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

Valeria Vincenza Alvino,William Cathery,Marco Fagnano,Michael Kilcooley,Elisa Avolio,Dominga Iacobazzi,Filippo Rapetto,Paolo Madeddu,Mohamed T Ghorbel,Massimo Caputo,Michele Carrabba,Srinivas A Narayan,Anita C Thomas

doi:10.3389/fbioe.2021.715717

Valeria Vincenza Alvino, William Cathery + Show 11 more

Open Access

https://doi.org/10.3389/fbioe.2021.715717

Copy DOI

Abstract

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.

Highlights

Congenital defects of the pulmonary artery (PA) can occur as an isolated lesion or as an element of complex heart anomalies, as in the case of Tetralogy of Fallot
Cellularized vascular grafts can potentially overcome the shortcomings of currently used materials, and, if successfully passing all the development phases required for a marketing authorization, they might provide a better solution for the pediatric population
Bioengineering of small intestinal submucosa (SIS) grafts with syngeneic cardiac pericytes (CPs) resulted in some improvements regarding endothelialization but failed in the goal of conferring the graft with growth capacity

Summary

Introduction

Congenital defects of the pulmonary artery (PA) can occur as an isolated lesion or as an element of complex heart anomalies, as in the case of Tetralogy of Fallot. For patients with isolated valvular stenosis, balloon valvuloplasty is the treatment of choice; whereas patients with more complex defects require a palliative shunt intervention followed by, often multiple, attempts of definitive correction (Lenoir et al, 2017). Prosthetic or biological materials used for PA reconstruction are not ideal substitutes due to their thrombogenicity, limited durability, and inadequate growth and regeneration potential (Manavitehrani et al, 2019). Cellularized vascular grafts can potentially overcome the shortcomings of currently used materials, and, if successfully passing all the development phases required for a marketing authorization, they might provide a better solution for the pediatric population. Several cell populations have been tested in animal models, including mesenchymal stromal cells, endothelial cells or induced pluripotent stem cells, yet the quest for the ideal cell type(s) is still open, as reviewed in (Avolio et al, 2015a; Jover et al, 2021)

Methods

Results

Discussion

Conclusion