Abstract
The prognosis of elderly individuals with idiopathic pulmonary fibrosis (IPF) remains poor. Fibroblastic foci, in which aggregates of proliferating fibroblasts and myofibroblasts are involved, are the pathological hallmark lesions in IPF to represent focal areas of active fibrogenesis. Fibroblast heterogeneity in fibrotic lesions hampers the discovery of the pathogenesis of pulmonary fibrosis. Therefore, to determine of the pathogenesis of IPF, identification of functional fibroblasts is warranted. This study was aimed to determine the role of fibroblasts positive for meflin, identified as a potential marker for mesenchymal stromal cells, during the development of pulmonary fibrosis. We characterised meflin-positive cells in a single cell atlas established by single-cell RNA sequencing (scRNA-seq)-based profiling of 243 472 cells from 32 IPF lungs and 29 normal lung samples. scRNA-seq combined with in situ RNA hybridisation identified proliferating fibroblasts positive for meflin in fibroblastic foci, not dense fibrosis, of fibrotic lungs in IPF patients. We determined the role of fibroblasts positive for meflin using bleomycin (BLM)-induced pulmonary fibrosis. A BLM-induced lung fibrosis model for meflin-deficient mice showed that fibroblasts positive for meflin had anti-fibrotic property to prevent pulmonary fibrosis. Although transforming growth factor-β-induced fibrogenesis and cell senescence with senescence-associated secretory phenotype were exacerbated in fibroblasts via the repression or lack of meflin, these were inhibited in meflin-deficient fibroblasts with meflin reconstitution. These findings provide evidence to show the biological importance of meflin expression on fibroblasts and myofibroblasts in the active fibrotic region of pulmonary fibrosis.
Footnotes
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Conflict of interest: Dr. Matson has nothing to disclose.
Conflict of interest: Dr. Nakahara has nothing to disclose.
Conflict of interest: Dr. Hashimoto received a research grant from Boehringer Ingelheim, outside the submitted work.
Conflict of interest: Dr. Sakamoto has nothing to disclose.
Conflict of interest: Dr. Enomoto has nothing to disclose.
Conflict of interest: Dr. Adams reports In addition, Dr. Adams has a patent 62/849,644 pending.
Conflict of interest: Dr. Yokoi has nothing to disclose.
Conflict of interest: Dr. Omote has nothing to disclose.
Conflict of interest: Dr. Poli reports In addition, Dr. Poli has a patent 62/849,644 pending.
Conflict of interest: Dr. Ando has nothing to disclose.
Conflict of interest: Dr. Wakahara has nothing to disclose.
Conflict of interest: Dr. Suzuki has nothing to disclose.
Conflict of interest: Dr. Inoue has nothing to disclose.
Conflict of interest: Dr. Hara has nothing to disclose.
Conflict of interest: Dr. Mizutani has nothing to disclose.
Conflict of interest: Dr. Imaizumi has nothing to disclose.
Conflict of interest: Dr. Kawabe has nothing to disclose.
Conflict of interest: Dr. Rosas reports In addition, Dr. Rosas has a patent 62/849,644 pending.
Conflict of interest: Dr. Takahashi has nothing to disclose.
Conflict of interest: Dr. Kaminski reports personal fees from Biogen Idec, personal fees from Boehringer Ingelheim, personal fees from Third Rock, personal fees from Pliant, personal fees from Samumed, personal fees from NuMedii, personal fees from Indaloo, personal fees from Theravance, personal fees from LifeMax, personal fees from Three Lake Partners, personal fees from Optikira, non-financial support from MiRagen, outside the submitted work; In addition, Dr. Kaminski has a patent 62/849,644 pending.
Conflict of interest: Dr. Hasegawa has nothing to disclose.
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- Received April 15, 2020.
- Accepted May 7, 2021.
- Copyright ©The authors 2021. For reproduction rights and permissions contact permissions{at}ersnet.org