Lung regeneration: a tale of mice and men

Abstract

The respiratory system is the main site of gas exchange with the external environment in complex terrestrial animals. Within the trachea and lungs are multiple different tissue niches each consisting of a myriad of cells types with critical roles in air conduction, gas exchange, providing important niche specific cell-cell interactions, connection to the cardiovascular system, and immune surveillance. How the respiratory system responds to external insults and executes the appropriate regenerative response remains challenging to study given the plethora of cell and tissue interactions for this to occur properly. This review will examine the various cell types and tissue niches found within the respiratory system and provide a comparison between mouse and human lungs and trachea to highlight important similarities and differences. Defining the critical gaps in knowledge in human lung and tracheal regeneration is critical for future development of therapies directed towards respiratory diseases.

Keywords: Endothelium; Epithelium; Human; Lung regeneration; Mesenchyme; Niche.

Fig. 1.

Anatomical differences between the mouse and human respiratory system. Mice have far fewer generations of branched airways than human lungs. The bronchial blood supply extends far more distally into the peripheral lung in humans than mice, where is only supplies the trachea. At the terminal end of the airways, the human lung contains respiratory bronchioles which consist of the most distal airways interspersed with alveoli. The murine conducting airways terminate into alveolar sacs.

Fig. 2.

The gas exchange niche: the lung alveolus. (A) Intermediate bronchioles in mice end in the alveolar region. In the mouse lung this transition is referred to as the bronch-oalveolar duct junction, the niche for the broanchoalveolar stem cells or BASC, as is depicted in this image. This has not been found in the human lung; in humans there are additional generations of airways referred to as respiratory bronchioles (not depicted), which replace this transition between intermediate bronchioles and alveolus. (B) Both human and mouse alveoli are lined with AT1 and AT2 cells including a subset of AT2 cells called AEPs. Multiple mesenchymal cell types are found in the alveolar niche including the mesenchymal alveolar niche cell, which express Lgr5, and the Axin2+ myofibrogenic progenitor cell. (C) Table of cell types found in human/mouse alveoli.

Fig. 3.

Differences between the architecture and cellular composition of human and mouse airways. (A) The mouse and human trachea as well as the large intrapulmonary airways of the human contain a complex airway epithelia as well as glandular structures callled submucosal glands. (B) Intermediate human airways contain a basal cell layer and significant numbers of goblet cells whereas the mouse intermediate airways (C) lack extensive numbers of goblet cells and also lack basal cells. (C) The mouse intermediate airway connect directly with the alveolar region. (D) Humans have respiratory bronchioles which contain poorly characterized “low cuboidal epithelial cells”. Respiratory bronchioles connect in an interspersed manner with multiple alveolar units before ending directly into the peripheral alveolar space. (E) Table of cell types found in human and/or mouse airways.