A WNT mimetic with broad spectrum FZD-specificity decreases fibrosis and improves function in a pulmonary damage model
Abstract Background Wnt/β-catenin signaling is critical for lung development and AT2 stem cell maintenance in adults, but excessive pathway activation has been associated with pulmonary fibrosis, both in animal models and human diseases such as idiopathic pulmonary fibrosis (IPF). IPF is a detriment...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2024-04-01
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| Series: | Respiratory Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12931-024-02786-2 |
| _version_ | 1827291423050825728 |
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| author | Mehaben Patel Yorick Post Natalie Hill Asmiti Sura Jay Ye Trevor Fisher Nicholas Suen Mengrui Zhang Leona Cheng Ariel Pribluda Hui Chen Wen-Chen Yeh Yang Li Hélène Baribault Russell B. Fletcher |
| author_facet | Mehaben Patel Yorick Post Natalie Hill Asmiti Sura Jay Ye Trevor Fisher Nicholas Suen Mengrui Zhang Leona Cheng Ariel Pribluda Hui Chen Wen-Chen Yeh Yang Li Hélène Baribault Russell B. Fletcher |
| author_sort | Mehaben Patel |
| collection | DOAJ |
| description | Abstract Background Wnt/β-catenin signaling is critical for lung development and AT2 stem cell maintenance in adults, but excessive pathway activation has been associated with pulmonary fibrosis, both in animal models and human diseases such as idiopathic pulmonary fibrosis (IPF). IPF is a detrimental interstitial lung disease, and although two approved drugs limit functional decline, transplantation is the only treatment that extends survival, highlighting the need for regenerative therapies. Methods Using our antibody-based platform of Wnt/β-catenin modulators, we investigated the ability of a pathway antagonist and pathway activators to reduce pulmonary fibrosis in the acute bleomycin model, and we tested the ability of a WNT mimetic to affect alveolar organoid cultures. Results A WNT mimetic agonist with broad FZD-binding specificity (FZD1,2,5,7,8) potently expanded alveolar organoids. Upon therapeutic dosing, a broad FZD-binding specific Wnt mimetic decreased pulmonary inflammation and fibrosis and increased lung function in the bleomycin model, and it impacted multiple lung cell types in vivo. Conclusions Our results highlight the unexpected capacity of a WNT mimetic to effect tissue repair after lung damage and support the continued development of Wnt/β-catenin pathway modulation for the treatment of pulmonary fibrosis. |
| first_indexed | 2024-04-24T12:36:48Z |
| format | Article |
| id | doaj.art-f27d31a51f9a492fa22352567892c341 |
| institution | Directory Open Access Journal |
| issn | 1465-993X |
| language | English |
| last_indexed | 2024-04-24T12:36:48Z |
| publishDate | 2024-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj.art-f27d31a51f9a492fa22352567892c3412024-04-07T11:27:54ZengBMCRespiratory Research1465-993X2024-04-0125111210.1186/s12931-024-02786-2A WNT mimetic with broad spectrum FZD-specificity decreases fibrosis and improves function in a pulmonary damage modelMehaben Patel0Yorick Post1Natalie Hill2Asmiti Sura3Jay Ye4Trevor Fisher5Nicholas Suen6Mengrui Zhang7Leona Cheng8Ariel Pribluda9Hui Chen10Wen-Chen Yeh11Yang Li12Hélène Baribault13Russell B. Fletcher14Surrozen, Inc.Surrozen, Inc.Surrozen, Inc.Surrozen, Inc.Surrozen, Inc.Surrozen, Inc.Surrozen, Inc.Surrozen, Inc.Surrozen, Inc.Surrozen, Inc.Surrozen, Inc.Surrozen, Inc.Surrozen, Inc.Surrozen, Inc.Surrozen, Inc.Abstract Background Wnt/β-catenin signaling is critical for lung development and AT2 stem cell maintenance in adults, but excessive pathway activation has been associated with pulmonary fibrosis, both in animal models and human diseases such as idiopathic pulmonary fibrosis (IPF). IPF is a detrimental interstitial lung disease, and although two approved drugs limit functional decline, transplantation is the only treatment that extends survival, highlighting the need for regenerative therapies. Methods Using our antibody-based platform of Wnt/β-catenin modulators, we investigated the ability of a pathway antagonist and pathway activators to reduce pulmonary fibrosis in the acute bleomycin model, and we tested the ability of a WNT mimetic to affect alveolar organoid cultures. Results A WNT mimetic agonist with broad FZD-binding specificity (FZD1,2,5,7,8) potently expanded alveolar organoids. Upon therapeutic dosing, a broad FZD-binding specific Wnt mimetic decreased pulmonary inflammation and fibrosis and increased lung function in the bleomycin model, and it impacted multiple lung cell types in vivo. Conclusions Our results highlight the unexpected capacity of a WNT mimetic to effect tissue repair after lung damage and support the continued development of Wnt/β-catenin pathway modulation for the treatment of pulmonary fibrosis.https://doi.org/10.1186/s12931-024-02786-2WNT mimeticWnt signalingPulmonary fibrosisIPFAT2 cellAT2 organoid |
| spellingShingle | Mehaben Patel Yorick Post Natalie Hill Asmiti Sura Jay Ye Trevor Fisher Nicholas Suen Mengrui Zhang Leona Cheng Ariel Pribluda Hui Chen Wen-Chen Yeh Yang Li Hélène Baribault Russell B. Fletcher A WNT mimetic with broad spectrum FZD-specificity decreases fibrosis and improves function in a pulmonary damage model Respiratory Research WNT mimetic Wnt signaling Pulmonary fibrosis IPF AT2 cell AT2 organoid |
| title | A WNT mimetic with broad spectrum FZD-specificity decreases fibrosis and improves function in a pulmonary damage model |
| title_full | A WNT mimetic with broad spectrum FZD-specificity decreases fibrosis and improves function in a pulmonary damage model |
| title_fullStr | A WNT mimetic with broad spectrum FZD-specificity decreases fibrosis and improves function in a pulmonary damage model |
| title_full_unstemmed | A WNT mimetic with broad spectrum FZD-specificity decreases fibrosis and improves function in a pulmonary damage model |
| title_short | A WNT mimetic with broad spectrum FZD-specificity decreases fibrosis and improves function in a pulmonary damage model |
| title_sort | wnt mimetic with broad spectrum fzd specificity decreases fibrosis and improves function in a pulmonary damage model |
| topic | WNT mimetic Wnt signaling Pulmonary fibrosis IPF AT2 cell AT2 organoid |
| url | https://doi.org/10.1186/s12931-024-02786-2 |
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