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Post‐pneumonectomy Compensatory Lung Growth is Associated with Spatially Dependent Blood‐Borne Myofibroblast Recruitment
Author(s) -
Ysasi Alexandra,
Gibney Barry,
Chamoto Kenji,
Valenzuela Cristian,
Bennett Robert,
Wagner Willi,
Ackermann Maximilian,
Tsuda Akira,
Mentzer Steven
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1042.2
Subject(s) - pneumonectomy , lung , population , compensatory growth (organ) , pathology , myofibroblast , lung volumes , biology , andrology , chemistry , medicine , endocrinology , fibrosis , kidney , environmental health
In several mammalian species, including rodents and humans, removing one lung results in the compensatory growth of the remaining lung. Following left pneumonectomy in mice, lung growth involves an increase in lung volume (46.03% in 14 days, p<0.01), weight (45.56% in 14 days, p<0.01) and cell number (46.77% in 14 days, p<0.05). An increase in lung volume with no change in mean linear intercept (59.70 +/− 2.00 μm) yields an increase in surface area (29.88 × 10 3 cm 2 /kg at day14, p<0.05), indicating an increase in the number of alveoli. However, histologic clues to the mechanism of lung growth are lacking. Post‐pneumonectomy lung growth is rarely associated with the cellular aggregates typically associated with tissue repair. To investigate the possibility of a distributed, blood‐borne delivery of regenerative cells, we studied a parabiotic wild‐type (WT) green fluorescent protein (GFP) cross‐circulation model. After WT pneumonectomy, the remaining WT lung was studied with whole‐lobe serial section fluorescence histology and automated multi‐wavelength cell scoring. Analysis of whole‐lobe image stacks demonstrated that 9.30% of all lung cells are derived from the peripheral blood (GFP+), with this number increasing 64.70% within 14 days of pneumonectomy (p<0.05). Within this GFP+ population, cells co‐expressing the myofibroblast marker cytoplasmic alpha smooth muscle actin (αSMA) increased more than 4‐fold within 14 days of pneumonectomy (4.17% of total cells, p<0.01). These GFP+/αSMA+ cells migrated from heterogeneous subpleural regions of the lung starting 3 days after pneumonectomy (average distance from the pleura=321.48μm). The blood‐derived cells migrated into the septa of centrally located remodeling alveoli by day 14 (average distance from the pleura=1345.12μm, p<0.01). In contrast, other cell types such as GFP+/CD34+ endothelial progenitor cells did not display this spatial autocorrelation. When compared to finite element analyses of post‐pneumonectomy lung deformation, the heterogeneous subpleural regions with myofibroblast recruitment correlated with areas of maximal lung stretch. Finally, morphometry of the migrating myofibroblasts demonstrated a progressive change in the cell shape factor from round on day 3 (average shape factor=0.48), to elongated at day 14 (average shape factor= 0.38, p<0.01)—findings that suggest cell integration into the architecture of the remodeling lung. We conclude that the selective recruitment and directed migration of blood‐borne myofibroblasts is a fundamental mechanism of lung repair and regeneration.