Decoding the IGF1 signaling gene regulatory network behind alveologenesis from a mouse model of bronchopulmonary dysplasia

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Abstract

Lung development is precisely controlled by underlying Gene Regulatory Networks (GRN). Disruption of genes in the network can interrupt normal development and cause diseases such as bronchopulmonary dysplasia (BPD)–a chronic lung disease in preterm infants with morbid and sometimes lethal consequences characterized by lung immaturity and reduced alveolarization. Here, we generated a transgenic mouse exhibiting a moderate severity BPD phenotype by blocking IGF1 signaling in secondary crest myofibroblasts (SCMF) at the onset of alveologenesis. Using approaches mirroring the construction of the model GRN in sea urchin’s development, we constructed the IGF1 signaling network underlying alveologenesis using this mouse model that phenocopies BPD. The constructed GRN, consisting of 43 genes, provides a bird’s-eye view of how the genes downstream of IGF1 are regulatorily connected. The GRN also reveals a mechanistic interpretation of how the effects of IGF1 signaling are transduced within SCMF from its specification genes to its effector genes and then from SCMF to its neighboring alveolar epithelial cells with WNT5A and FGF10 signaling as the bridge. Consistently, blocking WNT5A signaling in mice phenocopies BPD as inferred by the network. A comparative study on human samples suggests that a GRN of similar components and wiring underlies human BPD. Our network view of alveologenesis is transforming our perspective to understand and treat BPD. This new perspective calls for the construction of the full signaling GRN underlying alveologenesis, upon which targeted therapies for this neonatal chronic lung disease can be viably developed.

Data availability

Sequencing data generated for this study have been deposited in GEO under the accession code GSE182886.All other data generated or analyzed during this study are included in the manuscript and supporting files.Source Data files have been provided in Figure 3-Source Data 1&2, Figure 4-Source Data 1&2, and Figure 6-Source Data 1.An online repository of the network and the data presented in this paper has been made available to the public at https://sites.google.com/view/the-alveologenesis-grn/home.

The following data sets were generated

1. Gao F
2. Li C
3. Minoo P
(2021) Decoding A Gene Regulatory Network Behind Bronchopulmonary Dysplasia
NCBI Gene Expression Omnibus, GSE182886.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE182886

The following previously published data sets were used

1. Li C
2. Lee MK
3. Gao F
4. Webster S
5. Di H
6. Duan J
7. Yang C
8. Bhopal N
9. Pryhubar G
10. Smith SM
11. Borok Z
12. Bellusci S
13. Minoo P
(2019) The Secondary Crest Myofibroblast PDGFRa Controls Elastogenesis Pathway via a Secondary Tier of Signaling Networks During Alveogenesis
NCBI Gene Expression Omnibus, GSE126457.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE126457
1. Wang Y
2. Tang N
3. Cai T
(2018) The single cell RNA seq of pulmonary alveolar epithelial cells
NCBI Gene Expression Omnibus, GSE106960.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE106960
1. The LungMAP Consortium
(2019) LungMAP Consortium Data
NCBI Gene Expression Omnibus, GSE128810.

http://www.lungmap.net
1. Negretti NM
2. Plosa EJ
3. Benjamin JT
4. Schuler BA
5. Habermann AC
6. Jetter C
7. Gulleman P
8. Taylor CJ
9. Nichols D
10. Matlock BK
11. Guttentag SH
12. Blackwell TS
13. Banovich NE
14. Kropski JA
15. Sucre JM
(2021) A Single Cell Atlas of Alveolar Development
NCBI Gene Expression Omnibus, GSEGSE165063.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE165063
1. Schuler BA
2. Habermann AC
3. Plosa EJ
4. Taylor CJ
5. Jetter C
6. Negretti NM
7. Kapp ME
8. Benjamin JT
9. Gulleman P
10. Nichols DS
11. Braunstein LZ
12. Hackett A
13. Koval M
14. Guttentag SH
15. Blackwell TS
16. Webber SA
17. Banovich NE
18. Kropski JA
19. Sucre JM
(2020) Age-determined expression of priming protease TMPRSS2 and localization of SARS-CoV-2 in lung epithelium
NCBI Gene Expression Omnibus, GSEGSE160876.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE160876
(2021) The genomic, epigenomic and biophysical cues controlling the emergence of the gas exchange niche in the lung
NCBI Gene Expression Omnibus, GSE149563.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE149563

Article and author information

Author details

Feng Gao

Department of Pediatrics, University of Southern California, Los Angeles, United States

For correspondence
fremontgao@gmail.com

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-8764-1107
Changgong Li

Department of Pediatrics, University of Southern California, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Susan M Smith

Department of Pediatrics, University of Southern California, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Neil Peinado

Department of Pediatrics, University of Southern California, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Golenaz Kohbodi

Department of Pediatrics, University of Southern California, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Evelyn Tran

Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Yong-Hwee Eddie Loh

USC Libraries Bioinformatics Services, University of Southern California, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Wei Li

Department of Nephrology, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, China

Competing interests
The authors declare that no competing interests exist.
Zea Borok

Department of Medicine, University of California, San Diego, San Diego, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-8673-8177
Parviz Minoo

Department of Pediatrics, University of Southern California, Los Angeles, United States

For correspondence
minoo@usc.edu

Competing interests
The authors declare that no competing interests exist.

Funding

National Heart, Lung, and Blood Institute (5R01HL144932-04)

Changgong Li

National Heart, Lung, and Blood Institute (5R01HL143059-04)

Parviz Minoo

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: BPD and non-BPD postnatal human lung tissues were provided by the International Institute for the Advancement of Medicine and the National Disease Research Interchange, and were classified exempt from human subject regulations per the University of Rochester Research Subjects Review Board protocol (RSRB00056775).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.