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Negrete-García, M.C.;  Ramos-Abundis, J.D.J.;  Alvarado-Vasquez, N. Exosomal Micro-RNAs as Intercellular Communicators. Encyclopedia. Available online: https://encyclopedia.pub/entry/29154 (accessed on 18 December 2025).
Negrete-García MC,  Ramos-Abundis JDJ,  Alvarado-Vasquez N. Exosomal Micro-RNAs as Intercellular Communicators. Encyclopedia. Available at: https://encyclopedia.pub/entry/29154. Accessed December 18, 2025.
Negrete-García, María Cristina, Javier De Jesús Ramos-Abundis, Noé Alvarado-Vasquez. "Exosomal Micro-RNAs as Intercellular Communicators" Encyclopedia, https://encyclopedia.pub/entry/29154 (accessed December 18, 2025).
Negrete-García, M.C.,  Ramos-Abundis, J.D.J., & Alvarado-Vasquez, N. (2022, October 13). Exosomal Micro-RNAs as Intercellular Communicators. In Encyclopedia. https://encyclopedia.pub/entry/29154
Negrete-García, María Cristina, et al. "Exosomal Micro-RNAs as Intercellular Communicators." Encyclopedia. Web. 13 October, 2022.
Exosomal Micro-RNAs as Intercellular Communicators
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This entry is adapted from the peer-reviewed paper 10.3390/ijms231911047

Communication between neighboring or distant cells is made through a complex network that includes extracellular vesicles (EVs). Exosomes, which are a subgroup of EVs, are released from most cell types and have been found in biological fluids such as urine, plasma, and airway secretions like bronchoalveolar lavage (BAL), nasal lavage, saliva, and sputum. Mainly, the cargo exosomes are enriched with mRNAs and microRNAs (miRNAs), which can be transferred to a recipient cell consequently modifying and redirecting its biological function. The effects of miRNAs derive from their role as gene expression regulators by repressing or degrading their target mRNAs. Various types of research are focused on evaluating the potential of exosomal miRNAs as biomarkers for the prognosis and diagnosis of different pathologies.

exosomes extracellular vesicles miRNA

1. Introduction

The pulmonary microenvironment is constituted of heterogeneous cell groups with different functions, and understandably, an adequate communication between them is indispensable in maintaining homeostasis and physiological processes [1][2]. Not long ago, chemokines, cytokines, growth factors, and adhesion molecules were considered the principal protagonists in intercellular communication. But recently, extracellular vesicles (EVs) have gained importance due to their substantial role as intercellular communicators via the transfer of their cargo to neighboring or distant cells [3][4][5][6]. EVs are structures delimited by a lipid bilayer of diverse sizes, shapes, and distinct biogenesis pathways. According to their size, EVs have been classified into exosomes (30–120 nm), microvesicles (MVs, 50–1000 nm), and apoptotic bodies of 50–2000 nm in diameter [3][6][7]. Exosomes play important roles in cell-to-cell communication, tissue repair, immune response and organism development [8][9]. Their content influences many cellular functions such as cell proliferation, differentiation, angiogenesis and modulation of the immune system [5][9][10]. It has been suggested that EVs can act as biomarkers for the diagnosis and prognosis of different respiratory diseases, since they are secreted by different cell types, both in normal cellular processes and pathological conditions [11][12][13]. Their content or cargo is heterogeneous, it is composed of proteins, lipids, and nucleic acids such as microRNAs (miRNAs), and is associated with their origin and the cellular microenvironment [6][14][15]. The cargo can be internalized by the recipient cell mainly by endocytosis or by direct fusion of exosomes with the membrane of the target cell to deliver their content into the cytosol [3][16][17]. The cargo delivery modifies and redirects the biological functions of the recipient cell, partially in response to the miRNAs present, and consequently regulating the post-transcriptional gene expression, differentiation, proliferation, and cell-to-cell interaction by repressing or degrading their target mRNAs [18][19].
On the other hand, idiopathic pulmonary fibrosis (IPF) is a progressive chronic interstitial lung disease of unknown etiology characterized by scar tissue accumulation and the histological picture of usual interstitial pneumonia (UIP), leading to a progressive decline of lung function with generally an average survival of 3–5 years after diagnosis, poor prognosis, with no cure and, consequently with few therapeutic options [20][21]. The incidence and prevalence of IPF increases with age and is diagnosed mostly in male patients older than 65 years. In this context, the immune system’s role in developing IPF has been widely discussed. Although many of the innate immune cells participate in mediating the inflammatory process, the role that they may play in the long run has been questioned [22], a reason why the importance of inflammation in the IPF etiology is still controversial and sometimes considered an epiphenomenon of fibrosis. Some evidence reported an increase in absolute values of neutrophils, macrophages, eosinophils, and epithelial cells in induced sputum from IPF patients in comparison to healthy subjects [23]. Moreover, an increase in the expression of defensins (DEFA3 and DEFA4) in acute exacerbations of IPF versus controlled IPF was detected [24]. The polarization of macrophages has also been involved with IPF. Although the M2 phenotype is normally considered anti-inflammatory, when the injury is persistent this phenotype is responsible for secreting pro-fibrotic factors such as TGFβ, PDGF, and VEGF which induces the activation and transformation of fibroblasts [25].

2. Exosomal-miRNAs as Intercellular Communicators

Inter-cellular communication includes signaling molecules and/or direct contact between cells [26]. In this complex landscape, non-coding RNAs like miRNAs have an important role, especially by the significant effects observed after their delivery to target cells [27]. The first evidence of the horizontal transfer of genetic information through EVs and the effects on the recipient cell were described in 2006. The transfer of exosomal mRNA and proteins from embryonic stem cells to hematopoietic progenitor cells was demonstrated [28]. In 2007 Valadi et al. provided the first evidence of the exosomal mRNA transfer between mouse donor cells and human recipient cells in an in vivo assay [29]. Shortly after, in 2008 Al-Nedawi, K et al., reported that oncogenic activity could be transferred through MVs and they named such vesicles “oncosomes” [30]. All these works indicated that the transfer of RNAs and proteins from exosomes, confers new functional and biological properties to the recipient cell.
Based on these findings, the protein and miRNAs enclosed into exosomes sparked interest as possible biomarkers. Taylor, D et al. demonstrated that exosomal miRNA profiling of circulating exosomes from tumors could be used as diagnostic marker between patients with benign ovarian disease and ovarian cancer [31]. Despite this evidence, the utility of exosomal miRNAs as probable prognostic biomarkers in tumoral diseases, and proofs of functional miRNA transfer with neighboring and/or distant recipient cells were scarce. In 2010 Pegtel M et al. hypothesized that miRNAs transferred through exosomes might have an important function as intercellular communicators by inhibiting the expression of their mRNA targets. To confirm this hypothesis, the researchers used as a model, EBV infection, demonstrating that miRNAs from exosomes of EBV-infected cells were transferred and delivered to subcellular sites repressing the gene expression in uninfected recipient cells [32]. In the same context, two years later the transfer of exosomal miRNAs between DCs was reported, confirming a new cell model of posttranscriptional regulation through exosomes [18]. A year later, Ismail et al. demonstrated that EVs-miRNAs derived from macrophages induce differentiation of their target cells, a fact that supports the role of EVs-miRNAs in the development of immune functions [33]. Considering all this information, the importance of EVs as vehicles of intercellular communication is confirmed as a relevant issue for future work.

3. Exosomal-miRNAs as Intercellular Communicators in IPF

Until recently, the impact of exosomal-miRNA in airway diseases, especially in IPF, had been not sufficiently emphasized. This was probably a consequence of a controversial paper published by Cheville et al., who suggested that the copy number of miRNAs in each EV was very low and possibly had no biological effect, and this assumption created a certain skepticism about EV´s functional role in vivo. The researchers reported that regardless of the exosome source (plasma, seminal fluid, mast cells, or ovarian cancer cells), over 100 exosomes were necessary to observe one copy of a given miRNA, which would significantly limit its effect on the cell or organism [34]. However, some recent research reported using optimized methods for exosome purification, confirming both in vitro and in vivo many different biological effects derived from the isolated exosomes [7][35][36][37].
The role of exosomes in IPF is a current study issue, and the increasing number of publications about this topic further supports its relevance. Therefore, researchers made a revision and analysis of the most recent papers that evaluated both the importance of exosomal- miRNAs as intercellular communicators, and as protagonists in the onset and progression of IPF.
As far as people know, the first study reporting the presence of exosomal miRNAs in serum of IPF patients was made by Makiguchi et al. These researchers reported the presence of serum exosomal miR-21-5p in a bleomycin fibrosis mouse model (BLM-fibrosis mouse model) as well as in serum from IPF patients. They suggest that the overexpression of miR-21-5p could be clinically associated with the risk of death in IPF [13].
The loss of Thy-1 (CD90) expression had been previously shown to correlate with active fibrogenesis in IPF due to its role as a regulator of myofibroblast differentiation. Moreover, Thy-1-integrinβ5 heterotypic interaction (in trans) also contributes by inhibiting the myofibroblastic differentiation induced by TGFβ [38][39]. In 2017 Shentu et al. investigated if Thy-1 expression was important in fibroblast uptake of EVs from MSCs (m-EVs) in comparison with EVs derived from normal human lung fibroblasts (NHLF) (f-EVs). Additionally, the researchers evaluated their role in myofibroblast differentiation and reported that m-EVs, but not f-EVs, suppressed TGFβ-induced myofibroblastic differentiation in a Thy-1 (CD90) dependent way, and moreover, that the interaction of Thy-1-β-integrins facilitated the mEVs uptake by fibroblasts. They also demonstrated the presence of miR-630 in m-EVs, but not in f-EVs, and that it plays an anti-fibrotic role during the differentiation of myofibroblasts by inhibiting the expression of different profibrotic genes [40]. In the study performed by Yao et al. it was reported that lung tissue of a BLM-fibrosis rat model had an over-expression of miR-328 and a under-expression of the family with sequence similarity 13-member A (FAM13A) gene. researchers  examined the role of exosomes derived from alveolar M2 Macrophages (AM2Mfs) of the BLM-fibrotic rat model and co-cultured with pulmonary interstitial fibroblasts. The results showed an over-expression of COL1A1, COL3A1, and ACTA2 (α-SMA) genes as well as a promotion in the proliferation of the fibroblasts. Finally, in in vivo studies where exosomal miR-328 was silenced using an antagomir, the fibrotic lung area was reported to be significantly inhibited, which was related to a decrease in the number of α-SMA and collagen-I positive cells. Results support the importance of inhibiting the expression of exosomal miR-328 and the regulation of its target gene FAM13 expression to attenuate the development of PF [41]. In addition to the role of EVs as intercellular communicators, the importance of some transmembrane proteins as regulators of the specific content within EVs has been recently reported. An example is Syndecan-1 protein, which besides participating in the exosome’s biogenesis, intervenes as a regulator in miRNA sorting into exosomes in lung tumorigenesis [42]. Syndecan-1 controls lung epithelial migration and adhesion processes [43]. A recent study performed in 2019 by Parimon et al. demonstrated that Syndecan-1 is overexpressed by AECII in IPF patients and in the BLM-fibrosis mouse model. Functional assays made in Syndecan-1 wild-type (WT) and with Syndecan-1 deficient (Sdc1−/−) mice treated with bleomycin, showed that Syndecan-1 promotes the proliferation and expansion of fibroblasts; moreover, it induces the epithelial reprogramming to the fibrotic phenotype through signaling pathways that involve TGFβ and Wnt/β-catenin. When EVs isolated from BALF of fibrotic lungs (F-EVs) were re-instilled intratracheally into the BLM-fibrosis-mouse model (WT and Sdc1−/−), they showed that F-EVs exacerbated lung fibrosis in the WT-BLM-mouse model in comparison with Sdc1−/− animals. Similar results were obtained in co-culture assays using lung epithelial cells with F-EVs from mice that were WT and with Sdc1−/− BLM-fibrosis. Therefore, the researchers concluded that F-EVs in fibrotic lungs increased the fibroproliferative signals through TGFβ and Wnt/β-catenin signaling pathways activity, and that Syndecan-1 facilitates the effect of F-EVs by reprogramming lung epithelial cells to the profibrotic phenotype. With additional experiments using miRNA-Seq of F-EVs isolated from the different BLM-mouse models, researchers observed that F-EVs from WT mice, in comparison with Sdc1−/− mice, had significant under-expression of the anti-fibrotic miR-503-5p, miR-34-b-5p, miR-144-3p, miR-142-3p. Additionally, they found that miR-144-3p and miR-142-3p had a similar trend of decreased EV levels in IPF patients versus control subjects, with an analogy to WT versus Sdc1−/− animal models, respectively. Thereby, they concluded that Syndecan-1 controls the packaging of antifibrotic miRNAs into EVs. Finally, they found that mice treated with Sdc1−/− EVs had reduced lung fibrosis compared with those receiving WT-EVs. The collagen content was also significantly reduced in Sdc1−/− EV-treated mice, while WT fibrotic mice did not show incremental fibrosis compared to saline controls. All these experiments demonstrated that Syndecan-1drives lung fibrosis in vivo through the regulation of EV-cargo [44].
Another study that supports the importance of exosomes as cell communication vesicles was carried out in 2020 by Kadota et al. The researchers evaluated whether EVs isolated from conditioned media (CM) of lung fibroblasts obtained from IPF subjects (F-EVs) or of EVs of NHLF (NF-EVs), could transfer their miRNAs to human bronchial epithelial cells (HBECs) and induce IPF-related phenotypic alterations. In the coculture of F-EVs with HBECs, a p21 and p16 over-expression were observed, and notably a positive staining of β-galactosidase, suggesting a probable role of F-EVs in cell senescence induction. In addition, an increase both in the intracellular levels of ROS (inROS) and in mitochondrial ROS (mtROS) production were found, a fact that could be associated with the aberrant activation of the DNA damage response (DDR). researchers also compared the profiles of miRNAs-cargo between F-EVs and NF-EVs and found six miRNAs significantly upregulated (miR-19a-3p, miR-23b-3p, miR-127-3p, miR-145-5p, miR-424-5p, miR-494-3p) in the F-EVs. Mitochondrial damage and the presence of senescence characteristics in the epithelial cells were associated with the transfer of miR-23b-3p and miR-494-3p to HEBC and with the inhibition of their specific targets SIRT3 [45].
It is well known that the cell-free secretome from stem cells can elicit protection and higher regeneration than the cells alone [46]. In 2020 Dinh and et al. evaluated the effect of lung spheroid cell’s-secretome (LSC-Sec), or lung spheroid cell exosomes (LSC-Exo) on lung regeneration in fibrosis mouse models induced by silica or bleomycin. Previous evidence showed that LSC-Sec and mesenchymal stem cell secretomes (MSC-Sec) attenuated fibrosis in mouse models, BLM-fibrosis models and silica-fibrosis mouse models, concluding that both treatments reduced fibrosis by preserving alveolar epithelial structures. Considering that a secretome is not only comprised of soluble proteins but also exosomes, the researchers evaluated whether tissue regeneration could be attributed to the exosomal miRNAs found in LSC-exosomes, and compared the results with those observed using MSC-exosomes of a BLM-fibrosis rat model. In both cases protective effects that maintain normal lung architecture and attenuate the fibrotic process, lung apoptosis, and collagen deposition were observed. The differential expression profiles of miRNAs showed that among the 42-upregulated miRNAs in LSC-Exo, miR-99a-5p and miR-100-5p and the anti-fibrotic miR-30a-3p were significant, while let-7a-5p and let-7f-5p were the most upregulated in the MSC-Exo. However, the potential targets of these expressed miRNAs were not determined, a question that should be answered in the following research reports. Additional experiments showed that both LSC-Sec as well as LSC-Exo promote lung repair in pulmonary fibrosis [47].
It has been recognized that bone mesenchymal stem cells (BMSCs) have the property of repairing injured tissues [48][49][50][51]. In this regard, in 2020 Wan et al. determined that the EVs derived from BMSCs inhibit proliferation, migration, invasion, and differentiation of the HFLF cell line (LL29). Likewise, a lower expression of miR-29 in lung tissues of IPF patients compared with tissues from healthy subjects was observed, confirming its anti-fibrotic role through regulation of genes such as COL1A1 and COL3A1. By exploring the mechanism by which BMSCs-EVs inhibited HFLF activation and IPF progression, HFLF cells were transfected with a miR-29 mimic, and as a result the inhibition of fibroblasts differentiation into myofibroblasts was observed. When the BMSC-EVs were transfected with a miR-29b-3p inhibitor and co-cultured with the HFLFs, their proliferation, migration, and invasion capacity were increased. Similarly, BMSC-EVs suppressed IPF progression in the IPF mouse model. Additional experiments showed that miR-29b-3p from BMSCs-EVs directly targets FZD6. Therefore, the researchers concluded that the protective effect of miR-29b-3p obtained from BMSCs-EVs happens through downregulation of its target FZD6, which may provide a novel treatment for IPF [52].
In the same year, another study evaluated whether the miRNAs derived from exosomes from sera of a BLM-fibrosis mouse model were involved in the fibroblast-to-myofibroblast differentiation in IPF. To verify this, the differential expression profiles of miRNAs extracted from exosomes of sera in both mice treated or not with bleomycin was determined. miR-22 was upregulated and its role in myofibroblast differentiation was studied. The transfection of human embryonic lung fibroblasts (HELF) with miR-22 mimic, or with miR-22 inhibitor in cells stimulated or not with TGFβ1, showed that miR-22 mimic transfection induces a decrease in α-SMA expression. In contrast, an over-expression of this gene was reported in the presence of miR-22 inhibitor. Additionally, miR-22 decreased the phosphorylation of ERK1/2 and the expression of connective tissue growth factor (CTGF) induced by TGFβ1. Finally, when miR-22 mimic was administrated after bleomycin challenge in the fibrosis mouse model, the collagen content in the lungs and the α-SMA expression were attenuated too, suggesting that exosomal miR-22 could be a therapeutic agent for the treatment of IPF [53].
Meanwhile, Guiot et al. assessed the impact of exosomal miRNAs on the progression of IPF, focusing specifically on the activity of miR-142-3p, which was significantly upregulated in exosomes from sputum and plasma of patients with IPF. The researchers had previously observed a positive correlation between the levels of exosomal miR-142-3p with the percentage of sputum macrophages in IPF patients. Therefore, they decided to evaluate the biological effect of this miRNA in AECs (A549 cell line) and in lung fibroblasts (LF) (MRC5 cell line) transfected with miR-142-3p mimics. Results showed a reduction both in the expression of TGFβRI mRNA, as well as in cellular proliferation. Therefore, they concluded that miR-142-3p had anti-fibrotic properties. Additionally, they studied the effect of exosomes obtained from macrophages on the expression of profibrotic genes. In co-culture assays from AECs and LF and THP1 macrophage-exosomes, they observed an increment of miR-142-3p levels in both cell lines, demonstrating that these exosomes can transfer miR-142-3p to the recipient cells. These vesicles were able to suppress profibrotic activation both in epithelial cells and in lung fibroblasts [54].
Another recent work evaluated the effect of miRNA-EVs on the physiology and pathogenic process of IPF by studying EVs from human bronchial epithelial cells (HBEC- EVs), and EVs from human small airway epithelial cells (HSAEC-EVs). In normal human primary lung fibroblasts (NHPLF) stimulated with TGFβ, and co-cultured with each EV type, it was observed that HBEC-EVs attenuated TGFβ-induced myofibroblasts differentiation by suppressing the expression of COL1A1and ACTA2 more efficiently than HSAEC-EVs. When the effect of these EVs as promoters of senescence on lung epithelial cells was examined, it was found that HBEC-EVs inhibited p21 expression and β-galactosidase induced by TGFβ. Additional experiments showed that both canonical and non-canonical WNT signaling pathways were the main mechanisms for HBEC-EVs mediated suppression of myofibroblast TGFβ-induced differentiation. It was also reported that 25 of the 30 miRNAs highly expressed in HBEC-EVs were downregulated in IPF lung samples, whereas 5 miRNAs were upregulated. The bioinformatic analysis of these miRNAs, determined that the 30 miRNAs present in HBEC-EVs negatively regulate TGFβ signaling, with a concomitant effect on WNT pathways. The analysis of the RNA-seq data of the recipient cells (NHPLF), reflected upstream participation of WNT5A, WNT3A, WNT1 and WNT10B, although only WNT5A and WNT10B were detectable by qRT-PCR. Among the 16 miRNAs targeting WNT5A were miR-26a, miR-26b, miR-141a, and miR-200a, which are included in the 30 most abundant in HEBC-EVs; while among the 19 miRNAs targeting WNT10B, were miR-16, miR-29, miR-29c and miR-148a. In mimic transfection assays of these miRNAs, it was demonstrated that only transfections with miR-16 and miR-148a mimics significantly suppressed WNT10B expression. And moreover, the anti-fibrotic properties of miR-16, miR-26a, miR26b, miR-141, miR148a, and miR-200a were confirmed by their ability to suppress TGFβ-induced myofibroblast differentiation. Additional experiments suggested also the likelihood that this specific miRNAs-cargo was responsible for HBEC senescence via regulation of the WNT signaling pathway. After probing the anti-fibrotic properties of HBEC-EVs in a BLM-mouse model, the results showed a significant attenuation of BLM-induced lung fibrosis, a consequence of diminution in the β-catenin expression in the lungs of these EV-treated mice. Likewise, the senescence markers p16 and p21 were clearly suppressed by HBEC-EVs treatment via negative regulation of TGFβ-WNT crosstalk. Taking these results together, the HBEC-EVs can be a promising cell-free antifibrotic modality for the treatment of IPF, via TGFβ-WNT signal pathways crosstalk [55].
In 2021 Inomata et al. analyzed the exosomal-miRNAs profile of serum from a BLM-fibrosis mouse model and in animals without challenge. They found over-expression of exosomal-miR-16 on day 14, in comparison to animals without bleomycin treatment, and decided to study the role of miR-16 in fibrosis both in vivo and in vitro assays. Interestingly, an anti-fibrotic effect in a BLM-fibrosis mouse model treated with miR-16 mimic administration on day 14 was observed. In these animals, the secretion of secreted protein acidic and rich in cysteine (SPARC) in serum, a protein involved with ECM formation and activated by the mTORC pathway, was inhibited. Additionally, miR-16 mimic or a negative control oligo was transfected into normal lung fibroblasts (HFL-1). Results obtained showed that miR-16 mimic significantly inhibited rapamycin-insensitive companion of mTOR (Rictor) expression in these lung fibroblasts. Therefore, the antifibrotic role of miR-16 in lung fibrosis by inhibiting the mTORC2-SPARC axis was demonstrated [56][57].
On the other hand, Zhou et al. investigated whether the release of miR-186, an anti-fibrotic miRNA in IPF, and its presence in the BMSC-EVs could interfere in the progression of IPF in a murine model. They co-cultured HFLF and BMSC-EVs and observed that the viability and invasiveness of the lung fibroblasts were significantly diminished, while apoptosis showed a significant increase after coculture with BMSC-EVs. By Western-blot and RT-qPCR analysis they identified a reduced expression of α-SMA and collagen I in this fibroblasts culture. When the effect of BMSC-EVs in a BLM-fibrosis mouse model was studied and compared with untreated animals, the results showed a decrease in collagen synthesis and a reduction in myofibroblastic markers. As already mentioned, miR-186 plays an antifibrotic role in IPF, an observation confirmed by the down-expression of this miRNA in lung tissues of IPF patients in comparison to control subjects. The highest expression levels of miR-186 were observed in the BMSC-EVs from control subjects, compared to BMSCs alone. Moreover, the effect of this specific miRNA released from BMSC-EVs was investigated both in vitro and in vivo assays. To study the effect on fibroblasts, transfection assays with miR-186 inhibitor, and negative control (NC) inhibitor into BMSCs were performed. The results showed that the expression of miR-186 was diminished in HLFF co-cultured with BMSC-EVs transfected with miR-186 inhibitor, compared to the HLFF treated with BMSC-EVs and with NC inhibitor. In contrast, the proliferation, migration and invasion were significantly incremented and a significantly higher expression of α-SMA and collagen I in these same fibroblasts was detected. Bioinformatic analysis pointed out SRY-related HMG box transcription factor 4 (SOX 4) as a key transcription factor involved in the progression of IPF. Therefore, they investigated whether miR-186 affected IPF by targeting SOX4 and its downstream gene, Dickkopf-1 (DKK1). When the researchers investigated the effect of treatment with BMSC-EVs on PF in the BLM-fibrosis mouse model, they observed a decreased expression of α-SMA and collagen 1, which was increased after miR-186 expression in BMSCs. Moreover, they demonstrated that EV-miR186 could target SOX4 and downregulate DKK1 to alleviate the occurrence of IPF [58][59][60].
Although the therapeutic utility of EVs derived from umbilical cord-derived MSCs (uMSCs-EVs) and BMSC-EVs had been reported in previous studies [51][61][62], the molecular mechanisms involved are still only partly understood. In this regard, Shi et al. studied the effect of uMSCs-EVs in comparison with MSCs alone in a BLM-fibrosis mouse model. Results showed that both treatments improved the survival rate and body weight of BLM-challenged mice in comparison to mice treated with PBS. In addition, the degree of lung tissue damage and collagen deposition were also improved. Likewise, a reduction in the expression levels of α-SMA, fibronectin (FNT), TGFβII and TGFβRII in lung tissues of mouse models treated with either treatment was described. Additional results confirmed that uMSC-EVs prevented myofibroblast differentiation by inhibiting the TGFβ signaling pathway in a normal mouse lung fibroblast (NMLF) cell line incubated with TGFβ. When the levels and functions of miRNAs enriched in uMSC-EVs were evaluated, it was found that miR-21-5p, miR-23a-3p, miR-125b-5p, let-7f/a, and miR-145-5p were highly expressed in the uMSC-EVs. On the other hand, in silico analysis, reported that miR-21-5p and miR-23a-3p directly target TGFβII and TGFβRII, respectively. Additional experiments showed that uMSC-EVs could inhibit myofibroblast differentiation by miR-21-5p and miR-23-3p and the down-expression of their respective targets TGFβ2 and TGFβR2 [63].
Recently, Santos-Álvarez et al. analyzed the differential expression of miRNAs in the EVs-cargo obtained from two lung fibrotic cell lines (LL29 and LL97) and compared them with the results obtained from a normal human lung fibroblasts cell line (CCD19). After bioinformatic analysis, it was shown that 77 miRNAs were upregulated and 68 down-regulated. Moreover, they highlighted the presence of 117 novel miRNAs. After pathway enrichment analyses, potential target genes involved with cell proliferation, regulation of apoptosis, pathways in cancer, and proteoglycans in cancer were defined. Therefore, the researchers suggested that miRNAs contained in EVs-cargo could be helpful as biomarkers for fibrogenesis, diagnosis, and therapeutic intervention of IPF [64].

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Subjects: Biochemistry & Molecular Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : María Cristina Negrete-García , Javier de Jesús Ramos-Abundis , Noé Alvarado-Vasquez
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Update Date: 14 Oct 2022
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