Maladaptive functional changes in alveolar fibroblasts due to perinatal hyperoxia impair epithelial differentiation
Infants born prematurely worldwide have up to a 50% chance of developing bronchopulmonary dysplasia (BPD), a clinical morbidity characterized by dysregulated lung alveolarization and microvascular development. It is known that PDGFR alpha–positive (PDGFRA+) fibroblasts are critical for alveolarizati...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-03-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.152404 |
| _version_ | 1818242279386644480 |
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| author | Matthew R. Riccetti Mereena George Ushakumary Marion Waltamath Jenna Green John Snowball Sydney E. Dautel Mehari Endale Bonny Lami Jason Woods Shawn K. Ahlfeld Anne-Karina T. Perl |
| author_facet | Matthew R. Riccetti Mereena George Ushakumary Marion Waltamath Jenna Green John Snowball Sydney E. Dautel Mehari Endale Bonny Lami Jason Woods Shawn K. Ahlfeld Anne-Karina T. Perl |
| author_sort | Matthew R. Riccetti |
| collection | DOAJ |
| description | Infants born prematurely worldwide have up to a 50% chance of developing bronchopulmonary dysplasia (BPD), a clinical morbidity characterized by dysregulated lung alveolarization and microvascular development. It is known that PDGFR alpha–positive (PDGFRA+) fibroblasts are critical for alveolarization and that PDGFRA+ fibroblasts are reduced in BPD. A better understanding of fibroblast heterogeneity and functional activation status during pathogenesis is required to develop mesenchymal population–targeted therapies for BPD. In this study, we utilized a neonatal hyperoxia mouse model (90% O2 postnatal days 0–7, PN0–PN7) and performed studies on sorted PDGFRA+ cells during injury and room air recovery. After hyperoxia injury, PDGFRA+ matrix and myofibroblasts decreased and PDGFRA+ lipofibroblasts increased by transcriptional signature and population size. PDGFRA+ matrix and myofibroblasts recovered during repair (PN10). After 7 days of in vivo hyperoxia, PDGFRA+ sorted fibroblasts had reduced contractility in vitro, reflecting loss of myofibroblast commitment. Organoids made with PN7 PDGFRA+ fibroblasts from hyperoxia in mice exhibited reduced alveolar type 1 cell differentiation, suggesting reduced alveolar niche-supporting PDGFRA+ matrix fibroblast function. Pathway analysis predicted reduced WNT signaling in hyperoxia fibroblasts. In alveolar organoids from hyperoxia-exposed fibroblasts, WNT activation by CHIR increased the size and number of alveolar organoids and enhanced alveolar type 2 cell differentiation. |
| first_indexed | 2024-12-12T13:42:42Z |
| format | Article |
| id | doaj.art-b64d940fd4a04216a9cec3d2b72e8c02 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-12T13:42:42Z |
| publishDate | 2022-03-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-b64d940fd4a04216a9cec3d2b72e8c022022-12-22T00:22:46ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-03-0175Maladaptive functional changes in alveolar fibroblasts due to perinatal hyperoxia impair epithelial differentiationMatthew R. RiccettiMereena George UshakumaryMarion WaltamathJenna GreenJohn SnowballSydney E. DautelMehari EndaleBonny LamiJason WoodsShawn K. AhlfeldAnne-Karina T. PerlInfants born prematurely worldwide have up to a 50% chance of developing bronchopulmonary dysplasia (BPD), a clinical morbidity characterized by dysregulated lung alveolarization and microvascular development. It is known that PDGFR alpha–positive (PDGFRA+) fibroblasts are critical for alveolarization and that PDGFRA+ fibroblasts are reduced in BPD. A better understanding of fibroblast heterogeneity and functional activation status during pathogenesis is required to develop mesenchymal population–targeted therapies for BPD. In this study, we utilized a neonatal hyperoxia mouse model (90% O2 postnatal days 0–7, PN0–PN7) and performed studies on sorted PDGFRA+ cells during injury and room air recovery. After hyperoxia injury, PDGFRA+ matrix and myofibroblasts decreased and PDGFRA+ lipofibroblasts increased by transcriptional signature and population size. PDGFRA+ matrix and myofibroblasts recovered during repair (PN10). After 7 days of in vivo hyperoxia, PDGFRA+ sorted fibroblasts had reduced contractility in vitro, reflecting loss of myofibroblast commitment. Organoids made with PN7 PDGFRA+ fibroblasts from hyperoxia in mice exhibited reduced alveolar type 1 cell differentiation, suggesting reduced alveolar niche-supporting PDGFRA+ matrix fibroblast function. Pathway analysis predicted reduced WNT signaling in hyperoxia fibroblasts. In alveolar organoids from hyperoxia-exposed fibroblasts, WNT activation by CHIR increased the size and number of alveolar organoids and enhanced alveolar type 2 cell differentiation.https://doi.org/10.1172/jci.insight.152404DevelopmentPulmonology |
| spellingShingle | Matthew R. Riccetti Mereena George Ushakumary Marion Waltamath Jenna Green John Snowball Sydney E. Dautel Mehari Endale Bonny Lami Jason Woods Shawn K. Ahlfeld Anne-Karina T. Perl Maladaptive functional changes in alveolar fibroblasts due to perinatal hyperoxia impair epithelial differentiation JCI Insight Development Pulmonology |
| title | Maladaptive functional changes in alveolar fibroblasts due to perinatal hyperoxia impair epithelial differentiation |
| title_full | Maladaptive functional changes in alveolar fibroblasts due to perinatal hyperoxia impair epithelial differentiation |
| title_fullStr | Maladaptive functional changes in alveolar fibroblasts due to perinatal hyperoxia impair epithelial differentiation |
| title_full_unstemmed | Maladaptive functional changes in alveolar fibroblasts due to perinatal hyperoxia impair epithelial differentiation |
| title_short | Maladaptive functional changes in alveolar fibroblasts due to perinatal hyperoxia impair epithelial differentiation |
| title_sort | maladaptive functional changes in alveolar fibroblasts due to perinatal hyperoxia impair epithelial differentiation |
| topic | Development Pulmonology |
| url | https://doi.org/10.1172/jci.insight.152404 |
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