Tissues respond in different ways to injury to repair and regenerate lost cells and damaged architecture. The lung responds robustly to injury through activation of spatially restricted stem/progenitor cell populations and through re-entry of differentiated cells into the cell cycle. This robust response to injury stands in contrast to the normal homeostatic state, which is remarkably quiescent. One school of thought suggests that quiescence is a default state in many tissues resulting from lack of growth stimuli as demonstrated in culture conditions. However, this does not fully explain how cells remain quiescent within a complex microenvironment in vivo during tissue homeostasis. An alternative hypothesis is that quiescence is actively maintained through as yet unknown molecular pathways. Such an active process would be important for the delicate balance between cellular quiescence required for maintaining tissue integrity during normal homeostasis and the rapid regenerative response after injury. Such information is important given that disruption in this state could lead to re-activation of cell proliferation in an uncontrolled manner and may underlie several lung diseases including pulmonary fibrosis and cancer. The Hedgehog (Hh) pathway is a hallmark signaling pathway that coordinates epithelial-mesenchymal interactions during development in multiple organs including the lung, through paracrine activation of smoothened (Smo)-mediated downstream signaling events. Of the three known Hh ligands, sonic hedgehog (Shh) is the best understood, is highly expressed during lung development, and plays an essential role in lung morphogenesis. Despite its clear role in organ development, little is known about whether or how Hh signaling coordinates epithelial-mesenchymal interactions in the adult lung to maintain tissue homeostasis or modulate injury and regeneration. Hh signaling activity has been noted in the adult lung through expression of the downstream effector Gli1, along with studies suggesting hedgehog promotes mesenchymal proliferation in vitro. However, Hh's function in normal adult tissue quiescence or its role in injury and regeneration in the lung has not been examined in in vivo models. Our preliminary data suggest that Hh signaling is active in the adult lung and is used to maintain mesenchymal quiescence during normal homeostasis as well as after injury in the proximal airways. Thus, Hh signaling plays a critical role in maintainig lung quiescence and is important in the response of the lung to injury.

Public Health Relevance

This project will examine the importance of maintaining cellular quiescence in the adult lung. The information gained from these studies will provide novel insight into how cells in the lung remain quiescent during homeostasis and how disruption in quiescence affects normal adult lung function. While previous studies have examined the importance of promoting cell proliferation in the adult lung, these are some of the first studies t explore what keeps cells from proliferating. Such information will provide a novel platform to better understand this process in human diseases such as fibrosis and cancer.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL132349-03
Application #
9447192
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Lin, Sara
Project Start
2016-04-15
Project End
2020-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Herriges, Michael J; Tischfield, David J; Cui, Zheng et al. (2017) The NANCI-Nkx2.1 gene duplex buffers Nkx2.1 expression to maintain lung development and homeostasis. Genes Dev 31:889-903
Stabler, Collin T; Morrisey, Edward E (2017) Developmental pathways in lung regeneration. Cell Tissue Res 367:677-685
Frank, David B; Peng, Tien; Zepp, Jarod A et al. (2016) Emergence of a Wave of Wnt Signaling that Regulates Lung Alveologenesis by Controlling Epithelial Self-Renewal and Differentiation. Cell Rep 17:2312-2325