Advances and challenges in cell-based therapy for lung diseases

Chronic lung diseases remain a leading cause of morbidity and mortality worldwide, yet few therapies restore damaged lung tissue or halt disease progression. Cell-based therapies offer a potential strategy to address this gap by replacing or repairing disease-causing cell populations within the lung. Advances in stem cell biology, gene editing and regenerative medicine across multiple organ systems have established key principles for successful cellular therapies, including the identification of tissue stem/progenitor populations, the control of progenitor cell differentiation ex vivo and the enabling of homing and engraftment of exogenous cells within host tissues. In the lung, growing insight into epithelial regeneration, particularly the roles of airway basal cells and alveolar type 2 cells as resident progenitors, has provided a biological rationale for cell replacement approaches. Recent preclinical studies demonstrate that transplanted epithelial progenitors can engraft, differentiate and contribute to functional airway or alveolar repair in animal models. Progress in macrophage transplantation for pulmonary alveolar proteinosis illustrates how disease-specific cellular therapies may translate toward clinical application. However, significant challenges remain, including efficient cell delivery to the lung, enhancing cell retention and performing safe niche preconditioning to permit engraftment. In this review, we summarize the biological foundations of lung regeneration, recent advances in lung cell-based therapies and emerging strategies for delivery, engraftment and translation to the clinic. Together, these developments suggest that regenerative cell therapies may ultimately provide disease-modifying treatments for both genetic and acquired lung diseases.