Mesenchymal stromal cell turnover in the normal adult lung revisited

Abstract

neg CD31 neg Sca-1 pos lung cells following long-term feeding of BrdU to mice in their drinking water reveals that lung mesenchymal stromal cells cycle continuously throughout life. Analysis of BrdU incorporation during long-term feeding and during chasing (delabeling) following replacement of BrdU-water with normal water shows that the CD45 neg CD31 neg Sca-1 pos lung mesenchymal stromal cell compartment turns over at a rate of ϳ2.26% per day with a time to half-cycled of 44 days, an estimated cell proliferation rate of 0.004/ day, and a cell death rate of 0.018/day. lung mesenchymal stromal cells; bromodeoxyuridine; cell cycling; cell turnover IN A BRIEF REVIEW PUBLISHED in 1983, documenting information about cell kinetics and cell turnover in the lung, Bowden (7) pertinently stated that "the study of cellular kinetics in the normal lung is prerequisite to an understanding of the pulmonary responses to injury and of the processes that initiate and control cellular regeneration and repair." It is therefore surprising that, despite the burgeoning interest in lung regeneration and repair in recent years, the field largely continues to rely on estimates of lung cell cycling and turnover in the steady state that predate that review (23,44).Those studies employed classical autoradiographic techniques and histomorphometry (17,47) to analyze the cell kinetics of often ill-defined cell populations in tracheal, bronchiolar, and alveolar regions of the lung, mostly in neonatal and young animals. They concluded that adult mouse lung bronchiolar and alveolar epithelial cell lineages turned over at a rate of no more than 1% per day in the steady state (7,13,23,44,45). More recent studies measuring bromodeoxyuridine (BrdU) incorporation in airway and alveolar epithelial cells by flow cytometry (42,46) or immunohistological analysis (38) are in broad agreement with this estimate. Analysis of genetically engineered mice has revealed that terminally differentiated ciliated airway epithelial cells are especially long lived, having an average half-life of 17 mo (37). Consequently, it is generally accepted that the adult lung epithelium is mitotically quiescent in the absence of injury (11,17,43) and that the very low basal rate of lung epithelial cell proliferation in the steady state is sufficient to account for replacement of airway and alveolar epithelial cells damaged by normal wear and tear.By comparison, little is known about the cell kinetic status of adult lung mesenchymal stromal cells in the steady state. Early studies reviewed by Kauffman (23) and by Evans and Shami (17) showed that the labeling index of lung interstitial fibroblasts in situ increased sharply to levels up to 8 -10 times higher than that of juxtaposed epithelial cells during perinatal lung growth and alveolar septation and then rapidly declined. Recent analysis of lung regeneration in adult mice postpneumonectomy also reveals a rapid but transient increase in the proliferative activity of lung mesenchymal stromal cells in the days immediately followin...