Cellular kinetics and modeling of bronchioalveolar stem cell response during lung regeneration

Abstract

Organ regeneration in mammals is hypothesized to require a functional pool of stem or progenitor cells, but the role of these cells in lung regeneration is unknown. Whereas postnatal regeneration of alveolar tissue has been attributed to type II alveolar epithelial cells (AECII), we reasoned that bronchioalveolar stem cells (BASCs) have the potential to contribute substantially to this process. To test this hypothesis, unilateral pneumonectomy (PNX) was performed on adult female C57/BL6 mice to stimulate compensatory lung regrowth. The density of BASCs and AECII, and morphometric and physiological measurements, were recorded on days 1, 3, 7, 14, 28, and 45 after surgery. Vital capacity was restored by day 7 after PNX. BASC numbers increased by day 3, peaked to 220% of controls (P<0.05) by day 14, and then returned to baseline after active lung regrowth was complete, whereas AECII cell densities increased to 124% of baseline (N/S). Proliferation studies revealed significant BrdU uptake in BASCs and AECII within the first 7 days after PNX. Quantitative analysis using a systems biology model was used to evaluate the potential contribution of BASCs and AECII. The model demonstrated that BASC proliferation and differentiation contributes between 0 and 25% of compensatory alveolar epithelial (type I and II cell) regrowth, demonstrating that regeneration requires a substantial contribution from AECII. The observed cell kinetic profiles can be reconciled using a dual-compartment (BASC and AECII) proliferation model assuming a linear hierarchy of BASCs, AECII, and AECI cells to achieve lung regrowth.

The three R’s of lung health and disease: repair, remodeling, and regeneration

“…The pneumonectomy model of lung reduction and regrowth in the mouse produces an extensive activation of cell proliferation that leads to restoration of pulmonary function, primarily through global cell proliferative responses and proportional regrowth of the remaining lobes of the lung (71)(72)(73)(74)(75)(76)(77). This process is likely similar to what occurs in the liver, in which extensive cellular loss results in regrowth almost solely due to proliferation of remaining cell populations, including hepatocytes (78).…”

Type IV collagen alpha chains of the basement membrane in the rat bronchioalveolar transitional segment

“…The CC10-positive/SP-C-positive cells are suggested to be bronchioalveolar stem cells (BASCs) (Kim et al, 2005), which self-renew themselves, and give rise to Clara cells, AT2 cells, or AT1 cells (either directly or via BASC-derived AT2 cells) (Giangreco et al, 2002;Kim et al, 2007). Thus, BASCs play an important role in both the maintenance and repair of bronchiolar and alveolar cells (Nolen-Walston et al, 2008). We presume that the BASCs, producing only the [ 1(IV)]2 2(IV) molecule in order to self-renew and self-maintain, obtain the ability to produce the 3(IV) 4(IV) 5(IV) or [ 5(IV)]2 6(IV) molecule prior to the differentiation to bronchiolar or alveolar epithelial cells, respectively.…”

Compensatory Lung Growth After Pneumonectomy

“…Bronchoalveolar stem cells (BASC) have also been implicated in CLG. Their proliferation and differentiation into alveolar epithelial cells type II and I, contribute between 0-25% to the regenerative lung growth process (Nolen-Walston, et al, 2008).…”