Defective alveolar regeneration in emphysema: identifying dysfunctional cellular crosstalk and novel therapeutic opportunities for tissue repair.

A key problem underlying COPD is the severe and irreversible lung tissue damage (emphysema) as consequence of hampered repair. Available therapies do not halt or reverse disease progression, and novel therapeutic strategies aimed at tissue repair are urgently awaited. To address this unmet need, ongoing research aims to provide insight into the cellular/molecular mechanisms underpinning defective lung repair in emphysema. Healthy lungs possess an intrinsic regenerative capacity based on alveolar epithelial progenitor cells that reside in their niche, which is composed of a supporting extracellular matrix, stromal cells and immune cells. While this stromal niche is vital for appropriate regenerative responses, emerging studies show that interactions within the stromal niche are defective in COPD, hampering alveolar repair. This review addresses the novel concept that restoring disrupted interactions within the diseased stromal niche may lead to repair of damaged lung tissue in COPD. The unavailability of successful strategies to achieve stromal health and support lung tissue repair may be due to an incomplete insight into the complex interactions within the alveolus. Moreover, inadequate delivery methods, with uncontrolled release and rapid clearance of regenerative compounds and therapeutic cells, contribute to the failed translation of novel findings into effective strategies. This review provides an overview of the current state of the field, including novel insights into the defective interactions that have been identified within the alveolar niche in COPD. Moreover, advanced models to study the alveolar niche and innovative strategies to therapeutically target this niche and restore stromal health in COPD are discussed.