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

Autor:	Raposo L; Cardiology Department, Hospital de Santa Cruz - Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal.; Centro Cardiovascular, Hospital da Luz - Lisboa, Luz Saúde, Lisbon, Portugal.; Nova Medical School, Lisbon, Portugal., Cerqueira RJ; Cardiovascular R&D Centre, UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal.; Department of Cardiothoracic Surgery, Hospital Universitário de São João, Porto, Portugal., Leite S; Cardiovascular R&D Centre, UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal.; Anta Family Health Unit, Espinho/Gaia Healthcare Centre, Espinho, Portugal.; ICBAS- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal., Moreira-Costa L; Cardiovascular R&D Centre, UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal., Laundos TL; ICBAS- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.; I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.; INEB - Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Porto, Portugal., Miranda JO; Cardiovascular R&D Centre, UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal., Mendes-Ferreira P; Cardiovascular R&D Centre, UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal.; Paris-Porto Pulmonary Hypertension Collaborative Laboratory (3PH), UMR_S 999, INSERM, Université Paris-Saclay, Paris, France., Coelho JA; Cardiovascular R&D Centre, UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal., Gomes RN; ICBAS- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.; I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.; INEB - Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Porto, Portugal., Pinto-do-Ó P; ICBAS- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.; I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.; INEB - Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Porto, Portugal., Nascimento DS; ICBAS- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.; I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.; INEB - Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Porto, Portugal., Lourenço AP; Cardiovascular R&D Centre, UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal.; Department of Anesthesiology, Hospital Universitário de São João, Porto, Portugal., Cardim N; Centro Cardiovascular, Hospital da Luz - Lisboa, Luz Saúde, Lisbon, Portugal.; Nova Medical School, Lisbon, Portugal., Leite-Moreira A; Cardiovascular R&D Centre, UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal.; Department of Cardiothoracic Surgery, Hospital Universitário de São João, Porto, Portugal.
Jazyk:	angličtina
Zdroj:	Frontiers in cardiovascular medicine [Front Cardiovasc Med] 2023 Jun 05; Vol. 10, pp. 1186574. Date of Electronic Publication: 2023 Jun 05 (Print Publication: 2023).
DOI:	10.3389/fcvm.2023.1186574
Abstrakt:	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 × 10 5 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/m 2 ; 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*m 2 /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. Competing Interests: LR has received honoraria fees from EcBIO™—R&D in Biotechnology, SA (Lisbon, Portugal), and has served as a member of advisory boards for the company. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (© 2023 Raposo, Cerqueira, Leite, Moreira-Costa, Laundos, Miranda, Mendes-Ferreira, Coelho, Gomes, Pinto-do-Ó, Nascimento, Lourenço, Cardim and Leite-Moreira.)
Databáze:	MEDLINE
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