Role of the Circadian Clock in Lung Regeneration

This submission has open access
Submission ID :
ESPR285
Submission Type
Submission Topic
Abstract: :

Introduction: Circadian rhythms provide an anticipatory mechanism for organisms that is beneficial for their survival. At the cellular level, these rhythms are generated by a core group of circadian genes. We have previously shown that circadian rhythms confer a time of day specific protection in influenza a Virus (IAV) infection. Mice infected at dawn had 3 fold better survival and less inflammation than those infected at dusk. Further, we have shown that this circadian protection was lost in adults exposed to hyperoxia as neonates. While we cannot control the time of exposure to IAV, these data suggest that altering the circadian health of the host could affect outcomes. However, it is not known if circadian rhythms affect lung regeneration independent of inflammation.

Objective: To determine if the circadian clock improves lung regeneration following IAV independent of the clock-gated inflammation.

Methods: We used a combination of in vivo experiments (wherein mice were infected with IAV at either dawn or dusk and lungs harvested on day 30 post-infection) and organotypic assays of lung epithelial cells from different levels of the respiratory tree that are known to contribute to regeneration.

Results: Mice recovered in the dusk group showed significantly more lung damage than the dawn group. Lung organoids from different levels of the respiratory tract exhibited robust diurnal oscillations underscoring their relevance in studying clock-controlled processes. In mice wherein the core clock gene, Bmal1 had been embryonically deleted, there was a loss of regenerative capacity- 50% reduction for CD104+ organoids and tracheospheres, and a 25% reduction in alveospheres. Since Bmal1 is known to have non-circadian effects which may be circumvented by using an inducible Bmal1 KO model, we repeated the organotypic assays in that model. We found that the phenotype of regenerative loss was conserved in both models of Bmal1 deletion –embryonic and that induced in adulthood. Based on our single-cell RNA seq data, we identified two downstream pathways for the circadian clock-wnt and FGF. We found that exogenous Wnt3a supplementation, but not FGF10, rescued the regenerative loss from Bmal1 deletion in organoids from both genetic models. We further speculate that the Wnt pathways may be implicated in the loss of circadian protection for influenza infection in adults exposed to neonatal hyperoxia.

Conclusion: Our organoid studies reveal a role for the clock, independent of clock gated inflammatory influences. We speculate that measures to boost the circadian health of the host would be an important and novel direction for improving lung regeneration following viral infections.

Children's Hospital Of Philadelphia
Children's Hospital of Philadelphia
University of Pennsylvania
University of Pennsylvania
University of Pennsylvania
Children's Hospital of Philadelphia

Similar Abstracts by Type

Submission ID
Submission Title
Submission Topic
Submission Type
Corresponding Author
ESPR157
Clinical Research
Original science
Aditya Chhikara
ESPR302
Epidemiology
Original science
Natasha Jouk
ESPR74
Clinical Research
Original science
Alexandra Mazo
32 hits