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 the pathogenesis of IPF, identification of functional fibroblasts is warranted. The aim of this study was 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. We determined the role of fibroblasts positive for meflin using bleomycin (BLM)-induced pulmonary fibrosis.
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. A BLM-induced lung fibrosis model for meflin-deficient mice showed that fibroblasts positive for meflin had anti-fibrotic properties to prevent pulmonary fibrosis. Although transforming growth factor-β-induced fibrogenesis and cell senescence with the 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.
Abstract
Fibroblastic foci are the pathological hallmark lesions in idiopathic pulmonary fibrosis. This study identified a novel population of fibroblasts positive for meflin in fibroblastic foci. Fibroblasts positive for meflin had anti-fibrotic properties. https://bit.ly/3fabMo6
Footnotes
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Author contributions: Y. Nakahara, N. Hashimoto and K. Sakamoto developed the concept and design of the study. Y. Nakahara, N. Hashimoto, K. Sakamoto, N. Omote, A. Ando, K. Wakahara, A. Suzuki, M. Inoue, A. Hara and Y. Mizutani acquired data. Y. Nakahara, N. Hashimoto, K. Sakamoto and T.S. Adams provided analyses. Y. Nakahara, N. Hashimoto and K. Sakamoto were involved in interpretation of data. T. Yokoi performed pathological assessment. A. Enomoto, T.S. Adams, S. Poli, I.O. Rosas and N. Kaminski provided essential material. Y. Nakahara and N. Hashimoto wrote the manuscript. M. Takahashi, K. Imaizumi, T. Kawabe, I.O. Rosas, N. Kaminski and Y. Hasegawa contributed to scientific discussion. All authors reviewed and approved the manuscript.
Conflict of interest: Y. Nakahara has nothing to disclose.
Conflict of interest: N. Hashimoto received a research grant from Boehringer Ingelheim, outside the submitted work.
Conflict of interest: K. Sakamoto has nothing to disclose.
Conflict of interest: A. Enomoto has nothing to disclose.
Conflict of interest: T.S. Adams is an inventor on a provisional patent application (62/849,644) that covers methods related to IPF-associated cell subsets.
Conflict of interest: T. Yokoi has nothing to disclose.
Conflict of interest: N. Omote has nothing to disclose.
Conflict of interest: S. Poli is an inventor on a provisional patent application (62/849,644) that covers methods related to IPF-associated cell subsets.
Conflict of interest: A. Ando has nothing to disclose.
Conflict of interest: K. Wakahara has nothing to disclose.
Conflict of interest: A. Suzuki has nothing to disclose.
Conflict of interest: M. Inoue has nothing to disclose.
Conflict of interest: A. Hara has nothing to disclose.
Conflict of interest: Y. Mizutani has nothing to disclose.
Conflict of interest: K. Imaizumi has nothing to disclose.
Conflict of interest: T. Kawabe has nothing to disclose.
Conflict of interest: I.O. Rosas is an inventor on a provisional patent application (62/849,644) that covers methods related to IPF-associated cell subsets.
Conflict of interest: M. Takahashi has nothing to disclose.
Conflict of interest: N. Kaminski served as a consultant to Biogen Idec, Boehringer Ingelheim, Third Rock, Pliant, Samumed, NuMedii, Indaloo, Theravance, LifeMax, Three Lake Partners and Optikira over the last 3 years and received nonfinancial support from MiRagen; and is an inventor on a provisional patent application (62/849,644) that covers methods related to IPF-associated cell subsets.
Conflict of interest: Y. Hasegawa has nothing to disclose.
Support statement: This work was supported by Grant-in-Aid for Young Scientists (B) (18K15948) to K. Sakamoto, AMED-CREST (Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology; 20gm1210009s0102 and 20gm0810007h0105) to A. Enomoto and M. Takahashi, Grant-in-Aid for challenging Exploratory Research (20K21599) to N. Hashimoto, CREST (Core Research for Evolutional Science and Technology; JPMJCR17H3) to N. Hashimoto, and the 24th Promotion Fund of the Annual Meeting of the Medical Society of Japan Commemorative Medicine to N. Hashimoto. This work was also supported by NIH grants R01 HL127349, U01 HL145567, U01 HL122626 and U54 HG008540 to N. Kaminski, NHLBI grant P01 HL114501 and support from the Pulmonary Fibrosis Fund to I.O. Rosa, and an unrestricted gift from Three Lake Partners to I.O. Rosa and N. Kaminski. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received April 15, 2020.
- Accepted May 7, 2021.
- Copyright ©The authors 2021. For reproduction rights and permissions contact permissions{at}ersnet.org
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