Interaction of epithelium and myofibroblasts through ERBB3‐PDGF growth pathways crosstalk drive the maturation of distal lung epithelium in late stage lung development
Rationale The last stage of lung development is realized by coordinated growth of septae from the alveolar walls to subdivide the distal saccules into alveoli, resulting in the expansion of surface area for gas exchange. The process is accompanied by microvascular maturation and underlying matrix formation of the interstitial scaffold. Secondary septation is driven by the orchestration of the distal epithelium, endothelium, and fibroblasts through the spatial and temporal distribution of various growth pathways and their crosstalk. This study investigated the role of the receptor tyrosine kinases 3 (ERBB3) pathway in the fibroblast‐epithelial crosstalk during septation using both in vitro co‐cultures and ex vivo organoid model as well as transgenic mice. Methods Primary myofibroblasts were extracted from neonatal C57BL/6wildtype (WT) mice at postnatal day 7 (PND7) and co‐cultured with a murine epithelial cell line (MLE12) in transwell inserts for 24h before sample collection. Gene expression was analyzed by quantitative PCR. Neonatal lung organoids were generated from primary lung epithelial cells (CD45‐/CD31‐) from neonatal C57BL/6 WT mice (PND7) and cultured in matrigel together with primary myofibroblasts from neonatal WT mice (PND7) as well as age matched mice heterozygot for the Platelet‐derived growth factor receptors (PDGF‐Rα+/‐). After organoid formation, cultures were treated with Neuregulin (NRG), an activating ligand of the ERBB3 receptor. We measured organoid number and size and Erbb3 signaling was assessed by immunofluorescence and quantitative gene expression analyses. Results Proximal culture with myofibroblasts upregulated the expression level of ERBB3 receptor in epithelial cells, as well as homeodomain‐only protein homeobox (HOPX), GATA‐binding factor 6 (GATA6), both of which are essential in the differentiation of distal epithelial cells and surfactant production during late stage lung development. In neonatal lung organoids, myofibroblasts with reduced PDGFRα expression led to reduction in organoid size and number. Treatment with the Erbb3 ligand NRG significantly increased both the expression and phosphorylation of Erbb3 in epithelial cells together with an upregulation of surfactant C (SPC) expression, and an increase in myofibroblasts PDGF‐R α expression. Conclusion Activated Erbb3 signaling results from the interaction with fibroblasts involving PDGF‐Rα signaling and drives distal epithelium maturation..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:36 |
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| Enthalten in: |
The FASEB Journal - 36(2022) |
| Beteiligte Personen: |
Zhang, Xin [VerfasserIn] |
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| BKL: |
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| Anmerkungen: |
© 2022 Federation of American Societies for Experimental Biology |
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| Umfang: |
1 |
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| doi: |
10.1096/fasebj.2022.36.S1.R2857 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
WLY006548652 |
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| 245 | 1 | 0 | |a Interaction of epithelium and myofibroblasts through ERBB3‐PDGF growth pathways crosstalk drive the maturation of distal lung epithelium in late stage lung development |
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| 520 | |a Rationale The last stage of lung development is realized by coordinated growth of septae from the alveolar walls to subdivide the distal saccules into alveoli, resulting in the expansion of surface area for gas exchange. The process is accompanied by microvascular maturation and underlying matrix formation of the interstitial scaffold. Secondary septation is driven by the orchestration of the distal epithelium, endothelium, and fibroblasts through the spatial and temporal distribution of various growth pathways and their crosstalk. This study investigated the role of the receptor tyrosine kinases 3 (ERBB3) pathway in the fibroblast‐epithelial crosstalk during septation using both in vitro co‐cultures and ex vivo organoid model as well as transgenic mice. Methods Primary myofibroblasts were extracted from neonatal C57BL/6wildtype (WT) mice at postnatal day 7 (PND7) and co‐cultured with a murine epithelial cell line (MLE12) in transwell inserts for 24h before sample collection. Gene expression was analyzed by quantitative PCR. Neonatal lung organoids were generated from primary lung epithelial cells (CD45‐/CD31‐) from neonatal C57BL/6 WT mice (PND7) and cultured in matrigel together with primary myofibroblasts from neonatal WT mice (PND7) as well as age matched mice heterozygot for the Platelet‐derived growth factor receptors (PDGF‐Rα+/‐). After organoid formation, cultures were treated with Neuregulin (NRG), an activating ligand of the ERBB3 receptor. We measured organoid number and size and Erbb3 signaling was assessed by immunofluorescence and quantitative gene expression analyses. Results Proximal culture with myofibroblasts upregulated the expression level of ERBB3 receptor in epithelial cells, as well as homeodomain‐only protein homeobox (HOPX), GATA‐binding factor 6 (GATA6), both of which are essential in the differentiation of distal epithelial cells and surfactant production during late stage lung development. In neonatal lung organoids, myofibroblasts with reduced PDGFRα expression led to reduction in organoid size and number. Treatment with the Erbb3 ligand NRG significantly increased both the expression and phosphorylation of Erbb3 in epithelial cells together with an upregulation of surfactant C (SPC) expression, and an increase in myofibroblasts PDGF‐R α expression. Conclusion Activated Erbb3 signaling results from the interaction with fibroblasts involving PDGF‐Rα signaling and drives distal epithelium maturation. | ||
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