Demise of lung transplants: exposing critical gaps in understanding lung stem cells

Lung transplantation is the only potentially curative therapy for end-stage chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and cystic fibrosis (CF), which together claim the lives of 150,000 patients each year in the USA (1). Yet less than 2,000 of these procedures are performed each year in the US due to donor availability, the need of specialized surgical and medical teams, and the overall unit costs that are approaching one million dollars. A further drag on this option is the high rates of lethal obliterative bronchiolitis (OB) appearing in these patients across centers (2). This vexing phenomenon largely accounts for low 5-year survival rate of lung transplants relative to other organ transplants, challenges our understanding of the pathophysiology OB, reveals enormous gaps in our knowledge of regenerative processes in the lung, and may ultimately force a reevaluation of strategies for addressing chronic lung disease. OB itself has features typical of organ rejection including inflammation and peribronchiolar and perivascular fibrosis, and ultimately results in small airway occlusion (2-4). However, the lung parenchyma is surprisingly spared in transplant-associated OB, arguing against a generalized allotypic response and perhaps a more specific response to the very cells responsible for the regenerative maintenance of the small airways. Swatek et al. (5) couple lung transplants between outbred ferrets known to yield an OB indistinguishable from that seen in human recipients with stem cell clonogenic analyses to reveal an altogether new facet of OB pathobiology. While their key findings that p63+/Krt5+ stem cells are progressively depleted from both small and large airways as well as destruction of submucosal glands (SMG) during lung rejection are detailed in the excellent editorial by Smirnova and Eickelberg (6), here we will focus some of the broader implications of Swatek et al. as they pertain to our limited understanding of airway stem cells, the potential of stem cell cloning to fill these gaps, and the very real possibility that such epithelial airway stem cells will form the basis of autologous solutions to the problem of chronic lung disease