title: Treatment with placenta-derived mesenchymal stem cells mitigates development of bronchiolitis obliterans in a murine model.
abstract: OBJECTIVE
  Bone marrow-derived mesenchymal stem cells (MSCs) have shown therapeutic potential in acute lung injury. Recently, placenta-derived human mesenchymal stem cells (PMSCs) have shown similarities with bone marrow-derived MSCs in terms of regenerative capabilities and immunogenicity. This study investigates the hypothesis that treatment with PMSCs reduces the development of bronchiolitis obliterans in a murine heterotopic tracheal transplant model.
  
  
  METHODS
  A murine heterotopic tracheal transplant model was used to study the continuum from acute to chronic rejection. In the treatment groups, PMSCs or PMSC-conditioned medium (PMSCCM) were injected either locally or intratracheally into the allograft. Phosphate-buffered saline (PBS) or blank medium was injected in the control groups. Tracheal luminal obliteration was assessed on sections stained with hematoxylin and eosin. Infiltration of inflammatory and immune cells and epithelial progenitor cells was assessed using immunohistochemistry and densitometric analysis.
  
  
  RESULTS
  Compared with injection of PBS, local injection of PMSCs significantly reduced luminal obliteration at 28 days after transplantation (P = .015). Intratracheal injection of PMSCs showed similar results to local injection of PMSCs compared with injection of PBS and blank medium (P = .022). Tracheas treated with PMSC/PMSCCM showed protection against the loss of epithelium on day 14, with an increase in P63+CK14+ epithelial progenitor cells and Foxp3+ regulatory T cells. In addition, injection of PMSCs and PMSCCM significantly reduced the number of neutrophils and CD3+ T cells on day 14.
  
  
  CONCLUSIONS
  This study demonstrates that treatment with PMSCs is protective against the development of bronchiolitis obliterans in an heterotopic tracheal transplant model. These results indicate that PMSCs could provide a novel therapeutic option to reduce chronic rejection after lung transplant.
authors.affiliation: Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia Health System, Charlottesville, Va.
authors.forename: Yunge
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia Health System, Charlottesville, Va.
authors.forename: Jacob R
authors.initials: JR
authors.lastname: Gillen
authors.affiliation: Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia Health System, Charlottesville, Va.
authors.forename: David A
authors.initials: DA
authors.lastname: Harris
authors.affiliation: Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia Health System, Charlottesville, Va.
authors.forename: Irving L
authors.initials: IL
authors.lastname: Kron
authors.affiliation: The Vascular and Cardiac Center for Adult Stem Cell Therapy, Indiana University School of Medicine, Indianapolis, Ind.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia Health System, Charlottesville, Va. Electronic address: cll2y@virginia.edu.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Lau
mesh_terms: D000208:Acute Disease; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001989:Bronchiolitis Obliterans / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017252:CD3 Complex / Q000378:metabolism; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D002908:Chronic Disease; D004195:Disease Models, Animal; D018450:Disease Progression; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D053547:Keratin-14 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D010920:Placenta / Q000166:cytology*; D011247:Pregnancy; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D014132:Trachea / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D015415:Biomarkers; D017252:CD3 Complex; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C507540:KRT14 protein, human; D053547:Keratin-14; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins