Human-umbilical cord matrix mesenchymal cells improved left ventricular contractility independently of infarct size in swine myocardial infarction with reperfusion

Luís Raposo; Rui J Cerqueira; Sara Leite; Liliana Moreira-Costa; Tiago L Laundos; Joana O Miranda; Pedro Mendes-Ferreira; João Almeida Coelho; Rita N Gomes; Perpétua Pinto-do-Ó; Diana S Nascimento; André P Lourenço; Nuno Cardim; Adelino Leite-Moreira

doi:10.3389/fcvm.2023.1186574

Human-umbilical cord matrix mesenchymal cells improved left ventricular contractility independently of infarct size in swine myocardial infarction with reperfusion

Front Cardiovasc Med. 2023 Jun 5:10:1186574. doi: 10.3389/fcvm.2023.1186574. eCollection 2023.

Authors

Luís Raposo^{1

2

3}, Rui J Cerqueira^{4

5}, Sara Leite^{4

6

7}, Liliana Moreira-Costa⁴, Tiago L Laundos^{7

8

9}, Joana O Miranda⁴, Pedro Mendes-Ferreira^{4

10}, João Almeida Coelho⁴, Rita N Gomes^{7

8

9}, Perpétua Pinto-do-Ó^{7

8

9}, Diana S Nascimento^{7

8

9}, André P Lourenço^{4

11}, Nuno Cardim^{2

3}, Adelino Leite-Moreira^{4

5}

Affiliations

¹ Cardiology Department, Hospital de Santa Cruz - Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal.
² Centro Cardiovascular, Hospital da Luz - Lisboa, Luz Saúde, Lisbon, Portugal.
³ Nova Medical School, Lisbon, Portugal.
⁴ Cardiovascular R&D Centre, UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal.
⁵ Department of Cardiothoracic Surgery, Hospital Universitário de São João, Porto, Portugal.
⁶ Anta Family Health Unit, Espinho/Gaia Healthcare Centre, Espinho, Portugal.
⁷ ICBAS- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.
⁸ I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
⁹ INEB - Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.
¹⁰ Paris-Porto Pulmonary Hypertension Collaborative Laboratory (3PH), UMR_S 999, INSERM, Université Paris-Saclay, Paris, France.
¹¹ Department of Anesthesiology, Hospital Universitário de São João, Porto, Portugal.

Abstract

Background: Human umbilical cord matrix-mesenchymal stromal cells (hUCM-MSC) have demonstrated beneficial effects in experimental acute myocardial infarction (AMI). Reperfusion injury hampers myocardial recovery in a clinical setting and its management is an unmet need. We investigated the efficacy of intracoronary (IC) delivery of xenogeneic hUCM-MSC as reperfusion-adjuvant therapy in a translational model of AMI in swine.

Methods: In a placebo-controlled trial, pot-belied pigs were randomly assigned to a sham-control group (vehicle-injection; n = 8), AMI + vehicle (n = 12) or AMI + IC-injection (n = 11) of 5 × 10⁵ hUCM-MSC/Kg, within 30 min of reperfusion. AMI was created percutaneously by balloon occlusion of the mid-LAD. Left-ventricular function was blindly evaluated at 8-weeks by invasive pressure-volume loop analysis (primary endpoint). Mechanistic readouts included histology, strength-length relationship in skinned cardiomyocytes and gene expression analysis by RNA-sequencing.

Results: As compared to vehicle, hUCM-MSC enhanced systolic function as shown by higher ejection fraction (65 ± 6% vs. 43 ± 4%; p = 0.0048), cardiac index (4.1 ± 0.4 vs. 3.1 ± 0.2 L/min/m²; p = 0.0378), preload recruitable stroke work (75 ± 13 vs. 36 ± 4 mmHg; p = 0.0256) and end-systolic elastance (2.8 ± 0.7 vs. 2.1 ± 0.4 mmHg*m²/ml; p = 0.0663). Infarct size was non-significantly lower in cell-treated animals (13.7 ± 2.2% vs. 15.9 ± 2.7%; Δ = -2.2%; p = 0.23), as was interstitial fibrosis and cardiomyocyte hypertrophy in the remote myocardium. Sarcomere active tension improved, and genes related to extracellular matrix remodelling (including MMP9, TIMP1 and PAI1), collagen fibril organization and glycosaminoglycan biosynthesis were downregulated in animals treated with hUCM-MSC.

Conclusion: Intracoronary transfer of xenogeneic hUCM-MSC shortly after reperfusion improved left-ventricular systolic function, which could not be explained by the observed extent of infarct size reduction alone. Combined contributions of favourable modification of myocardial interstitial fibrosis, matrix remodelling and enhanced cardiomyocyte contractility in the remote myocardium may provide mechanistic insight for the biological effect.

Keywords: MSC; mesenchymal cells; myocardial infarction; reperfusion; umbilical-cord.

Grants and funding

This work was funded by: i) national funds through FCT - Portuguese Foundation for Science and Technology, under the scope of the Cardiovascular R&D Center - UnIC (UIDB/00051/2020 and UIDP/00051/2020); ii) “la Caixa” Banking Foundation and FCT under the project code LCF/PR/HP17/52190002”; iii) the QREN project 2013/30196; and iv) the European Structural and Investment Funds (ESIF), under the Lisbon Portugal Regional Operational Program and National Funds through FCT [POCI-01-0145-FEDER-030985]. RNG and TLL were funded by the FCT individual fellowships [SFRH/BD/144490/2019] and [PD/BD/127997/2016], respectively. Funding sources had no interference in the design of the study, study governance, data collection and analysis, nor in manuscript writing or its scientific and intellectual content.