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

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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

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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.

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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

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