The Cellular and Physiological Basis for Lung Repair and Regeneration: Past, Present, and Future

Abstract

The respiratory system, which includes the trachea, airways, and distal alveoli, is a complex multi-cellular organ that intimately links with the cardiovascular system to accomplish gas exchange. In this review and as members of the NIH/NHLBI-supported Progenitor Cell Translational Consortium, we discuss key aspects of lung repair and regeneration. We focus on the cellular compositions within functional niches, cell-cell signaling in homeostatic health, the responses to injury, and new methods to study lung repair and regeneration. We also provide future directions for an improved understanding of the cell biology of the respiratory system, as well as new therapeutic avenues.

Figure 1

Alveolar Cell Lineages Involved in Lung Repair and Regeneration (A) The human distal airways connect with the alveolar niche through a transitional respiratory airway (also called the respiratory bronchiole or RB) region. The RB is lined with a simple but poorly characterized cuboidal epithelium while the more intermediate airways exhibit a pseudostratified epithelium containing secretory, goblet, and ciliated cells that may exhibit as yet distinct heterogeneity. Of note, basal cells are found in human intermediate and respiratory airways. (B) Mice do not have respiratory bronchioles and transition from the intermediate airways, which exhibit a pseudostratified nature but lack basal cells, into the alveolar region. The distal BADJ region in the mouse lung, which is not found in the human lung, contains the BASC population. The architecture and cell lineages found in both the mouse and human lungs are very similar and contain both AT1 and AT2 epithelial lineages as well as various mesenchymal lineages and vascular endothelial cells. (C) The various cell types found in the distal airways and alveolus of the human and mouse lung.

Figure 2

Airway Cell Lineages Involved in Lung Repair and Regeneration Structure of the pseudostratified large airways and trachea of the mouse lung showing submucosal glands which are lined with both myoepithelial cells and other luminal secretory lineages. The smaller airways of the mouse lung contain various luminal secretory and ciliated epithelial lineages as shown. Some of these including the BASCs and the H2-K1^high secretory cell subtypes have been proposed to generate alveolar epithelium after severe injury.

Figure 3

A Schematic of the Directed Differentiation of hiPSCs to Lung Epithelial Cells The key signaling factors and the main stages of the in vitro derivation of lung epithelial cells are provided. Following lung specification, late withdrawal of CHIR gives rise to mature AT2 cells (dark red). Early withdrawal of CHIR gives rise to airway progenitors (light blue) or a mixture of mature airway cells (dark blue) and AT2 cells, depending on the protocol used.

Figure 4

Bioengineering Approach to the Recovery of Injured Lungs Three methodological advances have been combined to enable functional recovery of lungs damaged by cold ischemia and gastric aspiration. (A) Multiday normothermic support of extracorporeal lungs using cross-circulation with a recipient in a clinically relevant swine model. (B) Targeted treatment of the most injured lung regions, with the preservation of the surrounding lung tissue, through the local removal of damaged cells and their replacement with healthy therapeutic cells. (C) Removal of injured lung epithelium from the targeted regions of the lung, with preservation of the basement membranes and the vascular compartment.

Figure 5

Macroscopic Appearance of Injured Lungs over 36 h on Cross-circulation (A) Gross appearance of ischemic lungs and the corresponding thermal images for ischemic lungs damaged by gastric aspiration. The increase in heat exchange indicates improved vascular perfusion. (B) Pressure-volume loops during ischemic recovery. The increase volume and decreased pressure indicates improved pulmonary function to the level necessary for lung transplant (reproduced with permission from O’Neill et al., 2017).