Mesenchymal stromal cell therapy as promising option to increase organ availability and reduce graft failure
Franziska Olm1,2,3,4, Dag Edström2,3,4,5, Margareta Mittendorfer2,3,4, Haider Ghaidan1,2,3,4, Anna Niroomand2,3,4,6, Gabriel Hirdman2,3,4, Martin Stenlo2,3,4,5, Leif Pierre1,2,3,4, Snejana Hyllen2,3,4,5, Sandra Lindstedt1,2,3,4.
1Dept. of Cardiothoracic Surgery and Transplantation, Skåne University Hospital, Lund, Sweden; 2Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden; 3Dept. of Clinical Sciences, Lund University, Lund, Sweden; 4Lund Stem Cell Center, Lund University, Lund, Sweden; 5Dept. of Cardiothoracic Anaesthesia and Intensive Care, Skåne University Hospital, Lund, Sweden; 6Rutgers Robert University, New Brunswick, NJ, United States
Introduction: Lung transplantation (LTx) is an established therapeutic option for end-stage pulmonary disease. However, waiting lists are long and the treatments remains hampered by donor lung scarcity accompanied with high early and late mortality rates. Novel treatment options to regenerate marginal donor lungs turned down for transplant are needed to combat both waiting list mortality and post-operative complications such as primary graft dysfunction (PGD). Although donor numbers increase, donor organ utility is low due to acute lung injury (ALI) which can be induced by gastric aspiration. Mesenchymal stromal cells (MSCs) have caught attention for organ regeneration as they display an array of potentially beneficial effects: they are known to be immunomodulatory, antifibrotic and microbiocidal. MSCs have demonstrated tissue regenerative capacities as documented in preclinical studies, e.g., improved function of diseased lungs.
Aim: The aim of the current study is to evaluate the effect of MSCs administered to aspiration damaged lungs during ex vivo lung perfusion (EVLP) and to recipients post transplantation with a focus on their capacity to improve damaged lungs and to decrease the incidence of PGD at 72h post transplantation.
Materials and Methods: Lung injury was induced in 12 donor pigs using gastric content with a pH of 2. The donor-recipient pairs were randomized to receive MSCs or placebo treatment during the beginning of EVLP and post LTx. Lungs were treated with EVLP for 4 hours followed by a left lung transplantation. The recipient was kept under anesthesia and closely monitored for three days post LTx. In the final phase of the experimental setup an isolated assessment of the transplanted lung was achieved following a right pneumonectomy. Treatment effects were assessed by clinically relevant parameters, including PaO2/FiO2 ratio, pulmonary vascular resistance (PVR), and lactate, further by histopathological changes, immune cell counts in peripheral blood and cytokine and chemokine levels in plasma and bronchoalveolar lavage fluid during the course of the experiment.
Results:The lung functionality as evaluated by the PaO2/FiO2 ratios showed significantly increased lung function in treated recipients compared to both the non-treated recipients and to all lungs at the time of confirmed ALI. A tendency of higher PVR was seen among the non-treated recipients however, not significantly. Lactate was unchanged in both groups. Lung injury scores were also reduced in the treated group as compared to the non-treated group and to the lungs after lung injury was induced. On the third day of follow-up of the recipients, all recipients in the treatment group had PGD grade 0, while the non-treated group consisted of one recipient with grade 0, three with grade 2 and two with grade 3.
Conclusion: MSC treatment emerges as a promising therapeutic option for restoring injured donor lungs for reacceptance into the donor pool and decreasing the incidence of PGD.
