Adult stem cells underlying lung regeneration

Abstract

Despite the massive toll in human suffering imparted by degenerative lung disease, including COPD, idiopathic pulmonary fibrosis and ARDS, the scientific community has been surprisingly agnostic regarding the potential of lung tissue, and in particular the alveoli, to regenerate. However, there is circumstantial evidence in humans and direct evidence in mice that ARDS triggers robust regeneration of lung tissue rather than irreversible fibrosis. The stem cells responsible for this remarkable regenerative process has garnered tremendous attention, most recently yielding a defined set of cloned human airway stem cells marked by p63 expression but with distinct commitment to differentiated cell types typical of the upper or lower airways, the latter of which include alveoli-like structures in vitro and in vivo. These recent advances in lung regeneration and distal airway stem cells and the potential of associated soluble factors in regeneration must be harnessed for therapeutic options in chronic lung disease.

Figure 1

Association of Krt5 pods with influenza-damaged lung. Left: Histological appearance of lung at 21 d post-influenza showing normal appearing tissue together with regions of damage and dense immune cell infiltrates. Right: Krt5 immunohistochemistry revealing Krt5 pods in interstitial regions marked by less dense infiltrates.

Figure 2

Expression of alveolar antigen in Krt5 pods at 15 d post-infection. Left: Distribution of antigen recognized by 1H8 monoclonal antibody in normal lung. Right: Co-staining of Krt5 and 1H8 monoclonal antibody in lung at 15 d post-influenza infection.

Figure 3

Schematic for development of stem cell pedigrees. Colonies derived from single cells are isolated and expanded for multiple, parallel analyses.

Figure 4

TASCs show dual commitment to airway and squamous fates. Left: Single colony of defined pedigree of TASCs stained with antibodies to p63. Right: Alternative fate commitment revealed by 3D growth in Matrigel, where squamous metaplasia is revealed, vs. air-liquid interface cultures, where airway epithelia predominates.

Figure 5

Differential fate commitment of TASCs and DASCs. Left: TASCs and DASCs colonies stained with anti-p63 appear indistinguishable and show gene expression differences in only 100–300 genes of 17,000 hybridizing transcripts as depicted in Venn diagram. Right: TASCs differentiating to airway epithelia in air-liquid interface culture, whereas DASCs differentiate to unilaminar, alveoli-like structures in 3D Matrigel culture.