Over 200,000 older Americans currently suffer from chronic age-associated fibrotic lung disease (Cordier and Cottin, 2013; Lederer and Martinez, 2018; Richeldi et al., 2017) annually (Hecker, 2018; Lederer and Martinez, 2018; Martinez et al., 2017; Raghu et al., 2016). Alveolar epithelial cell damage, proliferation of fibroblasts and extracellular matrix (ECM) accumulation lead to irreversible disruption of the lung architecture (Kinoshita and Goto, 2019). While the etiology of IPF remains unknown, there is an ongoing need for understanding mechanisms of disease and diagnostic and prognostic biomarkers of disease (Drakopanagiotakis et al., 2018; Tzouvelekis et al., 2016).

Extracellular vesicles (EVs), including exosomes and microvesicles, are potential candidates for elucidation of a biomarker signature for IPF and other fibrotic diseases (H Rashed et al., 2017). As a key component of cell–cell communication, EVs deliver miRNAs, mRNA, and tRNA into target cells (Yáñez-Mó et al., 2015). In addition, their systemic distribution in body fluids may reflect the presence of disease. The ease of collection and presence of exosomes in most body fluids, including blood, breast milk, saliva, urine, bile, pancreatic juice, cerebrospinal, and peritoneal fluids, have facilitated recent studies investigating their use as diagnostic and prognostic markers of disease (Keller et al., 2011; Raposo and Stoorvogel, 2013). Because exosomes are released by all cells and contain cargo from the cell of origin, it is conceivable that they deliver pathogenic materials leading to a disease phenotype. Whether the content of exosomes from different sources are the same has not been studied previously.

Molecular analysis of lung biopsies from individuals with IPF reveal a unique miRNA transcriptome compared with the miRNA transcriptome found from non-fibrotic lung biopsy samples providing evidence supporting the disease conferring properties of exosomes (Guiot et al., 2019). In serum isolated from individuals with IPF compared to control serum samples, there were 47 differentially expressed miRNAs (Yang et al., 2015). Njock et al. reported a signature of miR-142–3 p, miR-33a-5p, miR-let-7d-5p in sputum of individuals with IPF (Njock et al., 2019). Parimon et al. found that in lung tissue EVs isolated from mouse alveolar spaces and IPF lungs, TGF-β and Wnt signaling were increased after bleomycin (Bleo) treatment. These data trigger a hypothesis that dysregulation of miRNAs packaged in exosomes in diseased sources are involved in the development and progression of fibrosis (Guiot et al., 2019; Parimon et al., 2019).

To the best of our knowledge, there are no published studies using exosomes from urine of individuals with IPF (U-IPFexo) or any urine-derived exosomes in the investigation of fibrotic lung disease. In the present study we isolated and characterized exosomes isolated from the urine of 16 male individuals with IPF and 10 age and sex-matched control individuals to test the hypothesis that U-IPFexo cargo could promote a fibrotic phenotype. We found a a fibrotic miRNA expression pattern in serum and urine derved from the same individual with IPF. Our results also confirmed that several miRNAs previously reported in the lung, serum, and sputum from individuals with IPF (Njock et al., 2019; Pandit and Milosevic, 2015; Rajasekaran et al., 2015) could be identified in urine, lung, and serum IPFexo.

Intravenous infusion of urine exosomes isolated from both normal and diseased individuals using in vivo bioluminescent imaging system, revealed fairly rapid biodistribution to the lung. Ex vivo human and mouse lung punch studies and in vivo mouse models were used to functionally assess the effect of tissue (lungs) and systemic (urine and serum) exosomes isolated from individuals with IPF and ‘control’ exosomes isolated from urine and fibroblasts from control lungs (Habermann et al., 2019). U-IPFexo conveyed a pro-fibrotic lung phenotype and inhibited skin tissue repair. The unique signature was specific to IPFexo, and not only transferred a pro-fibrotic lung phenotype to control mice but further increased markers of lung fibrosis in vivo. Since body weight is independently associated with survival of individuals with IPF, we used body weight as a surrogate for stage of disease and found that mice lost more body weight after treatment with U-IPFexo than with Bleo treatment alone (Mogulkoc et al., 2018; Nakatsuka et al., 2018). We also included urine exosomes from subjects with non-cystic fibrosis (non-CF) bronchiectasis or asthma (non-fibrotic lung diseases) in in vivo experiments. Mice receiving these exosomes did not exhibit changes in fibrotic markers. These findings suggest that markers of lung fibrosis are specific, may be detected systemically, outside of the lung, and can communicate the pathology to different tissues. Importantly, urine exosomes have the potential to be used as disease-defining biomarkers in patients with IPF.

A complete list of source data including antibodies and primer sequences are included as supplement 1. An overview of the study is shown in Figure 1.

Figure 1

Download asset Open asset

EVs isolated from various tissues, cells and body fluids contain bioactive molecules such as proteins, lipids, and RNAs derived from the cell of origin (Collino et al., 2010; Vizoso et al., 2017). Most recently, studies on exosomes have focused on miRNAs, small noncoding RNA molecules able to influence protein expression. Since exosomes act as an interface for cell-cell communication, we investigated IPF disease exosomes and the ability of these ‘diseased’ exosomes to promote fibrotic lung disease and impair skin wound healing. Our study is the first to report that exosomes isolated from urine of IPF patients, U-IPFexo, confer a disease phenotype in vivo, in human ex vivo lung punches and impair ex vivo wound healing in mouse and human tissues. In a similar manner, MF-IPFexo activated markers of fibrosis in ex vivo lung punches compared to punches treated with lung fibroblast-derived exosomes isolated from the lung tissue of age and sex-matched individuals without fibrotic lung disease.

Changes in miRNAs have been implicated in gene expression associated with the development of IPF (Njock et al., 2019; Pandit and Milosevic, 2015; Yang et al., 2015). We found dysregulated expression of miRNAs; miR-let-7, miR-29a, miR-181b, and miR-199 in the isolated U-IPFexo compared to control exosomes. These miRNAs are known to regulate expression of pro-fibrotic, inflammatory and ECM encoding genes (McDonough et al., 2019b; Minnis et al., 2015; Njock et al., 2019; Noetel et al., 2012; Rajasekaran et al., 2015; Wang et al., 2016) and found in lung, serum, and sputum of individuals with IPF (Elliot et al., 2019; McDonough et al., 2019a; Pandit et al., 2010; Pandit and Milosevic, 2015; Rajasekaran et al., 2015; Yang et al., 2015), (Figure 10).

Figure 10

Download asset Open asset

Micro RNA let-7 regulates ERα protein expression as well as the regulation of downstream fibrotic inducers including TGF-β cell signaling pathways (Elliot et al., 2019). Dysregulation of miR-let-7 contributes to endothelial/epithelial to mesenchymal transition (Endo/EMT) in the lung (Pandit and Milosevic, 2015; Rajasekaran et al., 2015), heart (Wang et al., 2016) and kidney (Srivastava et al., 2020), often leading to fibrosis. Njock et al reported a positive correlation between diffusing capacity of the lungs for carbon monoxide/alveolar volume (DLCO/VA) and presence of let-7d (Njock et al., 2019). Dysregulation of miR-29 in the lung alters expression of MMP-2 and collagen1α1, while miR-199 regulates caveolin-1 (Cushing et al., 2011; Montgomery et al., 2014; Pandit and Milosevic, 2015; Rubio et al., 2018; Yang et al., 2013). Rescue of miR-181b, an inhibitor of NF-κB targets, suppressed TGFB in burns and in a Bleo model of lung injury (Song and Li, 2015; Sun et al., 2012). Increasing miR-181b expression mitigated TGF-B1 induced EMT in vitro and alleviated alveolar septal thickening and decreased collagen and MMP expression in vivo (Song and Li, 2015).

Collectively these data suggest the exosomes have an inherent ability to deliver expression of dysregulated miRNAs and may promote a disease phenotype. When distinct regions of lung tissue were analyzed from the same IPF lung and the histology labeled as minimal, moderate and end-stage disease severity divergent sets of genes and miRNA expression were dependent on the severity of diseased tissue (McDonough et al., 2019a). MicroRNA let-7, a critical marker in our studies, was associated with end-stage fibrotic lung disease. In a recent study, PBMC miRNA expression correlated with survival in individuals with IPF (Casanova et al., 2021), supporting the disease conferring role of miRNA expression as a potential signature of disease. In the present study, we compared expression of miRNAs from urine-derived exosomes and serum-derived exosomes isolated from the same individuals with IPF. We acknowledge that the absence of differences in miRNA expression between urine and serum-derived exosomes may reflect our small sample size. These data warrant a larger study that is currently ongoing.

To demonstrate delivery of exosomes to the lungs, we performed biodistribution experiments using U-IPFexo and urine exosomes from control subjects (without lung disease). The urine-derived exosomes were located in the lungs of 18-month-old male mice within 5 min followed by a diminished signal at 24–48 hr; similar transit time was recorded whether the urine exosomes were prepared from individuals with IPF or controls. Additional studies showed that an exosome signal was no longer visualized in the mouse at 19 days post-injection. Our studies used ExoGlow-Vivo that employs an amine binding dye emitting in the near infrared (NIR) range instead of infrared lipophilic cyanine dye, DiIC18 (DiD) to label urine derived exosomes. Since the ExoGlow dye is non-lipophilic it provides a more specific signal when used in vivo. Similar transit times have been reported using DiD to label bone marrow mesenchymal stem cell- derived exosomes showing delivery after intravenous infusion to the lung at 5 min and to the liver and spleen at 24 hr (Grange et al., 2014). Exosomes derived from breast cancer cells have a similar profile of biodistribution: lung,>liver > spleen, kidney >heart > bone marrow (Wen et al., 2016).

To study cellular and tissue interplay in the lung (Uhl et al., 2015; Zscheppang et al., 2018) we evaluated how the exosomes integrated in ex vivo lung punches by loading exosomes with nanoparticles and performing TEM (Betzer et al., 2017; Zeringer et al., 2013). We found that the punch architecture was preserved after injection of exosomes compared to non-injected and PBS injected punches, and urine-derived exosomes were integrated into AEC I or AEC II cells. Our studies could not distinguish whether homing of the ‘diseased’ exosomes favored a specific cell type compared to injection with control exosomes. These extensive studies are ongoing in our laboratory.

Further studies using ex vivo lung punches from human non-fibrotic lung tissue and naïve 18-month-old male mice noted minimal effect on the histology of the lung punch after treatment with PBS or urine-derived exosomes isolated from age and sex-matched controls without lung disease. We found that treatment with U-IPFexo increased expression of fibrotic markers and pathways (α_v-integrin, collagen type I and TGFβ mRNA expression, c-Jun protein expression and MMP-9 and AKT activation). Additionally, there was a notable decrease in SPC positive cells in punches (AEC II cells) receiving U-or MF-IPFexo. Since AEC II are regarded as the progenitor population of the alveolus responsible for injury repair and homeostatic maintenance, these data suggest that IPFexo may be inhibiting the repair mechanism in AEC II.

We have previously reported an increase of ERα protein expression in cells and tissue isolated from lungs of male individuals with IPF (Elliot et al., 2019). Studies suggest that activation of ERα may be profibrotic in multiple organs including the lung (Pedram et al., 2010; Zhao et al., 2018). In the current investigation, we found at least ~1.4-fold increase in ERα protein expression in human and mouse punches treated with U-IPFexo or MF-IPFexo. Punches injected with MF-IPFexo also induced other components of fibrotic pathways consistent with data derived from punches injected with U-IPFexo. Furthermore, U-IPFexo impaired the wound healing response, supporting our hypothesis that exosome cargo delivered signals impairing wound repair in skin. This suggests that the systemic feature of IPF exosomes may predispose impaired tissue healing, which can have significant clinical implications and will be further investigated.

We recognize that under our experimental conditions, lung punches lack immune recruitment, systemic perfusion and are under potentially hypoxic conditions. Therefore, we sought to determine if these exosomes would confer lung injury in vivo under normoxic conditions (21% oxygen) in old male C57BL/6 mice. We injected U-IPFexo into naive 18-month-old C57BL/6 mice and collected the lungs 21 days post-exosome treatment. Although there was no change in Ashcroft score, we noted increased collagen content (measured by hydroxyproline) and evidence of inflammatory cells including increased macrophages in lung tissue from mice treated with U-IPFexo compared to tissue from mice treated with control exosomes.

Another group of mice were treated with Bleo. Ashcroft score, collagen content, α_V-integrin and TGFβ mRNA expression increased in the lungs of mice treated with Bleo +U-IPFexo compared to mice treated with Bleo +vehicle and Bleo +control exosomes, suggesting that U-IPFexo escalated fibrotic pathways induced by Bleo in old male mice. There was no increase of TGFβ in lungs of mice treated with non-fibrotic exo. As reviewed, TGFβ is ubiquitous in chronic inflammatory lung diseases including COPD, IPF and asthma and may contribute to an immune-suppressed state (Thomas et al., 2016).

We also found an expected increase in MMP-2 activity in the lungs of U-IPFexo treated mice, as MMP-2 increases migration and invasiveness of lung myofibroblasts during Bleo-induced pulmonary fibrosis (Singh et al., 2017). This was in contrast to urine derived control exosomes or exosomes from urine of individuals with bronchiectasis or asthma. BW, historically shown to decrease with Bleo treatment (Cowley et al., 2019) was decreased in mice receiving Bleo +U-IPFexo compared to Bleo alone or Bleo +control exosomes. Loss of BW is associated with worse survival in individuals with IPF (Mogulkoc et al., 2018; Nakatsuka et al., 2018). Our studies also found similar changes in miRNA expression as reported in prior studies from patients with IPF (Tzouvelekis et al., 2016; Cushing et al., 2011; Disayabutr et al., 2016; Elliot et al., 2019; Guiot et al., 2019; Lino Cardenas et al., 2013; Njock et al., 2019; Omote and Sauler, 2020; Ortiz-Quintero et al., 2020; Pandit and Milosevic, 2015; Parimon et al., 2019; Shetty et al., 2017; Yang et al., 2015).

Our study demonstrates that U-IPFexo preparations contain disease invoking cargo. Parimon et al (Parimon et al., 2019) showed that antifibrotic microRNAs (miRs-144–3 p, –142–3 p, –34b-5p, –503–5 p) packaged into EVs regulate epithelial plasticity and potentially pulmonary fibrosis. Martin-Medina et al (Martin-Medina et al., 2018) reported an increase in the number of EV in BALF (bronchoalveolar lavage fluid) from Bleo-treated mice as well as from patients with IPF, that function as carriers for signaling mediators, such as WNT5A. Both studies reported that isolated EV preparations consisted predominantly of exosomes, although microvesicles were present, unlike our preparations that did not contain microvesicles. Neither study investigated urine-derived exosomes. In the present study, lung tissue isolated from naïve or Bleo-treated mice injected with U-IPFexo also exhibited the same changes in miRNA expression as found in ex vivo lung punches. The present study illustrates the potential correlation between changes in mRNA and protein expression (TGFβ, MMPs) and dysregulated miRNA expression suggesting that a miRNA signature could function as a potential biomarker for fibrotic lung disease. Reproducible biomarkers would enable early diagnosis and non-invasive detection methods are currently under investigation for multiple diseases (Tatler, 2019).

We further analyzed lungs from Bleo mice that were treated with exosomes derived from subjects with asthma or non-CF bronchiectasis, non-fibrotic lung diseases. We did not find an increase in the fibrotic markers studied and in fact noted a decrease in collagen content and integrin in the lung tissue. A limitation of our current studies includes a limited number of mice which will need to be expanded in future experiments. In addition, we recognize that subjects with asthma were not age matched to the control or IPF subjects. The decreased expression of miR-34a and –199, fibrotic inducing microRNAs highlight the differences in cargo content between exosomes from various lung diseases supporting future investigations (Usman et al., 2021; Weidner et al., 2021).

In an effort to detect expression of other potential fibrotic pathways, we analyzed the urine-exosomes for mRNA expression of TGFB, IGF, and Cav-1 (Frangogiannis, 2020; Garrett et al., 2019; Wicher et al., 2019). Because exosomes contain non-coding and other small coding RNAs, derived from transfer RNA (tRNA), ribosomal RNA (rRNA), small nuclear RNA (snRNA), and small nucleolar RNA (snoRNA) (Berrondo et al., 2016; Lv et al., 2014; Omote and Sauler, 2020; Pérez-Boza et al., 2018), we attempted to characterize the more easily studied expression of mRNA and mRNA fragments (Batagov and Kurochkin, 2013; Peake et al., 2014). As expected, we found no evidence of mRNA expression for our selected targets (supplement). However, the presence of 3’ UTR mRNA fragments which could bind miRNA and allow for RNA transcription to proceed in target cells ultimately altering the phenotype of otherwise healthy cells has been reported (Batagov and Kurochkin, 2013). This is an attractive hypothesis and warrants investigation especially in urine-derived exosomes that elicit a pathologic response (Batagov and Kurochkin, 2013). Further studies are in progress to expand our data and include determination of other disease provoking cargo that may be carried by IPF exosomes including tRNAs.

Our study provides the first evidence of circulating cargo found in U-IPFexo that confers disease in two target organs (lung and skin) and suggests a potential mechanism for initiation and/or progression of disease. To the best of our knowledge, the technology to completely empty exosome cargo to allow us to confirm the fibrotic role of specific miRNAs without damaging the exosomes, is not available. Our data suggest that IPF may have a systemic feature. In addition, urine-derived exosomes potentially represent a novel way to identify biomarkers for lung and fibrotic diseases and that miRNA profiling of urine-derived exosomes as biomarkers may lead to noninvasive assessments for earlier diagnosis. Overlap of miRNA expression yielding a fibrotic profile to produce a personalized panel of urine-derived miRNAs or fibromiRs to detect IPF and other lung and fibrotic diseases may be a future diagnostic and prognostic tool.

Numerical data used to generate the graphic figures is contained in source data files for Figures 2, 6, 7 and 8 and 8*S1.

1. 1. Aranda JF
   2. Canfrán-Duque A
   3. Goedeke L
   4. Suárez Y
   5. Fernández-Hernando C

   (2015) The mir-199-dynamin regulatory axis controls receptor-mediated endocytosis

   Journal of Cell Science 128:3197–3209.

   https://doi.org/10.1242/jcs.165233

   • PubMed
   • Google Scholar
2. 1. Ashcroft T
   2. Simpson JM
   3. Timbrell V

   (1988) Simple method of estimating severity of pulmonary fibrosis on a numerical scale

   Journal of Clinical Pathology 41:467–470.

   https://doi.org/10.1136/jcp.41.4.467

   • PubMed
   • Google Scholar
3. 1. Batagov AO
   2. Kurochkin IV

   (2013) Exosomes secreted by human cells transport largely mrna fragments that are enriched in the 3’-untranslated regions

   Biology Direct 8:12.

   https://doi.org/10.1186/1745-6150-8-12

   • PubMed
   • Google Scholar
4. 1. Berrondo C
   2. Flax J
   3. Kucherov V
   4. Siebert A
   5. Osinski T
   6. Rosenberg A
   7. Fucile C
   8. Richheimer S
   9. Beckham CJ

   (2016) Expression of the long non-coding RNA HOTAIR correlates with disease progression in bladder cancer and is contained in bladder cancer patient urinary exosomes

   PLOS ONE 11:e0147236.

   https://doi.org/10.1371/journal.pone.0147236

   • PubMed
   • Google Scholar
5. 1. Betzer O
   2. Perets N
   3. Angel A
   4. Motiei M
   5. Sadan T
   6. Yadid G
   7. Offen D
   8. Popovtzer R

   (2017) In vivo neuroimaging of exosomes using gold nanoparticles

   ACS Nano 11:10883–10893.

   https://doi.org/10.1021/acsnano.7b04495

   • PubMed
   • Google Scholar
6. 1. Casanova NG
   2. Zhou T
   3. Gonzalez-Garay ML
   4. Lussier YA
   5. Sweiss N
   6. Ma S-F
   7. Noth I
   8. Knox KS
   9. Garcia JGN

   (2021) MicroRNA and protein-coding gene expression analysis in idiopathic pulmonary fibrosis yields novel biomarker signatures associated to survival

   Translational Research 228:1–12.

   https://doi.org/10.1016/j.trsl.2020.07.009

   • PubMed
   • Google Scholar
7. 1. Collino F
   2. Deregibus MC
   3. Bruno S
   4. Sterpone L
   5. Aghemo G
   6. Viltono L
   7. Tetta C
   8. Camussi G

   (2010) Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of mirnas

   PLOS ONE 5:e11803.

   https://doi.org/10.1371/journal.pone.0011803

   • PubMed
   • Google Scholar
8. 1. Cordier JF
   2. Cottin V

   (2013) Neglected evidence in idiopathic pulmonary fibrosis: from history to earlier diagnosis

   The European Respiratory Journal 42:916–923.

   https://doi.org/10.1183/09031936.00027913

   • PubMed
   • Google Scholar
9. 1. Cowley PM
   2. Roberts CR
   3. Baker AJ

   (2019) Monitoring the health status of mice with bleomycin-induced lung injury by using body condition scoring

   Comparative Medicine 69:95–102.

   https://doi.org/10.30802/AALAS-CM-18-000060

   • PubMed
   • Google Scholar
10. 1. Cushing L
    2. Kuang PP
    3. Qian J
    4. Shao F
    5. Wu J
    6. Little F
    7. Thannickal VJ
    8. Cardoso WV
    9. Lü J

    (2011) Mir-29 is a major regulator of genes associated with pulmonary fibrosis

    American Journal of Respiratory Cell and Molecular Biology 45:287–294.

    https://doi.org/10.1165/rcmb.2010-0323OC

    • PubMed
    • Google Scholar
11. 1. Disayabutr S
    2. Kim EK
    3. Cha S-I
    4. Green G
    5. Naikawadi RP
    6. Jones KD
    7. Golden JA
    8. Schroeder A
    9. Matthay MA
    10. Kukreja J
    11. Erle DJ
    12. Collard HR
    13. Wolters PJ

    (2016) Mir-34 miRNAs regulate cellular senescence in type II alveolar epithelial cells of patients with idiopathic pulmonary fibrosis

    PLOS ONE 11:e0158367.

    https://doi.org/10.1371/journal.pone.0158367

    • PubMed
    • Google Scholar
12. 1. Drakopanagiotakis F
    2. Wujak L
    3. Wygrecka M
    4. Markart P

    (2018) Biomarkers in idiopathic pulmonary fibrosis

    Matrix Biology 68–69:404–421.

    https://doi.org/10.1016/j.matbio.2018.01.023

    • PubMed
    • Google Scholar
13. 1. Elliot S
    2. Periera-Simon S
    3. Xia X
    4. Catanuto P
    5. Rubio G
    6. Shahzeidi S
    7. El Salem F
    8. Shapiro J
    9. Briegel K
    10. Korach KS
    11. Glassberg MK

    (2019) Microrna let-7 downregulates ligand-independent estrogen receptor-mediated male-predominant pulmonary fibrosis

    American Journal of Respiratory and Critical Care Medicine 200:1246–1257.

    https://doi.org/10.1164/rccm.201903-0508OC

    • PubMed
    • Google Scholar
14. 1. Frangogiannis NG

    (2020) Transforming growth factor-β in tissue fibrosis

    The Journal of Experimental Medicine 217:e20190103.

    https://doi.org/10.1084/jem.20190103

    • PubMed
    • Google Scholar
15. 1. Garrett SM
    2. Hsu E
    3. Thomas JM
    4. Pilewski JM
    5. Feghali-Bostwick C

    (2019) Insulin-Like growth factor (IGF) -II- mediated fibrosis in pathogenic lung conditions

    PLOS ONE 14:e0225422.

    https://doi.org/10.1371/journal.pone.0225422

    • PubMed
    • Google Scholar
16. 1. Glassberg MK
    2. Choi R
    3. Manzoli V
    4. Shahzeidi S
    5. Rauschkolb P
    6. Voswinckel R
    7. Aliniazee M
    8. Xia X
    9. Elliot SJ

    (2014) 17Β-Estradiol replacement reverses age-related lung disease in estrogen-deficient C57BL/6J mice

    Endocrinology 155:441–448.

    https://doi.org/10.1210/en.2013-1345

    • PubMed
    • Google Scholar
17. 1. Grange C
    2. Tapparo M
    3. Bruno S
    4. Chatterjee D
    5. Quesenberry PJ
    6. Tetta C
    7. Camussi G

    (2014) Biodistribution of mesenchymal stem cell-derived extracellular vesicles in a model of acute kidney injury monitored by optical imaging

    International Journal of Molecular Medicine 33:1055–1063.

    https://doi.org/10.3892/ijmm.2014.1663

    • PubMed
    • Google Scholar
18. 1. Guiot J
    2. Struman I
    3. Louis E
    4. Louis R
    5. Malaise M
    6. Njock MS

    (2019) Exosomal miRNAs in lung diseases: from biologic function to therapeutic targets

    Journal of Clinical Medicine 8:E1345.

    https://doi.org/10.3390/jcm8091345

    • PubMed
    • Google Scholar
19. 1. Gurunathan S
    2. Kang MH
    3. Jeyaraj M
    4. Qasim M
    5. Kim JH

    (2019) Review of the isolation, characterization, biological function, and multifarious therapeutic approaches of exosomes

    Cells 8:307.

    https://doi.org/10.3390/cells8040307

    • PubMed
    • Google Scholar
20. Preprint

    1. Habermann AC
    2. Gutierrez AJ
    3. Bui LT
    4. Yahn SL
    5. Winters NI
    6. Calvi CL
    7. Peter L
    8. Chung MI
    9. Taylor CJ
    10. Jetter C
    11. Raju L
    12. Roberson J
    13. Ding G
    14. Wood L
    15. Sucre JM
    16. Richmond BW
    17. Serezani AP
    18. McDonnell WJ
    19. Mallal SB
    20. Bacchetta MJ
    21. Loyd JE
    22. Shaver CM
    23. Ware LB
    24. Bremner R
    25. Walia R
    26. Blackwell TS
    27. Banovich NE
    28. Kropski JA

    (2019) Single-Cell RNA-Sequencing Reveals Profibrotic Roles of Distinct Epithelial and Mesenchymal Lineages in Pulmonary Fibrosis

    bioRxiv.

    https://doi.org/10.1101/753806

    • Google Scholar
21. 1. Hecker L

    (2018) Mechanisms and consequences of oxidative stress in lung disease: therapeutic implications for an aging populace

    American Journal of Physiology. Lung Cellular and Molecular Physiology 314:L642–L653.

    https://doi.org/10.1152/ajplung.00275.2017

    • PubMed
    • Google Scholar
22. 1. H Rashed M
    2. Bayraktar E
    3. K Helal G
    4. Abd-Ellah MF
    5. Amero P
    6. Chavez-Reyes A
    7. Rodriguez-Aguayo C

    (2017) Exosomes: from garbage bins to promising therapeutic targets

    International Journal of Molecular Sciences 18:E538.

    https://doi.org/10.3390/ijms18030538

    • PubMed
    • Google Scholar
23. 1. Karl M
    2. Berho M
    3. Pignac-Kobinger J
    4. Striker GE
    5. Elliot SJ

    (2006) Differential effects of continuous and intermittent 17beta-estradiol replacement and tamoxifen therapy on the prevention of glomerulosclerosis: modulation of the mesangial cell phenotype in vivo

    The American Journal of Pathology 169:351–361.

    https://doi.org/10.2353/ajpath.2006.051255

    • PubMed
    • Google Scholar
24. 1. Keller S
    2. Ridinger J
    3. Rupp AK
    4. Janssen JWG
    5. Altevogt P

    (2011) Body fluid derived exosomes as a novel template for clinical diagnostics

    Journal of Translational Medicine 9:86.

    https://doi.org/10.1186/1479-5876-9-86

    • PubMed
    • Google Scholar
25. 1. Kinoshita T
    2. Goto T

    (2019) Molecular mechanisms of pulmonary fibrogenesis and its progression to lung cancer: a review

    International Journal of Molecular Sciences 20:E1461.

    https://doi.org/10.3390/ijms20061461

    • PubMed
    • Google Scholar
26. 1. Lederer DJ
    2. Martinez FJ

    (2018) Idiopathic pulmonary fibrosis

    The New England Journal of Medicine 379:797–798.

    https://doi.org/10.1056/NEJMc1807508

    • PubMed
    • Google Scholar
27. 1. Lino Cardenas CL
    2. Kaminski N
    3. Kass DJ

    (2013) Micromanaging microRNAs: using murine models to study microRNAs in lung fibrosis

    Drug Discovery Today. Disease Models 10:e145–e151.

    https://doi.org/10.1016/j.ddmod.2012.11.003

    • PubMed
    • Google Scholar
28. 1. Lv J
    2. Huang Z
    3. Liu H
    4. Liu H
    5. Cui W
    6. Li B
    7. He H
    8. Guo J
    9. Liu Q
    10. Zhang Y
    11. Wu Q

    (2014) Identification and characterization of long intergenic non-coding RNAs related to mouse liver development

    Molecular Genetics and Genomics 289:1225–1235.

    https://doi.org/10.1007/s00438-014-0882-9

    • PubMed
    • Google Scholar
29. 1. Martin-Medina A
    2. Lehmann M
    3. Burgy O
    4. Hermann S
    5. Baarsma HA
    6. Wagner DE
    7. De Santis MM
    8. Ciolek F
    9. Hofer TP
    10. Frankenberger M
    11. Aichler M
    12. Lindner M
    13. Gesierich W
    14. Guenther A
    15. Walch A
    16. Coughlan C
    17. Wolters P
    18. Lee JS
    19. Behr J
    20. Königshoff M

    (2018) Increased extracellular vesicles mediate wnt5a signaling in idiopathic pulmonary fibrosis

    American Journal of Respiratory and Critical Care Medicine 198:1527–1538.

    https://doi.org/10.1164/rccm.201708-1580OC

    • PubMed
    • Google Scholar
30. 1. Martinez FJ
    2. Collard HR
    3. Pardo A
    4. Raghu G
    5. Richeldi L
    6. Selman M
    7. Swigris JJ
    8. Taniguchi H
    9. Wells AU

    (2017) Idiopathic pulmonary fibrosis

    Nature Reviews. Disease Primers 3:17074.

    https://doi.org/10.1038/nrdp.2017.74

    • PubMed
    • Google Scholar
31. 1. McDonough JE
    2. Ahangari F
    3. Li Q
    4. Jain S
    5. Verleden SE
    6. Herazo-Maya J
    7. Vukmirovic M
    8. DeIuliis G
    9. Tzouvelekis A
    10. Tanabe N
    11. Chu F
    12. Yan X
    13. Verschakelen J
    14. Homer RJ
    15. Manatakis DV
    16. Zhang J
    17. Ding J
    18. Maes K
    19. De Sadeleer L
    20. Vos R
    21. Neyrinck A
    22. Benos PV
    23. Bar-Joseph Z
    24. Tantin D
    25. Hogg JC
    26. Vanaudenaerde BM
    27. Wuyts WA
    28. Kaminski N

    (2019a) Transcriptional regulatory model of fibrosis progression in the human lung

    JCI Insight 4:22.

    https://doi.org/10.1172/jci.insight.131597

    • PubMed
    • Google Scholar
32. 1. McDonough JE
    2. Kaminski N
    3. Thienpont B
    4. Hogg JC
    5. Vanaudenaerde BM
    6. Wuyts WA

    (2019b) Gene correlation network analysis to identify regulatory factors in idiopathic pulmonary fibrosis

    Thorax 74:132–140.

    https://doi.org/10.1136/thoraxjnl-2018-211929

    • PubMed
    • Google Scholar
33. 1. Minnis P
    2. Kane R
    3. Anglin R
    4. Walsh S
    5. Worrel J
    6. Khan F
    7. Lumsden RV
    8. Whitty S
    9. Keane MP

    (2015) Serum exosomes from IPF patients display a fibrotic mirna profile that correlates to clinical measures of disease severity

    Pulmonary Fibrosis: Mechanisms of Disease 46:A3845.

    https://doi.org/10.1183/13993003.congress-2015.PA3845

    • Google Scholar
34. 1. Mogulkoc N
    2. Sterclova M
    3. Müller V
    4. Kus J
    5. Hajkova M
    6. Jovanovic D
    7. Tekavec-Trkanjec J
    8. Janotova M
    9. Vasakova M

    (2018) Does body mass index have prognostic significance for patients with idiopathic pulmonary fibrosis?

    European Respiratory Journal 52:PA2210.

    https://doi.org/10.1183/13993003.congress-2018.PA2210

    • Google Scholar
35. 1. Montgomery RL
    2. Yu G
    3. Latimer PA
    4. Stack C
    5. Robinson K
    6. Dalby CM
    7. Kaminski N
    8. van Rooij E

    (2014) Microrna mimicry blocks pulmonary fibrosis

    EMBO Molecular Medicine 6:1347–1356.

    https://doi.org/10.15252/emmm.201303604

    • PubMed
    • Google Scholar
36. 1. Nakatsuka Y
    2. Handa T
    3. Kokosi M
    4. Tanizawa K
    5. Puglisi S
    6. Jacob J
    7. Sokai A
    8. Ikezoe K
    9. Kanatani KT
    10. Kubo T
    11. Tomioka H
    12. Taguchi Y
    13. Nagai S
    14. Chin K
    15. Mishima M
    16. Wells AU
    17. Hirai T

    (2018) The clinical significance of body weight loss in idiopathic pulmonary fibrosis patients

    Respiration; International Review of Thoracic Diseases 96:338–347.

    https://doi.org/10.1159/000490355

    • PubMed
    • Google Scholar
37. 1. Njock M-S
    2. Guiot J
    3. Henket MA
    4. Nivelles O
    5. Thiry M
    6. Dequiedt F
    7. Corhay J-L
    8. Louis RE
    9. Struman I

    (2019) Sputum exosomes: promising biomarkers for idiopathic pulmonary fibrosis

    Thorax 74:309–312.

    https://doi.org/10.1136/thoraxjnl-2018-211897

    • PubMed
    • Google Scholar
38. 1. Noetel A
    2. Kwiecinski M
    3. Elfimova N
    4. Huang J
    5. Odenthal M

    (2012) Microrna are central players in anti- and profibrotic gene regulation during liver fibrosis

    Frontiers in Physiology 3:49.

    https://doi.org/10.3389/fphys.2012.00049

    • PubMed
    • Google Scholar
39. 1. Omote N
    2. Sauler M

    (2020) Non-coding rnas as regulators of cellular senescence in idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease

    Frontiers in Medicine 7:603047.

    https://doi.org/10.3389/fmed.2020.603047

    • PubMed
    • Google Scholar
40. 1. Ortiz-Quintero B
    2. Buendía-Roldán I
    3. Ramírez-Salazar EG
    4. Balderas-Martínez YI
    5. Ramírez-Rodríguez SL
    6. Martínez-Espinosa K
    7. Selman M

    (2020) Circulating microrna signature associated to interstitial lung abnormalities in respiratory asymptomatic subjects

    Cells 9:E1556.

    https://doi.org/10.3390/cells9061556

    • PubMed
    • Google Scholar
41. 1. Pandit KV
    2. Corcoran D
    3. Yousef H
    4. Yarlagadda M
    5. Tzouvelekis A
    6. Gibson KF
    7. Konishi K
    8. Yousem SA
    9. Singh M
    10. Handley D
    11. Richards T
    12. Selman M
    13. Watkins SC
    14. Pardo A
    15. Ben-Yehudah A
    16. Bouros D
    17. Eickelberg O
    18. Ray P
    19. Benos PV
    20. Kaminski N

    (2010) Inhibition and role of let-7d in idiopathic pulmonary fibrosis

    American Journal of Respiratory and Critical Care Medicine 182:220–229.

    https://doi.org/10.1164/rccm.200911-1698OC

    • PubMed
    • Google Scholar
42. 1. Pandit KV
    2. Milosevic J

    (2015) MicroRNA regulatory networks in idiopathic pulmonary fibrosis

    Biochemistry and Cell Biology = Biochimie et Biologie Cellulaire 93:129–137.

    https://doi.org/10.1139/bcb-2014-0101

    • PubMed
    • Google Scholar
43. 1. Parimon T
    2. Yao C
    3. Habiel DM
    4. Ge L
    5. Bora SA
    6. Brauer R
    7. Evans CM
    8. Xie T
    9. Alonso-Valenteen F
    10. Medina-Kauwe LK
    11. Jiang D
    12. Noble PW
    13. Hogaboam CM
    14. Deng N
    15. Burgy O
    16. Antes TJ
    17. Königshoff M
    18. Stripp BR
    19. Gharib SA
    20. Chen P

    (2019) Syndecan-1 promotes lung fibrosis by regulating epithelial reprogramming through extracellular vesicles

    JCI Insight 5:129359.

    https://doi.org/10.1172/jci.insight.129359

    • PubMed
    • Google Scholar
44. 1. Pastar I
    2. Stojadinovic O
    3. Sawaya AP
    4. Stone RC
    5. Lindley LE
    6. Ojeh N
    7. Vukelic S
    8. Samuels HH
    9. Tomic-Canic M

    (2016) Skin metabolite, farnesyl pyrophosphate, regulates epidermal response to inflammation, oxidative stress, and migration

    Journal of Cellular Physiology 231:2452–2463.

    https://doi.org/10.1002/jcp.25357

    • PubMed
    • Google Scholar
45. 1. Peake PW
    2. Pianta TJ
    3. Succar L
    4. Fernando M
    5. Pugh DJ
    6. McNamara K
    7. Endre ZH

    (2014) A comparison of the ability of levels of urinary biomarker proteins and exosomal mRNA to predict outcomes after renal transplantation

    PLOS ONE 9:e98644.

    https://doi.org/10.1371/journal.pone.0098644

    • PubMed
    • Google Scholar
46. 1. Pedram A
    2. Razandi M
    3. O’Mahony F
    4. Lubahn D
    5. Levin ER

    (2010) Estrogen receptor-beta prevents cardiac fibrosis

    Molecular Endocrinology 24:2152–2165.

    https://doi.org/10.1210/me.2010-0154

    • PubMed
    • Google Scholar
47. 1. Pérez-Boza J
    2. Lion M
    3. Struman I

    (2018) Exploring the RNA landscape of endothelial exosomes

    RNA 24:423–435.

    https://doi.org/10.1261/rna.064352.117

    • PubMed
    • Google Scholar
48. 1. Potier M
    2. Karl M
    3. Zheng F
    4. Elliot SJ
    5. Striker GE
    6. Striker LJ

    (2002) Estrogen-Related abnormalities in glomerulosclerosis-prone mice: reduced mesangial cell estrogen receptor expression and prosclerotic response to estrogens

    The American Journal of Pathology 160:1877–1885.

    https://doi.org/10.1016/S0002-9440(10)61134-0

    • PubMed
    • Google Scholar
49. 1. Raghu G
    2. Chen SY
    3. Hou Q
    4. Yeh WS
    5. Collard HR

    (2016) Incidence and prevalence of idiopathic pulmonary fibrosis in US adults 18-64 years old

    The European Respiratory Journal 48:179–186.

    https://doi.org/10.1183/13993003.01653-2015

    • PubMed
    • Google Scholar
50. 1. Raghu G
    2. Remy-Jardin M
    3. Richeldi L
    4. Thomson CC
    5. Inoue Y
    6. Johkoh T
    7. Kreuter M
    8. Lynch DA
    9. Maher TM
    10. Martinez FJ
    11. Molina-Molina M
    12. Myers JL
    13. Nicholson AG
    14. Ryerson CJ
    15. Strek ME
    16. Troy LK
    17. Wijsenbeek M
    18. Mammen MJ
    19. Hossain T
    20. Bissell BD
    21. Herman DD
    22. Hon SM
    23. Kheir F
    24. Khor YH
    25. Macrea M
    26. Antoniou KM
    27. Bouros D
    28. Buendia-Roldan I
    29. Caro F
    30. Crestani B
    31. Ho L
    32. Morisset J
    33. Olson AL
    34. Podolanczuk A
    35. Poletti V
    36. Selman M
    37. Ewing T
    38. Jones S
    39. Knight SL
    40. Ghazipura M
    41. Wilson KC

    (2022) Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT clinical practice guideline

    American Journal of Respiratory and Critical Care Medicine 205:e18–e47.

    https://doi.org/10.1164/rccm.202202-0399ST

    • PubMed
    • Google Scholar
51. 1. Rajasekaran S
    2. Rajaguru P
    3. Sudhakar Gandhi PS

    (2015) Micrornas as potential targets for progressive pulmonary fibrosis

    Frontiers in Pharmacology 6:254.

    https://doi.org/10.3389/fphar.2015.00254

    • PubMed
    • Google Scholar
52. 1. Raposo G
    2. Stoorvogel W

    (2013) Extracellular vesicles: exosomes, microvesicles, and friends

    The Journal of Cell Biology 200:373–383.

    https://doi.org/10.1083/jcb.201211138

    • PubMed
    • Google Scholar
53. 1. Richeldi L
    2. Collard HR
    3. Jones MG

    (2017) Idiopathic pulmonary fibrosis

    Lancet 389:1941–1952.

    https://doi.org/10.1016/S0140-6736(17)30866-8

    • PubMed
    • Google Scholar
54. 1. Rubio GA
    2. Elliot SJ
    3. Wikramanayake TC
    4. Xia X
    5. Pereira-Simon S
    6. Thaller SR
    7. Glinos GD
    8. Jozic I
    9. Hirt P
    10. Pastar I
    11. Tomic-Canic M
    12. Glassberg MK

    (2018) Mesenchymal stromal cells prevent bleomycin-induced lung and skin fibrosis in aged mice and restore wound healing

    Journal of Cellular Physiology 233:5503–5512.

    https://doi.org/10.1002/jcp.26418

    • PubMed
    • Google Scholar
55. 1. Schmittgen TD
    2. Livak KJ

    (2008) Analyzing real-time PCR data by the comparative C (T) method

    Nature Protocols 3:1101–1108.

    https://doi.org/10.1038/nprot.2008.73

    • PubMed
    • Google Scholar
56. 1. Shetty SK
    2. Tiwari N
    3. Marudamuthu AS
    4. Puthusseri B
    5. Bhandary YP
    6. Fu J
    7. Levin J
    8. Idell S
    9. Shetty S

    (2017) P53 and miR-34a feedback promotes lung epithelial injury and pulmonary fibrosis

    The American Journal of Pathology 187:1016–1034.

    https://doi.org/10.1016/j.ajpath.2016.12.020

    • PubMed
    • Google Scholar
57. 1. Singh B
    2. Kasam RK
    3. Sontake V
    4. Wynn TA
    5. Madala SK

    (2017) Repetitive intradermal bleomycin injections evoke T-helper cell 2 cytokine-driven pulmonary fibrosis

    American Journal of Physiology. Lung Cellular and Molecular Physiology 313:L796–L806.

    https://doi.org/10.1152/ajplung.00184.2017

    • PubMed
    • Google Scholar
58. Conference

    1. Song L
    2. Li D

    (2015) Toll like receptor 4 activation upregulates miR-181b attenuating pulmonary fibrosis via targeting TGFBR1

    Annual Congress 2015.

    https://doi.org/10.1183/13993003.congress-2015.OA2933

    • Google Scholar
59. 1. Srivastava SP
    2. Goodwin JE
    3. Kanasaki K
    4. Koya D

    (2020) Inhibition of angiotensin-converting enzyme ameliorates renal fibrosis by mitigating DPP-4 level and restoring antifibrotic microRNAs

    Genes 11:E211.

    https://doi.org/10.3390/genes11020211

    • PubMed
    • Google Scholar
60. 1. Stojadinovic O
    2. Tomic-Canic M

    (2013) Human ex vivo wound healing model

    Methods in Molecular Biology 1037:255–264.

    https://doi.org/10.1007/978-1-62703-505-7_14

    • PubMed
    • Google Scholar
61. 1. Sun X
    2. Icli B
    3. Wara AK
    4. Belkin N
    5. He S
    6. Kobzik L
    7. Hunninghake GM
    8. Vera MP
    9. Blackwell TS
    10. Baron RM
    11. Feinberg MW
    12. MICU Registry

    (2012) MicroRNA-181b regulates NF-κb-mediated vascular inflammation

    The Journal of Clinical Investigation 122:1973–1990.

    https://doi.org/10.1172/JCI61495

    • PubMed
    • Google Scholar
62. 1. Tashiro J
    2. Elliot SJ
    3. Gerth DJ
    4. Xia X
    5. Pereira-Simon S
    6. Choi R
    7. Catanuto P
    8. Shahzeidi S
    9. Toonkel RL
    10. Shah RH
    11. El Salem F
    12. Glassberg MK

    (2015) Therapeutic benefits of young, but not old, adipose-derived mesenchymal stem cells in a chronic mouse model of bleomycin-induced pulmonary fibrosis

    Translational Research 166:554–567.

    https://doi.org/10.1016/j.trsl.2015.09.004

    • PubMed
    • Google Scholar
63. 1. Tatler AL

    (2019) Recent advances in the non-invasive assessment of fibrosis using biomarkers

    Current Opinion in Pharmacology 49:110–115.

    https://doi.org/10.1016/j.coph.2019.09.010

    • PubMed
    • Google Scholar
64. 1. Thomas BJ
    2. Kan-O K
    3. Loveland KL
    4. Elias JA
    5. Bardin PG

    (2016) In the shadow of fibrosis: innate immune suppression mediated by transforming growth factor-β

    American Journal of Respiratory Cell and Molecular Biology 55:759–766.

    https://doi.org/10.1165/rcmb.2016-0248PS

    • PubMed
    • Google Scholar
65. 1. Tsukui T
    2. Sun K-H
    3. Wetter JB
    4. Wilson-Kanamori JR
    5. Hazelwood LA
    6. Henderson NC
    7. Adams TS
    8. Schupp JC
    9. Poli SD
    10. Rosas IO
    11. Kaminski N
    12. Matthay MA
    13. Wolters PJ
    14. Sheppard D

    (2020) Collagen-Producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis

    Nature Communications 11:1920.

    https://doi.org/10.1038/s41467-020-15647-5

    • PubMed
    • Google Scholar
66. 1. Tzouvelekis A
    2. Herazo-Maya J
    3. Sakamoto K
    4. Bouros D

    (2016) Biomarkers in the evaluation and management of idiopathic pulmonary fibrosis

    Current Topics in Medicinal Chemistry 16:1587–1598.

    https://doi.org/10.2174/1568026616666150930120959

    • PubMed
    • Google Scholar
67. 1. Uhl FE
    2. Vierkotten S
    3. Wagner DE
    4. Burgstaller G
    5. Costa R
    6. Koch I
    7. Lindner M
    8. Meiners S
    9. Eickelberg O
    10. Königshoff M

    (2015) Preclinical validation and imaging of Wnt-induced repair in human 3D lung tissue cultures

    The European Respiratory Journal 46:1150–1166.

    https://doi.org/10.1183/09031936.00183214

    • PubMed
    • Google Scholar
68. 1. Usman K
    2. Hsieh A
    3. Hackett TL

    (2021) The role of miRNAs in extracellular matrix repair and chronic fibrotic lung diseases

    Cells 10:1706.

    https://doi.org/10.3390/cells10071706

    • PubMed
    • Google Scholar
69. 1. Vizoso FJ
    2. Eiro N
    3. Cid S
    4. Schneider J
    5. Perez-Fernandez R

    (2017) Mesenchymal stem cell secretome: toward cell-free therapeutic strategies in regenerative medicine

    International Journal of Molecular Sciences 18:E1852.

    https://doi.org/10.3390/ijms18091852

    • PubMed
    • Google Scholar
70. 1. Wang J
    2. Liew OW
    3. Richards AM
    4. Chen YT

    (2016) Overview of microRNAs in cardiac hypertrophy, fibrosis, and apoptosis

    International Journal of Molecular Sciences 17:E749.

    https://doi.org/10.3390/ijms17050749

    • PubMed
    • Google Scholar
71. 1. Weidner J
    2. Bartel S
    3. Kılıç A
    4. Zissler UM
    5. Renz H
    6. Schwarze J
    7. Schmidt-Weber CB
    8. Maes T
    9. Rebane A
    10. Krauss-Etschmann S
    11. Rådinger M

    (2021) Spotlight on microRNAs in allergy and asthma

    Allergy 76:1661–1678.

    https://doi.org/10.1111/all.14646

    • PubMed
    • Google Scholar
72. 1. Wen SW
    2. Sceneay J
    3. Lima LG
    4. Wong CSF
    5. Becker M
    6. Krumeich S
    7. Lobb RJ
    8. Castillo V
    9. Wong KN
    10. Ellis S
    11. Parker BS
    12. Möller A

    (2016) The biodistribution and immune suppressive effects of breast cancer-derived exosomes

    Cancer Research 76:6816–6827.

    https://doi.org/10.1158/0008-5472.CAN-16-0868

    • PubMed
    • Google Scholar
73. 1. Wicher SA
    2. Prakash YS
    3. Pabelick CM

    (2019) Caveolae, caveolin-1 and lung diseases of aging

    Expert Review of Respiratory Medicine 13:291–300.

    https://doi.org/10.1080/17476348.2019.1575733

    • PubMed
    • Google Scholar
74. 1. Yáñez-Mó M
    2. Siljander PRM
    3. Andreu Z
    4. Zavec AB
    5. Borràs FE
    6. Buzas EI
    7. Buzas K
    8. Casal E
    9. Cappello F
    10. Carvalho J
    11. Colás E
    12. Cordeiro-da Silva A
    13. Fais S
    14. Falcon-Perez JM
    15. Ghobrial IM
    16. Giebel B
    17. Gimona M
    18. Graner M
    19. Gursel I
    20. Gursel M
    21. Heegaard NHH
    22. Hendrix A
    23. Kierulf P
    24. Kokubun K
    25. Kosanovic M
    26. Kralj-Iglic V
    27. Krämer-Albers EM
    28. Laitinen S
    29. Lässer C
    30. Lener T
    31. Ligeti E
    32. Linē A
    33. Lipps G
    34. Llorente A
    35. Lötvall J
    36. Manček-Keber M
    37. Marcilla A
    38. Mittelbrunn M
    39. Nazarenko I
    40. Nolte-’t Hoen ENM
    41. Nyman TA
    42. O’Driscoll L
    43. Olivan M
    44. Oliveira C
    45. Pállinger É
    46. Del Portillo HA
    47. Reventós J
    48. Rigau M
    49. Rohde E
    50. Sammar M
    51. Sánchez-Madrid F
    52. Santarém N
    53. Schallmoser K
    54. Ostenfeld MS
    55. Stoorvogel W
    56. Stukelj R
    57. Van der Grein SG
    58. Vasconcelos MH
    59. Wauben MHM
    60. De Wever O

    (2015) Biological properties of extracellular vesicles and their physiological functions

    Journal of Extracellular Vesicles 4:27066.

    https://doi.org/10.3402/jev.v4.27066

    • PubMed
    • Google Scholar
75. 1. Yang T
    2. Liang Y
    3. Lin Q
    4. Liu J
    5. Luo F
    6. Li X
    7. Zhou H
    8. Zhuang S
    9. Zhang H

    (2013) Mir-29 mediates TGFβ1-induced extracellular matrix synthesis through activation of PI3K-Akt pathway in human lung fibroblasts

    Journal of Cellular Biochemistry 114:1336–1342.

    https://doi.org/10.1002/jcb.24474

    • PubMed
    • Google Scholar
76. 1. Yang G
    2. Yang L
    3. Wang W
    4. Wang J
    5. Wang J
    6. Xu Z

    (2015) Discovery and validation of extracellular/circulating microRNAs during idiopathic pulmonary fibrosis disease progression

    Gene 562:138–144.

    https://doi.org/10.1016/j.gene.2015.02.065

    • PubMed
    • Google Scholar
77. 1. Zeringer E
    2. Li M
    3. Barta T
    4. Schageman J
    5. Pedersen KW
    6. Neurauter A
    7. Magdaleno S
    8. Setterquist R
    9. Vlassov AV

    (2013) Methods for the extraction and RNA profiling of exosomes

    World Journal of Methodology 3:11–18.

    https://doi.org/10.5662/wjm.v3.i1.11

    • PubMed
    • Google Scholar
78. 1. Zhao H
    2. Zhou L
    3. Li L
    4. Coon V J
    5. Chatterton RT
    6. Brooks DC
    7. Jiang E
    8. Liu L
    9. Xu X
    10. Dong Z
    11. DeMayo FJ
    12. Stulberg JJ
    13. Tourtellotte WG
    14. Bulun SE

    (2018) Shift from androgen to estrogen action causes abdominal muscle fibrosis, atrophy, and inguinal hernia in a transgenic male mouse model

    PNAS 115:E10427–E10436.

    https://doi.org/10.1073/pnas.1807765115

    • PubMed
    • Google Scholar
79. 1. Zscheppang K
    2. Berg J
    3. Hedtrich S
    4. Verheyen L
    5. Wagner DE
    6. Suttorp N
    7. Hippenstiel S
    8. Hocke AC

    (2018) Human pulmonary 3D models for translational research

    Biotechnology Journal 13:201700341.

    https://doi.org/10.1002/biot.201700341

    • PubMed
    • Google Scholar

Author details

1. Sharon Elliot

   DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, United States

   Contribution

   Conceptualization, Formal analysis, Supervision, Methodology, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   selliot28@hotmail.com

   Competing interests

   holds pending patent applications for Family - Mesenchymal stem cell-derived extracellular vesicles and uses thereof for treating and diagnosing fibrotic diseases (30309-001*), Family - Diagnostic and therapeutic uses of compositions comprising purified, enriched potent exosomes containing disease-based and therapy based signature cargo (130309-003*), and Family - Urine-derived exosomes from individuals with IPF carry pro-fibrotic cargo and impair tissue repair (130309-004*)

   "This ORCID iD identifies the author of this article:" 0000-0001-8622-1389

2. Paola Catanuto

   DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, United States

   Contribution

   Investigation, Visualization

   Competing interests

   No competing interests declared

3. Simone Pereira-simon

   DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, United States

   Contribution

   Investigation

   Competing interests

   No competing interests declared

4. Xiaomei Xia

   Department of Medicine, Division of Pulmonary, Critical Care and Sleep, University of Miami, Miami, United States

   Contribution

   Investigation

   Competing interests

   No competing interests declared

5. Shahriar Shahzeidi

   Medical Director, Grand Health Institute, Miami, United States

   Contribution

   Supervision, Investigation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

6. Evan Roberts

   Cancer Modeling Shared Resource Sylvester Comprehensive Cancer Center, University of Miami, Miami, United States

   Contribution

   Supervision, Investigation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

7. John Ludlow

   ZenBio Inc., Durham, United States

   Contribution

   Validation, Investigation, Methodology, Writing – review and editing

   Competing interests

   ZenBio

8. Suzana Hamdan

   1. Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, United States
   2. Dr. JT Macdonald Foundation Biomedical Nanotechnology Institute, University of Miami Miller School of Medicine, Miami, United States

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

9. Sylvia Daunert

   1. Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, United States
   2. Dr. JT Macdonald Foundation Biomedical Nanotechnology Institute, University of Miami Miller School of Medicine, Miami, United States
   3. Miami Clinical and Translational Science Institute, University of Miami Miller School of Medicine, Miami, United States

   Contribution

   Supervision, Validation, Methodology

   Competing interests

   participated on a paid role on the Scientific Advisory Board for Akron Biotech and roles on the Scientific Advisory Board for ICN2 and on the Board of Trustees for BIST. SD also received payments/stock options from Berg Pharma and stock options from Aanika Biosciences. The author has no other competing interests to declare

10. Jennifer Parra

    Department of Medicine, Division of Pulmonary, Critical Care and Sleep, University of Miami, Miami, United States

    Contribution

    Resources, Investigation, Methodology

    Competing interests

    No competing interests declared

11. Rivka Stone

    Wound Healing and Regenerative Medicine Research Program, Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami, Miami, United States

    Contribution

    Supervision, Writing – review and editing

    Competing interests

    No competing interests declared

12. Irena Pastar

    Wound Healing and Regenerative Medicine Research Program, Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami, Miami, United States

    Contribution

    Conceptualization, Supervision, Funding acquisition, Investigation, Methodology, Writing – review and editing

    Competing interests

    No competing interests declared

13. Marjana Tomic-Canic

    Wound Healing and Regenerative Medicine Research Program, Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami, Miami, United States

    Contribution

    Resources, Supervision, Investigation, Methodology, Writing – review and editing

    Competing interests

    DSMB, provisional patent, NIH support

14. Marilyn K Glassberg

    1. DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, United States
    2. Department of Medicine, Division of Pulmonary, Critical Care and Sleep, University of Miami, Miami, United States
    3. Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Chicago, United States

    Contribution

    Conceptualization, Resources, Supervision, Funding acquisition, Writing – review and editing

    Competing interests

    holds pending patent applications for Family - Mesenchymal stem cell-derived extracellular vesicles and uses thereof for treating and diagnosing fibrotic diseases (30309-001*), Family - Diagnostic and therapeutic uses of compositions comprising purified, enriched potent exosomes containing disease-based and therapy based signature cargo (130309-003*), and Family - Urine-derived exosomes from individuals with IPF carry pro-fibrotic cargo and impair tissue repair (130309-004*). MKG has a role as Chair, DMSB, Medical College of South Carolina, Mesenchymal Stem Cells in Type I Diabetes (T1D) Phase 1 trial (July 2019-present). The author has no other competing interests to declare

• 699

  views

• 98

  downloads

• 3

  citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.