Wharton's Jelly-Mesenchymal Stem Cell-Engineered Conduit for Pediatric Translation in Heart Defect

Abstract

The materials available for the Right Ventricular Outflow Tract (RVOT) reconstruction in patients with Tetralogy of Fallot (TOF)/pulmonary atresia come with the severe limitation of long-term degeneration and lack of growth potential, causing right ventricular dysfunction, aneurysm formation and arrhythmias, thus necessitating several high-risk reoperations throughout patients' life.In this study, we evaluated the capacity of Mesenchymal Stem Cells (MSCs) derived from the Wharton's Jelly (WJ-MSCs), the gelatinous inner portion of the umbilical cord, to grow and recellularize an extracellular matrix (ECM) graft in our optimised xeno-free, good manufacturing practice-compliant culture system. WJ-MSCs were phenotypically and functionally characterised by flow cytometry and multi-lineage differentiation capacity, respectively. The typical MSCs immunophenotype and functional characteristics were retained in our xeno-free culture system, as well as the capacity to grow and engraft onto a naturally occurring scaffold. Wharton's Jelly MSCs, from both human and swine source, showed excellent capacity to recellularize ECM graft producing a living cell-seeded construct.In addition, we have provided an in vivo proof of concept of feasibility of the cellularised conduit, engineered with swine Wharton's Jelly MSCs, to be used in a novel porcine model of main pulmonary artery reconstruction, where it showed good integration within the host tissue.Our study indicates that the addition of WJ-MSCs to the ECM scaffold can upgrade the material, converting it into a living tissue, with the potential to grow, repair and remodel the RVOT. These results could potentially represent a paradigm shift in paediatric cardiac intervention towards new modalities for effective and personalised surgical restoration of pulmonary artery and RVOT function in TOF/pulmonary atresia patients.

Umbilical Cord Pericytes Provide a Viable Alternative to Mesenchymal Stem Cells for Neonatal Vascular Engineering

“…A cell that can adapt to this environment effectively may be favorable for tissue engineering. We compared NG2 UCPs to a commercial line of Wharton's Jelly MSCs, which are often the focus of cell therapy and tissue engineering applications (29,30). NG2 UCPs remarkably outperformed their comparator regarding the ability to release SDF-1, VEGF-A, HGF, and MCP-1 under normoxia and hypoxia, while showing moderately lower levels of ANGPT-1.…”

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

“…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 .…”

Wharton’s Jelly–Mesenchymal Stem Cell–Engineered Conduit for Pulmonary Artery Reconstruction in Growing Piglets

“…WJ-MSCs were isolated from umbilical cord of newborn female piglets by mechanic dissociation, as previously described. 19 The isolated cells were fed with fresh medium every 3 days and expanded until passages 3 to 5. Fluorescence-activated cell sorting analysis was used to determine cell surface marker expression.…”

“…Fluorescence-activated cell sorting analysis was used to determine cell surface marker expression. 12 , 19 …”

“…We and others have found that WJ-MSCs are characterized by easy accessibility, extended plasticity, self-renewal capacity, long-term expansion, as well as immunoprivileged properties. 16 , 17 , 18 , 19 …”