Alveologenesis is the final phase of lung development where the surface area of the lung is increased by subdividing alveolar saccules through the formation of secondary septae (septal ridges), followed by thinning of the septal walls to generate an efficient air/blood gas exchange organ. Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth in which alveologenesis is impaired. BPD often results in chronic respiratory disease. An in-depth understanding of the mechanisms that regulate alveolar septation and septal wall maturation will be required to develop therapies for premature infants with BPD and for developing potential therapies for adult lung regeneration. However, there are specific knowledge gaps about the identity and regulation of progenitors that give rise to myofibroblasts (MyoFB), the functions of MyoFB and other mesenchymal cell types, and the mechanisms that terminate and clear MyoFB from the lung at the completion of secondary septation.
Fibroblast Growth Factor 18 (Fgf18) is expressed at high levels in MyoFB and AT1 cells during alveologenesis. Through lineage tracing of Fgf18-expressing cells, we find that MyoFB are cleared from the lung after the first stage of alveologenesis but that Fgf18-expressing AT1 cells are retained, suggesting that FGF18 could be involved in septal wall maturation.
We are using a combination of unique genetic tools to target specific cell populations in the neonatal lung, single-nucleus RNA sequencing, and cell sorting coupled with single-nucleus ATAC sequencing, to identify the cellular mechanisms by which the FGF signaling pathway regulates cellular interactions, cell proliferation, differentiation, and death, during the first and second stages of alveologenesis. Our research goals include the identification of novel transcriptional mechanisms that regulate MyoFB function during primary alveologenesis, and cellular mechanisms by which FGF signaling regulates septal maturation during secondary alveologenesis.
Selected Lung Biology Publications:
1. Guzy, R.D., Stoilov, I., Elton, T.J., Mecham, R.P., and Ornitz, D.M. (2015). Fibroblast growth factor 2 is required for epithelial recovery, but not for pulmonary fibrosis, in response to bleomycin. Am J Respir Cell Mol Biol 52, 116-128. 10.1165/rcmb.2014-0184OC.
2. Yin, Y., Castro, A.M., Hoekstra, M., Yan, T.J., Kanakamedala, A.C., Dehner, L.P., Hill, D.A., and Ornitz, D.M. (2015). Fibroblast Growth Factor 9 Regulation by MicroRNAs Controls Lung Development and Links DICER1 Loss to the Pathogenesis of Pleuropulmonary Blastoma. PLoS Genet 11, e1005242. 10.1371/journal.pgen.1005242.
3. Yin, Y., Ren, X., Smith, C., Guo, Q., Malabunga, M., Guernah, I., Zhang, Y., Shen, J., Sun, H., Chehab, N., et al. (2016). Inhibition of fibroblast growth factor receptor 3-dependent lung adenocarcinoma with a human monoclonal antibody. Dis Model Mech 9, 563-571. 10.1242/dmm.024760.
4. Guzy, R.D., Li, L., Smith, C., Dorry, S.J., Koo, H.Y., Chen, L., and Ornitz, D.M. (2017). Pulmonary fibrosis requires cell-autonomous mesenchymal fibroblast growth factor (FGF) signaling. J Biol Chem 292, 10364-10378. 10.1074/jbc.M117.791764.
5. Koo, H.Y., El-Baz, L.M., House, S., Cilvik, S.N., Dorry, S.J., Shoukry, N.M., Salem, M.L., Hafez, H.S., Dulin, N.O., Ornitz, D.M., and Guzy, R.D. (2018). Fibroblast growth factor 2 decreases bleomycin-induced pulmonary fibrosis and inhibits fibroblast collagen production and myofibroblast differentiation. J Pathol 246, 54-66. 10.1002/path.5106.
6. Oladipupo, S.S., Kabir, A.U., Smith, C., Choi, K., and Ornitz, D.M. (2018). Impaired tumor growth and angiogenesis in mice heterozygous for Vegfr2 (Flk1). Sci Rep 8, 14724. 10.1038/s41598-018-33037-2.
7. Hagan, A.S., Boylan, M., Smith, C., Perez-Santamarina, E., Kowalska, K., Hung, I.H., Lewis, R.M., Hajihosseini, M.K., Lewandoski, M., and Ornitz, D.M. (2019). Generation and validation of novel conditional flox and inducible Cre alleles targeting fibroblast growth factor 18 (Fgf18). Dev Dyn 248, 882-893. 10.1002/dvdy.85.
8. Dorry, S.J., Ansbro, B.O., Ornitz, D.M., Mutlu, G.M., and Guzy, R.D. (2020). FGFR2 Is Required for AEC2 Homeostasis and Survival after Bleomycin-induced Lung Injury. Am J Respir Cell Mol Biol 62, 608-621. 10.1165/rcmb.2019-0079OC.
9. Hagan, A.S., Zhang, B., and Ornitz, D.M. (2020). Identification of a FGF18-expressing alveolar myofibroblast that is developmentally cleared during alveologenesis. Development 147, dev.181032. 10.1242/dev.181032.
10. Yin, Y., and Ornitz, D.M. (2020). FGF9 and FGF10 activate distinct signaling pathways to direct lung epithelial specification and branching. Sci Signal 13, eaay4353. 10.1126/scisignal.aay4353.
11. Woo, K.V., Shen, I.Y., Weinheimer, C.J., Kovacs, A., Nigro, J., Lin, C.Y., Chakinala, M., Byers, D.E., and Ornitz, D.M. (2021). Endothelial FGF signaling is protective in hypoxia-induced pulmonary hypertension. J Clin Invest 131. 10.1172/JCI141467.
12. Hiller, B.E., Yin, Y., Perng, Y.C., de Araujo Castro, Í., Fox, L.E., Locke, M.C., Monte, K.J., López, C.B., Ornitz, D.M., and Lenschow, D.J. (2022). Fibroblast growth factor-9 expression in airway epithelial cells amplifies the type I interferon response and alters influenza A virus pathogenesis. PLoS pathogens 18, e1010228. 10.1371/journal.ppat.1010228.
13. Yin, Y., Koenitzer, J.R., Patra, D., Dietmann, S., Bayguinov, P., Hagan, A.S., and Ornitz, D.M. (2024). Identification of a myofibroblast differentiation program during neonatal lung development. Development 151. 10.1242/dev.202659.