Mesenchymal Stem Cell Pretreatment of Non-Heart-Beating-Donors in Experimental Lung Transplantation – Initial Experience

Abstract

Purpose To expand the limited donor pool, lung retrieval from non-heart-beating donors (NHBD) was introduced clinically. However, primary graft dysfunction with surfactant inactivation due to I/R-injury is a major cause of early mortality. Furthermore, donor-derived mesenchymal stem cell (MSC) expansion and fibrotic differentiation in the allograft results in deleterious bronchiolitis obliterans syndrome (BOS). Therefore, pretreatment of NHBD with recipient-specific bone-marrow-(BM)-derived MSC might improve postischemic surfactant function and reduce incidence of BOS by numerous parakrine, immunomodulating and tissue-remodeling properties especially on type-II-pneumocytes. Methods and Materials Asystolic pigs (n=5/group) were ventilated for 3h of warm ischemia (groups 1-3). 50x10 6 BM-MSC, each, were administered in pulmonary artery (group 2) or nebulized endobronchially (group 3) prior to preservation. After left-lung-transplantation grafts were reperfused for 4h. Hemodynamics (PVR), pO 2 /FiO 2 and dynamic compliance (DLC) were compared to lungs without pretreatment (group 1) and sham-controls (Sham). To prove and localize the Texas-red labelled MSCs in the lung, PCR was performed and cryosections were counter-stained with WGA and DAPI. Intra-alveolar edema was determined sterologically. Statistics comprised ANOVA with repeated measurements. Results PVR and DLC were superior in endobronchially pretreated MSC lungs as compared to endovascular MSC application and lungs without pretreatment. Oxygenation was worst after endovascular pretreatment. Stereology revealed low intrapulmonary edema in all groups (p>0.05), successful MSC application was proven by PCR. MSC were localized in alveola and capillaries. Conclusions Intrapulmonary deposition of BM-MSC in NHBD is feasible, but only endobronchial application optimizes DLC and PVR postoperatively. Due to immunomodulatory and paracrine effects on epithelial restitution, autologous-BM-MSC-based donor pretreatment for prevention or attenuation of limiting BOS is very promising in LTx.