Resident Tissue-Specific Mesenchymal Progenitor Cells Contribute to Fibrogenesis in Human Lung Allografts

Abstract

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

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

“…As a primary effector cell of fibrogenesis, mesenchymal cells play a key role in CLAD arising from OB or parenchymal fibrosis. While mesenchymal cells orchestrating fibrosis can potentially be derived from various sources, the mesenchymal population in the transplanted lung retains its donor origin and these graft-derived cells appear to be the predominant contributors to OB lesions (98,(128)(129)(130)(131). Investigation of fibrotic lesions in the HTT model have shown them to be derived from the recipients (132).…”

“…While in vitro models of OB have utility in showing how individual populations, such as bronchial epithelial cells, mesenchymal stromal cells, and airway smooth muscle cells, may contribute to disease (95)(96)(97)(98), animal models can provide a window into the events from transplant to the final fibrotic obliteration of small airways and is key to investigating the pathogenesis of OB and conducting preclinical studies of potential therapeutic interventions. Utilized models of post-lung-transplant OB are based on allogeneic lung tissue transplantation with a goal of reproducing fibrotic airway remodeling.…”

CXCL1 Inhibits Airway Smooth Muscle Cell Migration through the Decoy Receptor Duffy Antigen Receptor for Chemokines

“…Tissue fibrosis (4), inappropriate angiogenesis (5), cancer cell metastasis (6), and increased airway smooth muscle mass in asthma (7) are a few examples of progressively disproportionate cell migration. Attempts have been made to understand the source of migrating cells (8)(9)(10)(11)(12) with the hope of better understanding the role of migration in diseases such as asthma, where the origins of migrating cells are not known in vivo (13) and, hence, cannot be specifically targeted. However, regardless of the origins of migrating cells, active recruitment of cells from different sites, near or far, is central for disease chronicity and severity (8,14).…”

Stem cell therapy for idiopathic pulmonary fibrosis: How far are we from the bench to the bedside?

“…Except for transplanted MSCs, there are also evidences that lung resident stem/progenitor cells contribute to lung repair and regeneration [10,11,29,30]. Chemicals, cytokines and signaling pathways such as ATRA, KGF, Wnt/beta-catenin signaling pathway regulates the in vivo and in vitro differentiation of stem cells [74][75][76][77]. Further studies are necessitated to activate the regenerative potential of endogenous lung stem cells.…”