outcomes 14 days post-injection in experimental (CALM, <italic>n</italic> = 13; CALC, <italic>n</italic> = 17) and SHAM surgical mice (<italic>n</italic> = 4); and mature infarct size (CALM and CALC, both <italic>n</italic> = 6). We investigated ligand–receptor interactions (LRIs) in hESC-ECP cell populations, incorporating a publicly available C57BL/6J mouse cardiomyocyte-free scRNAseq dataset with naive, 1 day, and 3 days post-CAL hearts.</p></sec><sec><title>Results</title><p>Human embryonic stem cell-derived endothelial cell product injection reduces the infarct area (CALM: 54.5 ± 5.0%, CALC: 21.3 ± 4.9%), and end-diastolic (CALM: 87.8 ± 8.9 uL, CALC: 63.3 ± 2.7 uL) and end-systolic ventricular volume (CALM: 56.4 ± 9.3 uL, CALC: 33.7 ± 2.6 uL). LRI analyses indicate an alternative immunomodulatory effect mediated <italic>via</italic> viable hESC-ECP-resident signaling.</p></sec><sec><title>Conclusion</title><p>Delivery of the live hESC-ECP following CAL modulates the wound healing response during acute pathological remodeling, reducing infarct area, and preserving functional myocardium in this relatively acute model. Potential intrinsic myocardial cellular/hESC-ECP interactions indicate that discreet immunomodulation could provide novel therapeutic avenues to improve cardiac outcomes following myocardial infarction.</p></sec>