Endogenous Distal Airway Progenitor Cells, Lung Mechanics, and Disproportionate Lobar Growth Following Long-Term Postpneumonectomy in Mice

Abstract

Utilizing a model of post-pneumonectomy (PNY) compensatory lung growth in mice, we previously observed an increase in numbers of a putative endogenous distal airway progenitor cell population (CCSPpos/pro-SPCpos cells located at bronchoalveolar duct junctions (BADJ)), at 3, 7, and 14 days after pneumonectomy, returning to baseline at 28 days post-PNY. As the origin of these cells is poorly understood, we evaluated whether bone marrow cells contributed to the pool of these or other cells during prolonged post-PNY lung regrowth. Naïve and sex-mismatched chimeric mice underwent left PNY and were evaluated at 1, 2 and 3 months for numbers of BADJ CCSPpos/pro-SPCpos cells and presence of donor-derived marrow cells engrafted as airway or alveolar epithelium. Non-chimeric mice were also examined at 12 months after PNY for numbers of BADJ CCSPpos/pro-SPCpos cells. Notably, the right accessory lobe (RAL) continued to grow disproportionately over 12 months, a novel finding not previously described. Assessment of lung mechanics demonstrated an increase in lung stiffness following PNY, which significantly diminished over one year, but remained elevated relative to 1 year-old naïve controls. However, the number of CCSPpos/pro-SPCpos BADJ cells ≥1 month following PNY was equivalent to that found in naïve controls even after 12 months of continued RAL growth. Notably, no donor bone marrow-derived cells engrafted as airway or alveolar epithelial cells, including those at the BADJ, up to 3 months after PNY. These studies suggest that lung epithelial cells, including CCSPpos/pro-SPCpos cells, are not replenished from marrow-derived cells during post-PNY lung growth in mice.

Repair and Regeneration of the Respiratory System: Complexity, Plasticity, and Mechanisms of Lung Stem Cell Function

“…New alveolar tissue is preferentially laid down at the periphery of the lung (Foster et al, 2002; Massaro and Massaro, 1993) where mechanical strain of the septa is accentuated due to a relative lack of bronchovascular support (Yilmaz et al, 2011). Evidence exists for proliferation and changes in the behavior of multiple cell lineages in the PNX model, including bronchiolar cells, AEC2s, endothelial cells and Pdgfrα+ stromal cells (Chen et al, 2012b; Eisenhauer et al, 2013; Hoffman et al, 2010; Hsia, 2004; Thane et al, 2014; Voswinckel et al, 2004). …”

Lung regeneration: mechanisms, applications and emerging stem cell populations

“…This postnatal lung-growth model has been optimized in a variety of species, including rat, mouse and dog 84–87 , and was recently demonstrated to occur in a selected human case 88 . Most studies so far have suggested that lung growth after PNX involves rapid, coordinated proliferation of a broad diversity of lung lineages, including most epithelial and endothelial cells, and only a minority of reports suggest that specialized rare stem or progenitor cells, such as putative BASCs, have a specialized or initiating role in the process 85,89,90 . In marked contrast, when a highly selective injury model, such as naphthalene-induced ablation of mature club cells, is used, a rare subset of epithelial cells, variant club cells, that have survived the injury then reconstitute the airway in a process that shows features of classically defined facultative progenitors, including reactivation of proliferation.…”

Hematopoietic and Mesenchymal Stem Cells for the Treatment of Chronic Respiratory Diseases: Role of Plasticity and Heterogeneity

“…On the other hand, one recent study using a model of postpneumonectomy with compensatory lung growth in mice found that no donor BM-derived cells engrafted as airway or alveolar epithelial cells at the bronchoalveolar duct junction, a site where putative progenitor cells have been found [29]. The use of different lung injury models may be the reason for these divergent results, suggesting that the contribution of BM-derived cells to the endogenous pool of lung progenitor populations may vary with the lung disease, the type of injury and the repair process.…”