Lung regeneration: mechanisms, applications and emerging stem cell populations

Abstract

Recent studies have shown that the respiratory system has an extensive ability to respond to injury and regenerate lost or damaged cells. The unperturbed adult lung is remarkably quiescent, but after insult or injury progenitor populations can be activated or remaining cells can re-enter the cell cycle. Techniques including cell-lineage tracing and transcriptome analysis have provided novel and exciting insights into how the lungs and trachea regenerate in response to injury and have allowed the identification of pathways important in lung development and regeneration. These studies are now informing approaches for modulating the pathways that may promote endogenous regeneration as well as the generation of exogenous lung cell lineages from pluripotent stem cells. The emerging advances, highlighted in this Review, are providing new techniques and assays for basic mechanistic studies as well as generating new model systems for human disease and strategies for cell replacement.

Plasticity in the lung: making and breaking cell identity

“…These cells possess enormous reparative potential, which is unleashed following injury. However, recent studies have pointed to alternative facultative sources of cells that participate in repairing the damaged lung (Herriges and Morrisey, 2014;Hogan et al, 2014;Kotton and Morrisey, 2014). In this Review, we discuss our current and incomplete understanding of the diversity of epithelial stem and progenitor cells in the lung, as well as the surprising cellular plasticity of certain differentiated cells.…”

Stem cells and Bronchopulmonary Dysplasia - The five questions: Which cells, when, in which dose, to which patients via which route?

“…Thus, a direct interaction with injured cells may potentiate therapeutic efficacy and in the case of CM or CM products multiple treatments may be appropriate [35,63]. The concept of MSCs sensing, integrating, and responding to the surrounding is intriguing as MSCs potential to replace injured cells is not proven and a matter of constant debate [64][65][66]. For example, MSCs improve myocardial infarction without permanent replacement after intravenous application [67].…”

Exposure Memory and Lung Regeneration

“…Advances in understanding growth factor signaling in lung development portend considerable advances in lung regeneration (14). Elucidation of the specific signaling events in the epithelial differentiation, vascularization, mesenchyme, and immune development will enable targeted activation and switching in cell and molecular phenotypes.…”

“…Proximal to distal polarity develops through additional cytokine and growth factor signaling, with extensive and reiterative branching of the endoderm and mulitpotent progenitor cells giving rise to multiple epithelial lineages. Considerable progress has been made in defining the signaling pathways and mapping cell lineages (14).…”