Reconstruction of the pulmonary artery by a novel biodegradable conduit engineered with perinatal stem cell-derived vascular smooth muscle cells enables physiological vascular growth in a large animal model of congenital heart disease

Abstract

Lack of growth potential of available grafts represents a bottleneck in the correction of congenital heart defects. Here we used a swine small intestinal submucosa (SIS) graft functionalized with mesenchymal stem cell (MSC)-derived vascular smooth muscle cells (VSMCs), for replacement of the pulmonary artery in piglets. MSCs were expanded from human umbilical cord blood or new-born swine peripheral blood, seeded onto decellularized SIS grafts and conditioned in a bioreactor to differentiate into VSMCs. Results indicate the equivalence of generating grafts engineered with human or swine MSC-derived VSMCs. Next, we conducted a randomized, controlled study in piglets (12–15 kg), which had the left pulmonary artery reconstructed with swine VSMC-engineered or acellular conduit grafts. Piglets recovered well from surgery, with no casualty and similar growth rate in either group. After 6 months, grafted arteries had larger circumference in the cellular group (28.3 ± 2.3 vs 18.3 ± 2.1 mm, P < 0.001), but without evidence of aneurism formation. Immunohistochemistry showed engineered grafts were composed of homogeneous endothelium covered by multi-layered muscular media, whereas the acellular grafts exhibited a patchy endothelial cell layer and a thinner muscular layer. Results show the feasibility and efficacy of pulmonary artery reconstruction using clinically available grafts engineered with allogeneic VSMCs in growing swine.

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

“…Cells from fetal tissues, such as the placenta, amnion, and umbilical cord, are best suited for cases diagnosed prenatally ( Bongso et al, 2008 ; Pappa and Anagnou, 2009 ). 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 ).…”

“…Moreover, the differentiation of stromal cells into VSMCs involves an additional step in manufacturing, which results in increased complexity and delayed availability, both detrimental for cases requiring rapid correction. On the other hand, VSMCs derived from the differentiation of mesenchymal stromal cells conferred conduits with the growing capacity that was precluded to CPs ( Ghorbel et al, 2019 ; Iacobazzi et al, 2021 ). Considering that human CPs can be also induced to contractile VSMCs during culture expansion ( Ghorbel et al, 2019 ), it would be interesting to determine if seeding SIS grafts with CP-derived VSMCs may improve the graft capacity to remodel and grow after implantation in vivo .…”

Dimeric Thymosin β4 Loaded Nanofibrous Interface Enhanced Regeneration of Muscular Artery in Aging Body through Modulating Perivascular Adipose Stem Cell–Macrophage Interaction

“…Recent advances in tissue‐engineered blood vessels have enabled the modeling and improved understanding of complex biological phenomena. [ 14,15 ] Specifically, various methods to recreate critical components of the muscular remodeling have been developed to systematically study the cellular events and interactions involved in VPCs. Incorporating chemokines promoting stem cells recruitment in polymeric grafts and young cells engineered extracellular matrices have proven capable in promoting VPCs homing and myogenic differentiation.…”

Congenital Heart Disease: An Immunological Perspective

“…Models like this can help in studying the consequences of a particular CHD; however, the specific immune causes of the defects are likely not clearly elucidated from these downstream pathways. This also holds true for larger animal models, such as porcine ( 111 , 112 ) and ovine ( 113 ) models, where the structural heart defect needs to be created by fetal surgery and would therefore not mimic immune mechanisms that cause the initial defects in humans, but could model reactionary inflammatory and immune changes.…”