Mesenchymal Stromal Cell Therapy Regenerates Rejected Donor Lungs and Reduces Primary Graft Dysfunction Following Lung Transplantation

Abstract

<h3>Purpose</h3> Given critical shortages of donor lungs coupled with donor utilization rates hovering at a mere 20%, novel therapies are needed to increase the number of organs available for transplantation. Treatments which could regenerate lungs rejected for transplant should be explored to combat waiting list mortality and post-operative complications like primary graft dysfunction (PGD). Term amniotic fluid-derived mesenchymal stromal cells (TAF-MSCs) administered during ex vivo lung perfusion (EVLP) and post transplantation were studied under the hypothesis that the therapy could improve damaged lungs and reduce the incidence of PGD. <h3>Methods</h3> Donor pigs were treated with <i>E. coli-</i>derived lipopolysaccharide to induce acute lung injury as confirmed via blood gas values and histology. Harvested lungs were placed on EVLP for 4 hours, and the left lungs were transplanted. After recipients were monitored for three days, a right pneumectomy was performed and the transplanted left lung alone was evaluated for PGD. The treatment group received intravascular doses of TAF-MSCs during EVLP and at 2 timepoints following transplantation. Half of the lungs were maintained as a non-treated group which underwent the same EVLP and transplantation protocol. <h3>Results</h3> Cell counts of leukocytes were comparable in plasma at the induction of ARDS and in the perfusate during EVLP, however, lymphocytes were significantly decreased in the treated group relative to the non-treated during the first 24 hours following transplantation. Blinded histological scoring by a pathologist demonstrated that the treated lungs were significantly less injured than the non-treated ones and significantly less than biopsies taken at the time of confirmed ARDS. Furthermore, assessment of lung functionality through the PaO₂/FiO₂ ratio showed treated recipients had ratios significantly increased compared to transplanted non-treated recipients and to all lungs at the time of confirmed ARDS. All in the treated group were primary graft dysfunction (PGD) grade 0 on the third day of follow-up, while the non-treated group consisted of one grade 2 and the rest had PGD grade 3. <h3>Conclusion</h3> Delivery of intravascular TAF-MSCs at both EVLP and early during the post-transplantation period enabled recovery of lungs with acute lung injury and decreased the incidence of primary graft dysfunction.