Development of allograft rejection continues to be the major determinant of morbidity and mortality post-lung transplantation. We have recently demonstrated that a population of donor-derived mesenchymal stem cells are present in human lung allografts and can be isolated and expanded ex vivo. In this study, we investigated the impact of lung resident mesenchymal stem cells (LR-MSCs), derived from allografts of human lung transplant recipients, on T cell activation in vitro. Similar to bone marrow derived MSCs, LR-MSCs did not express MHC II nor the co-stimulatory molecules CD80 or CD86. In vitro, LR-MSCs profoundly suppressed the proliferative capacity of T cells in response to a mitogenic or an allogeneic stimulus. The immunosuppressive function of LR-MSCs was also noted in absence of direct cell contact, indicating that LR-MSCs mediated their effect predominantly via a soluble mediator. LR-MSCs isolated from lung transplant recipients demonstrated PGE2 secretion at baseline (385 ± 375 pg/ml) which increased in response to IL-1β (1149 ± 1081 pg/ml). Addition of prostaglandin synthesis inhibitors (indomethacin and NS-398) substantially abrogated LR-MSC-mediated immunosuppression, indicating that PGE2 may be one of the major soluble mediators impacting T cell activity. This is the first report to demonstrate that human tissue-derived MSCs isolated from an allogeneic environment, have the potential to mediate immunological responses in vitro.
Fibrotic obliteration of the small airways leading to progressive airflow obstruction, termed bronchiolitis obliterans syndrome (BOS), is the major cause of poor outcomes after lung transplantation. We recently demonstrated that a donor-derived population of multipotent mesenchymal stem cells (MSCs) can be isolated from the bronchoalveolar lavage (BAL) fluid of human lung transplant recipients. Herein, we study the organ specificity of these cells and investigate the role of local mesenchymal progenitors in fibrogenesis after lung transplantation. We demonstrate that human lung allograft-derived MSCs uniquely express embryonic lung mesenchyme-associated transcription factors with a 35,000-fold higher expression of forkhead/winged helix transcription factor forkhead box ( Chronic allograft rejection develops in up to 60% of patients who undergo lung transplantation by 5 years and is the leading cause of poor long-term outcomes after lung transplantation.1 As with other solid organ transplants, chronic allograft rejection in the lung manifests as a fibrotic response to repeated immune and nonimmune insults, leading to narrowing and obliteration of the small airways, a lesion termed bronchiolitis obliterans (BO).
2Subepithelial and/or intraluminal infiltration by myofibroblasts, differentiated mesenchymal cells with augmented collagen secretory and contractile functions, 3 is noted in human biopsy specimens that demonstrate BO.4 BO presents clinically as an obstructive ventilatory defect termed BO syndrome (BOS).5 BOS is the major cause of graft failure and long-term mortality, with no effective treatment options. 6,7 Understanding the origin of effector myofibroblasts in fibrotic lesions of BO is critical for therapeutic targeting of mechanisms of cell recruitment/differentiation.One potential source of mesenchymal cells participating in this disorganized repair response is the mesenchymal progenitors residing in the graft. The embryonic lung mesenchyme is derived from splanchnic mesoderm during orSupported by grants (R01DK082481 to P.H.K.; RO1HL094311 to M.P.-G.; RO1HL094622
Rationale: Bronchoalveolar lavage fluid (BAL) from human lung allografts demonstrates the presence of a multipotent mesenchymal stromal cell population. However, the clinical relevance of this novel cellular component of BAL and its association with bronchiolitis obliterans syndrome (BOS), a disease marked by progressive airflow limitation secondary to fibrotic obliteration of the small airways, remains to be determined. Objectives: In this study we investigate the association of number of mesenchymal stromal cells in BAL with development of BOS in human lung transplant recipients. Methods: Mesenchymal colony-forming units (CFUs) were quantitated in a cohort of 405 BAL samples obtained from 162 lung transplant recipients. Poisson generalized estimating equations were used to determine the predictors of BAL mesenchymal CFU count. Measurements and Main Results: Higher CFU counts were noted early post-transplantation; time from transplant to BAL of greater than 3 months predicted 0.4-fold lower CFU counts (P 5 0.0001). BOS diagnosis less than or equal to 365 days before BAL was associated with a 2.11-fold higher CFU count (P 5 0.02). There were 2.62-and 2.70-fold higher CFU counts noted in the presence of histologic diagnosis of bronchiolitis obliterans (P 5 0.05) and organizing pneumonia (0.0003), respectively. In BAL samples obtained from BOS-free patients greater than 6 months post-transplantation (n 5 173), higher mesenchymal CFU counts (>10) significantly predicted BOS onset in both univariate (hazard ratio, 5.61; 95% CI, 3.03-10.38; P , 0.0001) and multivariate (hazard ratio, 5.02; 95% CI, 2.40-10.51; P , 0.0001) Cox regression analysis. Conclusions: Measurement of mesenchymal CFUs in the BAL provides predictive information regarding future BOS onset.
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