Successful Reconstruction of the Right Ventricular Outflow Tract by Implantation of Thymus Stem Cell Engineered Graft in Growing Swine

Albertario, Ambra; Swim, Megan M.; Ahmed, Eltayeb Mohamed; Iacobazzi, Dominga; Yeong, Michael; Madeddu, Paolo; Ghorbel, Mohamed; Caputo, Massimo

doi:10.1016/j.jacbts.2019.02.001

Cited by 12 publications

(18 citation statements)

References 25 publications

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“…To note, as an alternative to local injection more physiological methods of administration could be employed. A promising example is offered by cardiac patches made of natural materials with specific biodegradable and biocompatible properties emulating closely the myocardial microenvironment (Albertario et al, 2019;McMahan et al, 2020), to be implanted upon corrective cardiac surgery. Such patches could be used as a matrix for storage and controlled release of agrin with different modalities.…”

Section: Protein Therapy Dosage and Costmentioning

confidence: 99%

Agrin-Mediated Cardiac Regeneration: Some Open Questions

Bigotti

Skeffington

Jones

et al. 2020

Front. Bioeng. Biotechnol.

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After cardiac injury, the mammalian adult heart has a very limited capacity to regenerate, due to the inability of fully differentiated cardiomyocytes (CMs) to efficiently proliferate. This has been directly linked to the extracellular matrix (ECM) surrounding and connecting cardiomyocytes, as its increasing rigidity during heart maturation has a crucial impact over the proliferative capacity of CMs. Very recent studies using mouse models have demonstrated how the ECM protein agrin might promote heart regeneration through CMs de-differentiation and proliferation. In maturing CMs, this proteoglycan would act as an inducer of a specific molecular pathway involving ECM receptor(s) within the transmembrane dystrophin-glycoprotein complex (DGC) as well as intracellular Yap, an effector of the Hippo pathway involved in the replication/regeneration program of CMs. According to the mechanism proposed, during mice heart development agrin gets progressively downregulated and ultimately replaced by other ECM proteins eventually leading to loss of proliferation/ regenerative capacity in mature CMs. Although the role played by the agrin-DGC-YAP axis during human heart development remains still largely to be defined, this scenario opens up fascinating and promising therapeutic avenues. Herein, we discuss the currently available relevant information on this system, with a view to explore how the fundamental understanding of the regenerative potential of this cellular program can be translated into therapeutic treatment of injured human hearts.

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Section: Protein Therapy Dosage and Costmentioning

confidence: 99%

Agrin-Mediated Cardiac Regeneration: Some Open Questions

Bigotti

Skeffington

Jones

et al. 2020

Front. Bioeng. Biotechnol.

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“…No animal study fulfilled all ten criteria for low risk of bias (Supplemental 11 ). One study [ 12 ] met eight of the criteria for a low risk of bias and four [ 10 , 11 , 14 , 34 ] studies met seven of the criteria. All studies were deemed to be at low risk of bias for similar groups at baseline, complete data, and selective reporting.…”

Section: Resultsmentioning

confidence: 99%

Safety and efficacy of cell therapies in pediatric heart disease: a systematic review and meta-analysis

Martinez¹,

Zoretic²,

Moreira

et al. 2020

Stem Cell Res Ther

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Background Adult clinical trials have reported safety and the therapeutic potential of stem cells for cardiac disease. These observations have now translated to the pediatric arena. We conducted a meta-analysis to assess safety and efficacy of cell-based therapies in animal and human studies of pediatric heart disease. Methods and results A literature search was conducted to examine the effects of cell-based therapies on: (i) safety and (ii) cardiac function. In total, 18 pre-clinical and 13 human studies were included. Pre-clinical: right ventricular dysfunction was the most common animal model (80%). Cardiac-derived (28%) and umbilical cord blood (24%) cells were delivered intravenously (36%) or intramyocardially (35%). Mortality was similar between cell-based and control groups (OR 0.94; 95% CI 0.05, 17.41). Cell-based treatments preserved ejection fraction by 6.9% ( p < 0.01), while intramyocardial at a dose of 1–10 M cells/kg optimized ejection fraction. Clinical: single ventricle physiology was the most common cardiac disease ( n = 9). Cardiac tissue was a frequent cell source, dosed from 3.0 × 10 5 to 2.4 × 10 7 cells/kg. A decrease in adverse events occurred in the cell-based cohort (OR 0.17, p < 0.01). Administration of cell-based therapies improved ejection fraction (MD 4.84; 95% CI 1.62, 8.07; p < 0.01). Conclusions In this meta-analysis, cell-based therapies were safe and improved specific measures of cardiac function. Implications from this review may provide methodologic recommendations (source, dose, route, timing) for future clinical trials. Of note, many of the results described in this study pattern those seen in adult stem cell reviews and meta-analyses.

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“…In this pilot study, two female swine were used as recipients and CPs were derived from a brother. Fluorescent in situ hybridization (FISH) was used to identify cells expressing the Y chromosome using a protocol described by us previously ( Albertario et al, 2019 ), with the exception of the probe, which was purchased from another vendor (Chromosome Science Labo, Japan) because the one used in ( Albertario et al, 2019 ) had been discontinued. Unfortunately, the study was unsuccessful because the Y chromosome could not be detected in a positive control (male heart biopsy).…”

Section: Discussionmentioning

confidence: 99%

“…In line with this, we reported the feasibility of using prosthetic conduits engineered with umbilical cord-derived mesenchymal stromal cells for the reconstruction of the PA in piglets ( Ghorbel et al, 2019 ; Swim et al, 2019 ). In cases requiring a two-stage correction, cells from an accessible post-natal tissue, like the thymus ( Iacobazzi et al, 2018 ; Albertario et al, 2019 ), or leftover material of palliative cardiac shunt surgery, could offer a scope to engineer available prostheses ( Avolio et al, 2015b ). Accordingly, we have proposed cardiac pericytes (CPs) as a cell source to engineer prosthetic grafts for the correction of right ventricle (RV) outflow defects ( Alvino et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Reconstruction of the Swine Pulmonary Artery Using a Graft Engineered With Syngeneic Cardiac Pericytes

Alvino

Thomas

Ghorbel

et al. 2021

Front. Bioeng. Biotechnol.

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The neonatal heart represents an attractive source of regenerative cells. Here, we report the results of a randomized, controlled, investigator-blinded preclinical study, which assessed the safety and effectiveness of a matrix graft cellularized with cardiac pericytes (CPs) in a piglet model of pulmonary artery (PA) reconstruction. Within each of five trios formed by 4-week-old female littermate piglets, one element (the donor) was sacrificed to provide a source of CPs, while the other two elements (the graft recipients) were allowed to reach the age of 10 weeks. During this time interval, culture-expanded donor CPs were seeded onto swine small intestinal submucosa (SIS) grafts, which were then shaped into conduits and conditioned in a flow bioreactor. Control unseeded SIS conduits were subjected to the same procedure. Then, recipient piglets were randomized to surgical reconstruction of the left PA (LPA) with unseeded or CP-seeded SIS conduits. Doppler echocardiography and cardiac magnetic resonance imaging (CMRI) were performed at baseline and 4-months post-implantation. Vascular explants were examined using histology and immunohistochemistry. All animals completed the scheduled follow-up. No group difference was observed in baseline imaging data. The final Doppler assessment showed that the LPA’s blood flow velocity was similar in the treatment groups. CMRI revealed a mismatch in the average growth of the grafted LPA and contralateral branch in both treatment groups. Histology of explanted arteries demonstrated that the CP-seeded grafts had a thicker luminal cell layer, more intraparietal arterioles, and a higher expression of endothelial nitric oxide synthase (eNOS) compared with unseeded grafts. Moreover, the LPA stump adjacent to the seeded graft contained more elastin and less collagen than the unseeded control. Syngeneic CP engineering did not accomplish the primary goal of supporting the graft’s growth but was able to improve secondary outcomes, such as the luminal cellularization and intraparietal vascularization of the graft, and elastic remodeling of the recipient artery. The beneficial properties of neonatal CPs may be considered in future bioengineering applications aiming to reproduce the cellular composition of native arteries.

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Successful Reconstruction of the Right Ventricular Outflow Tract by Implantation of Thymus Stem Cell Engineered Graft in Growing Swine

Abstract: Visual Abstract

Cited by 12 publications

References 25 publications

Agrin-Mediated Cardiac Regeneration: Some Open Questions

Agrin-Mediated Cardiac Regeneration: Some Open Questions

Safety and efficacy of cell therapies in pediatric heart disease: a systematic review and meta-analysis

Reconstruction of the Swine Pulmonary Artery Using a Graft Engineered With Syngeneic Cardiac Pericytes

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