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

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

doi:10.3389/fcvm.2022.953211

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

Front Cardiovasc Med. 2022 Oct 10:9:953211. doi: 10.3389/fcvm.2022.953211. eCollection 2022.

Authors

Ana-Mishel Spiroski^{1

2}, Ian R McCracken¹, Adrian Thomson³, Marlene Magalhaes-Pinto^{1

2}, Mukesh K Lalwani¹, Kathryn J Newton¹, Eileen Miller¹, Cecile Bénézech⁴, Patrick Hadoke¹, Mairi Brittan^{1

2}, Joanne C Mountford⁵, Abdelaziz Beqqali¹, Gillian A Gray¹, Andrew H Baker^{1

2}

Affiliations

¹ Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
² BHF Centre for Vascular Regeneration, University of Edinburgh, Edinburgh, United Kingdom.
³ Edinburgh Preclinical Imaging, University of Edinburgh, Edinburgh, United Kingdom.
⁴ Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
⁵ Scottish National Blood Transfusion Service, Edinburgh, United Kingdom.

Abstract

Background: 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.

Aim: 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.

Materials and methods: Following coronary artery ligation (CAL) to induce cardiac ischemia, we investigated infarct size at 1 day post-injection in media-injected controls (CALM, n = 11), hESC-ECP-injected mice (CALC, n = 10), and dead hESC-ECP-injected mice (CALD, n = 6); echocardiography-based functional outcomes 14 days post-injection in experimental (CALM, n = 13; CALC, n = 17) and SHAM surgical mice (n = 4); and mature infarct size (CALM and CALC, both n = 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.

Results: 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 via viable hESC-ECP-resident signaling.

Conclusion: 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.

Keywords: cell therapy; hESC-ECP; immunomodulation; ligand–receptor interaction; myocardial infarction; scRNAseq.

Abstract

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