TY - JOUR
T1 - Human embryonic stem cell-derived endothelial cell product injection attenuates cardiac remodeling in myocardial infarction
AU - Spiroski, Ana-Mishel
AU - McCracken, Ian
AU - Thomson, Adrian
AU - Magalhaes Pinto, Marlene
AU - Lalwani, Mukesh K.
AU - Newton, Kathryn
AU - Miller, Eileen
AU - Benezech, Cecile
AU - Hadoke, Patrick W F
AU - Brittan, Mairi
AU - Mountford, Joanne C
AU - Beqqali, Appie
AU - Gray, Gillian A
AU - Baker, Andrew H
N1 - Funding Information:
The British Heart Foundation supported this work (Program grant: RG/14/3/30706 to AHB, and project grant and FS/17/27/32698 to AHB). AHB was supported by the British Heart Foundation Chair of Translational Cardiovascular Sciences (CH/11/2/28733), European Research Council (EC 338991 VASCMIR). AHB, MB, and A-MS are supported by the BHF Centre for Vascular Regeneration (RM/17/3/33381), and AHB and MB are supported by the BHF Regenerative Medicine Centre (RM/13/2/30158). MB was supported by the British Heart Foundation (FS/16/4/31831).
Publisher Copyright:
Copyright © 2022 Spiroski, McCracken, Thomson, Magalhaes-Pinto, Lalwani, Newton, Miller, Bénézech, Hadoke, Brittan, Mountford, Beqqali, Gray and Baker.
PY - 2022/10/10
Y1 - 2022/10/10
N2 - Background: Mechanisms contributing to tissue remodelling of the infarcted heart following cell-based therapy remain elusive. Whilst cell-based interventions have the potential to influence the cardiac healing process, there is little direct evidence of preservation of functional myocardium. Aim: To investigate tissue remodelling in the infarcted heart following human embryonic stem cell-derived endothelial cell product (hESC-ECP) therapy. Methods: Following coronary artery ligation (CAL) to induce cardiac ischaemia, 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 naïve, 1- and 3-day post-CAL hearts. Results: hESC-ECP injection reduces infarct area (CALM: 54.5±5.0%, CALC: 21.3±4.9%), end diastolic (CALM: 87.8±8.9uL, CALC: 63.3±2.7uL) and end systolic ventricular volume (CALM: 56.4±9.3uL, CALC: 33.7±2.6uL). LRI analyses indicate an alternative immunomodulatory effect mediated via viable hESC-ECP-resident signalling. Conclusions: Delivery of the live hESC-ECP following CAL modulates the wound healing response during acute pathological remodelling, 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.
AB - Background: Mechanisms contributing to tissue remodelling of the infarcted heart following cell-based therapy remain elusive. Whilst cell-based interventions have the potential to influence the cardiac healing process, there is little direct evidence of preservation of functional myocardium. Aim: To investigate tissue remodelling in the infarcted heart following human embryonic stem cell-derived endothelial cell product (hESC-ECP) therapy. Methods: Following coronary artery ligation (CAL) to induce cardiac ischaemia, 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 naïve, 1- and 3-day post-CAL hearts. Results: hESC-ECP injection reduces infarct area (CALM: 54.5±5.0%, CALC: 21.3±4.9%), end diastolic (CALM: 87.8±8.9uL, CALC: 63.3±2.7uL) and end systolic ventricular volume (CALM: 56.4±9.3uL, CALC: 33.7±2.6uL). LRI analyses indicate an alternative immunomodulatory effect mediated via viable hESC-ECP-resident signalling. Conclusions: Delivery of the live hESC-ECP following CAL modulates the wound healing response during acute pathological remodelling, 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.
U2 - 10.3389/fcvm.2022.953211
DO - 10.3389/fcvm.2022.953211
M3 - Article
SN - 2297-055X
JO - Frontiers in Cardiovascular Medicine
JF - Frontiers in Cardiovascular Medicine
ER -