STAT3–BDNF–TrkB signalling promotes alveolar epithelial regeneration after lung injury

Andrew J. Paris; Katharina E. Hayer; Joseph H. Oved; Daphne C. Avgousti; Sushila A. Toulmin; Jarod A. Zepp; William J. Zacharias; Jeremy B. Katzen; Maria C. Basil; Madison M. Kremp; April R. Slamowitz; Sowmya Jayachandran; Aravind Sivakumar; Ning Dai; Ping Wang; David B. Frank; Laurence C. Eisenlohr; Edward Cantu; Michael F. Beers; Matthew D. Weitzman; Edward E. Morrisey; G. Scott Worthen

doi:10.1038/s41556-020-0569-x

STAT3–BDNF–TrkB signalling promotes alveolar epithelial regeneration after lung injury

Andrew J. Paris
, Katharina E. Hayer
, Joseph H. Oved
, Daphne C. Avgousti
, Sushila A. Toulmin
, Jarod A. Zepp
, William J. Zacharias
, Jeremy B. Katzen
, Maria C. Basil
, Madison M. Kremp
, April R. Slamowitz
, Sowmya Jayachandran
, Aravind Sivakumar
, Ning Dai
, Ping Wang
, David B. Frank
, Laurence C. Eisenlohr
, Edward Cantu
, Michael F. Beers
, Matthew D. Weitzman

Edward E. Morrisey, G. Scott Worthen

Surgery

Research output: Contribution to journal › Article › peer-review

123 Scopus citations

Abstract

Alveolar epithelial regeneration is essential for recovery from devastating lung diseases. This process occurs when type II alveolar pneumocytes (AT2 cells) proliferate and transdifferentiate into type I alveolar pneumocytes (AT1 cells). We used genome-wide analysis of chromatin accessibility and gene expression following acute lung injury to elucidate repair mechanisms. AT2 chromatin accessibility changed substantially following injury to reveal STAT3 binding motifs adjacent to genes that regulate essential regenerative pathways. Single-cell transcriptome analysis identified brain-derived neurotrophic factor (Bdnf) as a STAT3 target gene with newly accessible chromatin in a unique population of regenerating AT2 cells. Furthermore, the BDNF receptor tropomyosin receptor kinase B (TrkB) was enriched on mesenchymal alveolar niche cells (MANCs). Loss or blockade of AT2-specific Stat3, Bdnf or mesenchyme-specific TrkB compromised repair and reduced Fgf7 expression by niche cells. A TrkB agonist improved outcomes in vivo following lung injury. These data highlight the biological and therapeutic importance of the STAT3–BDNF–TrkB axis in orchestrating alveolar epithelial regeneration.

Original language	English
Pages (from-to)	1197-1210
Number of pages	14
Journal	Nature Cell Biology
Volume	22
Issue number	10
DOIs	https://doi.org/10.1038/s41556-020-0569-x
State	Published - Oct 1 2020

Bibliographical note

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.

Funding

We acknowledge S. M. Albelda, J. S. Brenner and A. E. Vaughan for help with preparing this manuscript, as well as the Pathology, Flow Cytometry, Nucleic Acid and PCR cores and the Center for Applied Genomics at the Children’s Hospital of Philadelphia Research Institute. This work was supported by the Parker B. Fellowship Program (A.J.P.) and multiple grants from the National Institutes of Health (K08 HL136698 (A.J.P.), R01 AI121321 (M.D.W.), R01 AI099479 (G.S.W.) and R01 DK114054 (G.S.W.)). We also thank the patients and families who donated lung tissue to support this research.

Funders	Funder number
National Institutes of Health (NIH)	R01 AI099479, R01 AI121321, R01 DK114054
National Heart, Lung, and Blood Institute (NHLBI)	K08HL136698

ASJC Scopus subject areas

Cell Biology

Access to Document

10.1038/s41556-020-0569-x

Cite this

Paris, A. J., Hayer, K. E., Oved, J. H., Avgousti, D. C., Toulmin, S. A., Zepp, J. A., Zacharias, W. J., Katzen, J. B., Basil, M. C., Kremp, M. M., Slamowitz, A. R., Jayachandran, S., Sivakumar, A., Dai, N., Wang, P., Frank, D. B., Eisenlohr, L. C., Cantu, E., Beers, M. F., ... Worthen, G. S. (2020). STAT3–BDNF–TrkB signalling promotes alveolar epithelial regeneration after lung injury. Nature Cell Biology, 22(10), 1197-1210. https://doi.org/10.1038/s41556-020-0569-x

@article{4c2116fd74444b75b89e0d9353308101,

title = "STAT3{\textendash}BDNF{\textendash}TrkB signalling promotes alveolar epithelial regeneration after lung injury",

abstract = "Alveolar epithelial regeneration is essential for recovery from devastating lung diseases. This process occurs when type II alveolar pneumocytes (AT2 cells) proliferate and transdifferentiate into type I alveolar pneumocytes (AT1 cells). We used genome-wide analysis of chromatin accessibility and gene expression following acute lung injury to elucidate repair mechanisms. AT2 chromatin accessibility changed substantially following injury to reveal STAT3 binding motifs adjacent to genes that regulate essential regenerative pathways. Single-cell transcriptome analysis identified brain-derived neurotrophic factor (Bdnf) as a STAT3 target gene with newly accessible chromatin in a unique population of regenerating AT2 cells. Furthermore, the BDNF receptor tropomyosin receptor kinase B (TrkB) was enriched on mesenchymal alveolar niche cells (MANCs). Loss or blockade of AT2-specific Stat3, Bdnf or mesenchyme-specific TrkB compromised repair and reduced Fgf7 expression by niche cells. A TrkB agonist improved outcomes in vivo following lung injury. These data highlight the biological and therapeutic importance of the STAT3{\textendash}BDNF{\textendash}TrkB axis in orchestrating alveolar epithelial regeneration.",

author = "Paris, \{Andrew J.\} and Hayer, \{Katharina E.\} and Oved, \{Joseph H.\} and Avgousti, \{Daphne C.\} and Toulmin, \{Sushila A.\} and Zepp, \{Jarod A.\} and Zacharias, \{William J.\} and Katzen, \{Jeremy B.\} and Basil, \{Maria C.\} and Kremp, \{Madison M.\} and Slamowitz, \{April R.\} and Sowmya Jayachandran and Aravind Sivakumar and Ning Dai and Ping Wang and Frank, \{David B.\} and Eisenlohr, \{Laurence C.\} and Edward Cantu and Beers, \{Michael F.\} and Weitzman, \{Matthew D.\} and Morrisey, \{Edward E.\} and Worthen, \{G. Scott\}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2020",

month = oct,

day = "1",

doi = "10.1038/s41556-020-0569-x",

language = "English",

volume = "22",

pages = "1197--1210",

number = "10",

}

Paris, AJ, Hayer, KE, Oved, JH, Avgousti, DC, Toulmin, SA, Zepp, JA, Zacharias, WJ, Katzen, JB, Basil, MC, Kremp, MM, Slamowitz, AR, Jayachandran, S, Sivakumar, A, Dai, N, Wang, P, Frank, DB, Eisenlohr, LC, Cantu, E, Beers, MF, Weitzman, MD, Morrisey, EE & Worthen, GS 2020, 'STAT3–BDNF–TrkB signalling promotes alveolar epithelial regeneration after lung injury', Nature Cell Biology, vol. 22, no. 10, pp. 1197-1210. https://doi.org/10.1038/s41556-020-0569-x

TY - JOUR

T1 - STAT3–BDNF–TrkB signalling promotes alveolar epithelial regeneration after lung injury

AU - Paris, Andrew J.

AU - Hayer, Katharina E.

AU - Oved, Joseph H.

AU - Avgousti, Daphne C.

AU - Toulmin, Sushila A.

AU - Zepp, Jarod A.

AU - Zacharias, William J.

AU - Katzen, Jeremy B.

AU - Basil, Maria C.

AU - Kremp, Madison M.

AU - Slamowitz, April R.

AU - Jayachandran, Sowmya

AU - Sivakumar, Aravind

AU - Dai, Ning

AU - Wang, Ping

AU - Frank, David B.

AU - Eisenlohr, Laurence C.

AU - Cantu, Edward

AU - Beers, Michael F.

AU - Weitzman, Matthew D.

AU - Morrisey, Edward E.

AU - Worthen, G. Scott

PY - 2020/10/1

Y1 - 2020/10/1

N2 - Alveolar epithelial regeneration is essential for recovery from devastating lung diseases. This process occurs when type II alveolar pneumocytes (AT2 cells) proliferate and transdifferentiate into type I alveolar pneumocytes (AT1 cells). We used genome-wide analysis of chromatin accessibility and gene expression following acute lung injury to elucidate repair mechanisms. AT2 chromatin accessibility changed substantially following injury to reveal STAT3 binding motifs adjacent to genes that regulate essential regenerative pathways. Single-cell transcriptome analysis identified brain-derived neurotrophic factor (Bdnf) as a STAT3 target gene with newly accessible chromatin in a unique population of regenerating AT2 cells. Furthermore, the BDNF receptor tropomyosin receptor kinase B (TrkB) was enriched on mesenchymal alveolar niche cells (MANCs). Loss or blockade of AT2-specific Stat3, Bdnf or mesenchyme-specific TrkB compromised repair and reduced Fgf7 expression by niche cells. A TrkB agonist improved outcomes in vivo following lung injury. These data highlight the biological and therapeutic importance of the STAT3–BDNF–TrkB axis in orchestrating alveolar epithelial regeneration.

AB - Alveolar epithelial regeneration is essential for recovery from devastating lung diseases. This process occurs when type II alveolar pneumocytes (AT2 cells) proliferate and transdifferentiate into type I alveolar pneumocytes (AT1 cells). We used genome-wide analysis of chromatin accessibility and gene expression following acute lung injury to elucidate repair mechanisms. AT2 chromatin accessibility changed substantially following injury to reveal STAT3 binding motifs adjacent to genes that regulate essential regenerative pathways. Single-cell transcriptome analysis identified brain-derived neurotrophic factor (Bdnf) as a STAT3 target gene with newly accessible chromatin in a unique population of regenerating AT2 cells. Furthermore, the BDNF receptor tropomyosin receptor kinase B (TrkB) was enriched on mesenchymal alveolar niche cells (MANCs). Loss or blockade of AT2-specific Stat3, Bdnf or mesenchyme-specific TrkB compromised repair and reduced Fgf7 expression by niche cells. A TrkB agonist improved outcomes in vivo following lung injury. These data highlight the biological and therapeutic importance of the STAT3–BDNF–TrkB axis in orchestrating alveolar epithelial regeneration.

UR - https://www.scopus.com/pages/publications/85091608602

UR - https://www.scopus.com/pages/publications/85091608602#tab=citedBy

U2 - 10.1038/s41556-020-0569-x

DO - 10.1038/s41556-020-0569-x

M3 - Article

C2 - 32989251

AN - SCOPUS:85091608602

SN - 1465-7392

VL - 22

SP - 1197

EP - 1210

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 10

ER -

STAT3–BDNF–TrkB signalling promotes alveolar epithelial regeneration after lung injury

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this