Evidence for lung repair and regeneration in humans: key stem cells and therapeutic functions of fibroblast growth factors

Regeneration carries the idea of regrowing partially or completely a missing organ.Repair,on the other hand,allows restoring the function of an existing but failing organ.The recognition that human lungs can both repair and regenerate is quite novel,the concept has not been widely used to treat patients.We present evidence that the human adult lung does repair and regenerate and introduce different ways to harness this power.Various types of lung stem cells are capable of proliferating and differentiating upon injury driving the repair/regeneration process.Injury models,primarily in mice,combined with lineage tracing studies,have allowed the identification of these important cells.Some of these cells,such as basal cells,broncho-alveolar stem cells,and alveolar type 2 cells,rely on fibroblast growth factor (FGF) signaling for their survival,proliferation and/or differentiation.While preclinical studies have shown the therapeutic benefits of FGFs,a recent clinical trial for acute respiratory distress syndrome (ARDS) using intravenous injection of FGF7 did not report the expected beneficial effects.We discuss the potential reasons for these negative results and propose the rationale for new approaches for future clinical trials,such as delivery of FGFs to the damaged lungs through efficient inhalation systems,which may be more promising than systemic exposure to FGFs.While this change in the administration route presents a challenge,the therapeutic promises displayed by FGFs are worth the effort.

Understanding myofibroblast origin in the fibrotic lung

Idiopathic pulmonary fibrosis(IPF)is characterized by accumulation of myofibroblasts(MYFs)and extracellular matrix components,which leads to severe distortion and scarring of the gas exchange units of the lung,the alveoli,and ultimately respiratory failure.Fibrosis-associated MYFs are therefore widely regarded as the culprits that compromise the architectural makeup of the lung in fibrotic disease.During the past decade,the cellular source of MYFs has been intensely investigated.The rationale for such studies is that identifying the origin of these cells might help identify novel therapeutic targets and candidates to treat IPF patients.Recent advances in basic and translational research employing lineage tracing and multi-omics approaches have helped address the identity of MYF precursors,highlight the underlying heterogeneity,and to a less extent investigate MYF fate during fibrosis resolution.In this review,we discuss the current understanding of such important aspects of MYF biology as well as recent developments in the treatment of IPF.