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

Ana-Mishel Spiroski; Ian McCracken; Adrian Thomson; Marlene Magalhaes Pinto; Mukesh K. Lalwani; Kathryn Newton; Eileen Miller; Cecile Benezech; Patrick W F Hadoke; Mairi Brittan; Joanne C Mountford; Appie 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

Ana-Mishel Spiroski, Ian McCracken, Adrian Thomson, Marlene Magalhaes Pinto, Mukesh K. Lalwani, Kathryn Newton, Eileen Miller, Cecile Benezech, Patrick W F Hadoke, Mairi Brittan, Joanne C Mountford, Appie Beqqali, Gillian A Gray, Andrew H Baker

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Journal	Frontiers in Cardiovascular Medicine
DOIs	https://doi.org/10.3389/fcvm.2022.953211
Publication status	Published - 10 Oct 2022

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10.3389/fcvm.2022.953211

fcvm-09-953211Final published version, 6.1 MBLicence: Creative Commons: Attribution (CC-BY)

1 Active
6 Finished

BHF Chair Transfer from Glasgow
Baker, A. (Principal Investigator)
UK-based charities
1/10/15 → 31/07/26
Project: Research
BHF Centre for Vascular Regeneration - Cross Centre activities
Baker, A. (Principal Investigator)
UK-based charities
1/10/17 → 30/09/21
Project: Research
Assessing the regulation and function of long non-coding RNA LINC00961 in vascular endothelial cell function
Baker, A. (Principal Investigator)
UK-based charities
1/05/17 → 30/04/20
Project: Research

Edinburgh Preclinical Imaging
Moran, C. (Manager), Thomson, A. (Manager), Lennen, R. J. (Manager), Tavares, A. (Manager), Alcaide-Corral, C. J. (Manager), Morgan, T. (Other), Cranston, I. (Other) & O'Rourke, K. (Other)
Deanery of Clinical Sciences
Facility/equipment: Facility
Institute for Regeneration and Repair Flow Cytometry Facility
Johnston, S. (Manager), Rossi, F. (Manager), Cryer, C. (Other) & Laird, A. (Other)
Institute of Regeneration and Repair
Facility/equipment: Facility

Cite this

Spiroski, A.-M., McCracken, I., Thomson, A., Magalhaes Pinto, M., Lalwani, M. K., Newton, K., Miller, E., Benezech, C., Hadoke, P. W. F., Brittan, M., Mountford, J. C., Beqqali, A., Gray, G. A., & Baker, A. H. (2022). Human embryonic stem cell-derived endothelial cell product injection attenuates cardiac remodeling in myocardial infarction. Frontiers in Cardiovascular Medicine. https://doi.org/10.3389/fcvm.2022.953211

@article{46baf546276d4846b641c5cf8ff88772,

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

abstract = "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 na{\"i}ve, 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.",

author = "Ana-Mishel Spiroski and Ian McCracken and Adrian Thomson and {Magalhaes Pinto}, Marlene and Lalwani, {Mukesh K.} and Kathryn Newton and Eileen Miller and Cecile Benezech and Hadoke, {Patrick W F} and Mairi Brittan and Mountford, {Joanne C} and Appie Beqqali and Gray, {Gillian A} and Baker, {Andrew H}",

note = "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 {\textcopyright} 2022 Spiroski, McCracken, Thomson, Magalhaes-Pinto, Lalwani, Newton, Miller, B{\'e}n{\'e}zech, Hadoke, Brittan, Mountford, Beqqali, Gray and Baker.",

year = "2022",

month = oct,

day = "10",

doi = "10.3389/fcvm.2022.953211",

language = "English",

journal = "Frontiers in Cardiovascular Medicine",

issn = "2297-055X",

publisher = "Frontiers Media SA",

}

Spiroski, A-M, McCracken, I, Thomson, A , Magalhaes Pinto, M , Lalwani, MK, Newton, K, Miller, E, Benezech, C , Hadoke, PWF , Brittan, M, Mountford, JC, Beqqali, A, Gray, GA & Baker, AH 2022, 'Human embryonic stem cell-derived endothelial cell product injection attenuates cardiac remodeling in myocardial infarction', Frontiers in Cardiovascular Medicine. https://doi.org/10.3389/fcvm.2022.953211

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 -

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

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Projects

BHF Chair Transfer from Glasgow

BHF Centre for Vascular Regeneration - Cross Centre activities

Assessing the regulation and function of long non-coding RNA LINC00961 in vascular endothelial cell function

Equipment

Edinburgh Preclinical Imaging

Institute for Regeneration and Repair Flow Cytometry Facility

Cite this