title: Mesenchymal stem cell pretreatment of non-heart-beating-donors in experimental lung transplantation.
abstract: BACKGROUND
  Lung transplantation (LTx) is still limited by organ shortage. To expand the donor pool, lung retrieval from non-heart-beating donors (NHBD) was introduced into clinical practice recently. However, primary graft dysfunction with inactivation of endogenous surfactant due to ischemia/reperfusion-injury is a major cause of early mortality. Furthermore, donor-derived human mesenchymal stem cell (hMSC) expansion and fibrotic differentiation in the allograft results in bronchiolitis obliterans syndrome (BOS), a leading cause of post-LTx long-term mortality. Therefore, pretreatment of NHBD with recipient-specific bone-marrow-(BM)-derived hMSC might have the potential to both improve the postischemic allograft function and influence the long-term development of BOS by the numerous paracrine, immunomodulating and tissue-remodeling properties especially on type-II-pneumocytes of hMSC.
  
  
  METHODS
  Asystolic pigs (n = 5/group) were ventilated for 3 h of warm ischemia (groups 2-4). 50x106 mesenchymal-stem-cells (MSC) were administered in the pulmonary artery (group 3) or nebulized endobronchially (group 4) before lung preservation. Following left-lung-transplantation, grafts were reperfused, pulmonary-vascular-resistance (PVR), oxygenation and dynamic-lung-compliance (DLC) were monitored and compared to control-lungs (group 2) and sham-controls (group 1). To prove and localize hMSC in the lung, cryosections were counter-stained. Intra-alveolar edema was determined stereologically. Statistics comprised ANOVA with repeated measurements.
  
  
  RESULTS
  Oxygenation (p = 0.001) and PVR (p = 0.009) following endovascular application of hMSC were significantly inferior compared to Sham controls, whereas DLC was significantly higher in endobronchially pretreated lungs (p = 0.045) with overall sham-comparable outcome regarding oxygenation and PVR. Stereology revealed low intrapulmonary edema in all groups (p > 0.05). In cryosections of both unreperfused and reperfused grafts, hMSC were localized in vessels of alveolar septa (endovascular application) and alveolar lumen (endobronchial application), respectively.
  
  
  CONCLUSIONS
  Preischemic deposition of hMSC in donor lungs is feasible and effective, and endobronchial application is associated with significantly better DLC as compared to sham controls. In contrast, transvascular hMSC delivery results in inferior oxygenation and PVR. In the long term perspective, due to immunomodulatory, paracrine and tissue-remodeling effects on epithelial and endothelial restitution, an endobronchial NHBD allograft-pretreatment with autologous mesenchymal-stem-cells to attenuate limiting bronchiolitis-obliterans-syndrome in the long-term perspective might be promising in clinical lung transplantation. Subsequent work with chronic experiments is initiated to further elucidate this important field.
authors.affiliation: Department of Cardiothoracic Surgery, Heart Center, University of Cologne, Kerpener Strasse 61, Cologne, 50924, Germany. Th.Wittwer-MD@t-online.de.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Wittwer
authors.forename: Parwis
authors.initials: P
authors.lastname: Rahmanian
authors.forename: Yeong-Hoon
authors.initials: YH
authors.lastname: Choi
authors.forename: Mohamed
authors.initials: M
authors.lastname: Zeriouh
authors.forename: Samira
authors.initials: S
authors.lastname: Karavidic
authors.forename: Klaus
authors.initials: K
authors.lastname: Neef
authors.forename: Astrid
authors.initials: A
authors.lastname: Christmann
authors.forename: Tanja
authors.initials: T
authors.lastname: Piatkowski
authors.forename: Anke
authors.initials: A
authors.lastname: Schnapper
authors.forename: Matthias
authors.initials: M
authors.lastname: Ochs
authors.forename: Christian
authors.initials: C
authors.lastname: Mühlfeld
authors.forename: Thorsten
authors.initials: T
authors.lastname: Wahlers
mesh_terms: D000818:Animals; D001989:Bronchiolitis Obliterans / Q000209:etiology / Q000517:prevention & control*; D005260:Female; D006323:Heart Arrest; D006801:Humans; D016040:Lung Transplantation; D045164:Mesenchymal Stem Cell Transplantation; D011183:Postoperative Complications / Q000517:prevention & control*; D055031:Primary Graft Dysfunction / Q000517:prevention & control*; D011897:Random Allocation; D015427:Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D034421:Sus scrofa; D014019:Tissue Donors; D020858:Tissue and Organ Harvesting / Q000379:methods*; D016896:Treatment Outcome