Perl Lab
Alveolar Regeneration

Restoring Lung Architecture in Neonatal and Adult Lung Injury

Bronchopulmonary dysplasia (BPD) remains a major complication in premature infants, despite advances in neonatal care such as prenatal corticosteroids, surfactant therapy, and noninvasive ventilation.

While these interventions have reduced the incidence of the classical fibrotic form of BPD, a newer phenotype has emerged. This modern form is characterized by an arrest in alveolar development, rather than by overt fibrosis or emphysema. Understanding and reversing this alveolar simplification is a central challenge in neonatal lung disease.

Regenerative Therapeutics: From Arrest to Re-Alveolarization

A promising therapeutic strategy involves regenerating lost alveolar structures by stimulating the formation of new alveolar septa. Secondary septation—an essential process in alveologenesis—is orchestrated by the coordinated actions of various signaling pathways, cellular populations, and gene networks.

Central to this process are interstitial myofibroblasts, which localize to the tips of developing septa and are crucial for alveolar maturation. Their differentiation and spatial organization are tightly regulated, especially by fibroblast growth factor (FGF) signaling, which we have shown to be essential for initiating, but not sustaining, septal formation. Disruption of FGF signaling in our transgenic mouse model recapitulates key features of alveolar arrest, providing a powerful tool for dissecting molecular drivers of alveologenesis.

New Insights from Mechanistic Studies

Recent research, including findings supported by NIH R56HL123969 and published in Am J Physiol Lung Cell Mol Physiol (PMID: 33479039), underscores the complexity of alveolar repair mechanisms. These studies demonstrate that:
  • Lung mesenchymal cell populations are highly heterogeneous and exhibit distinct lineage hierarchies during development and regeneration.
  • Specific subsets of mesenchymal progenitors contribute to alveolar myofibroblast populations critical for secondary septa formation.
  • Modulation of FGF and retinoic acid signaling pathways can enhance alveolar regeneration, potentially reversing structural lung damage post-injury.

Translational Vision

Our ongoing research aims to translate these findings into regenerative therapies for lung diseases involving alveolar simplification, such as BPD and emphysema. We are particularly focused on:

  • Defining the lineage trajectories of lung interstitial cells during both normal development and after injury (e.g., pneumonectomy models)
  • Elucidating the molecular circuits that regulate myofibroblast differentiation and spatial localization
  • Identifying novel therapeutic targets that can stimulate alveolar regeneration in neonatal and adult contexts

Funding and Acknowledgments

This work has evolved over several funding cycles, originally supported by an American Heart Association research grant (2008–2010) and subsequently by NIH R01 HL104003 (2010–2015).

Current efforts are supported in part by NIH R56HL123969, emphasizing our continued commitment to lung regeneration research with translational impact.