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