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Advances in regulating endothelial-mesenchymal transformation through exosomes

Stem Cell Research & Therapy volume 15, Article number: 391 (2024) Cite this article

Abstract

Endothelial-mesenchymal transformation (EndoMT) is the process through which endothelial cells transform into mesenchymal cells, affecting their morphology, gene expression, and function. EndoMT is a potential risk factor for cardiovascular and cerebrovascular diseases, tumor metastasis, and fibrosis. Recent research has highlighted the role of exosomes, a mode of cellular communication, in the regulation of EndoMT. Exosomes from diseased tissues and microenvironments can promote EndoMT, increase endothelial permeability, and compromise the vascular barrier. Conversely, exosomes derived from stem cells or progenitor cells can inhibit the EndoMT process and preserve endothelial function. By modifying exosome membranes or contents, we can harness the advantages of exosomes as carriers, enhancing their targeting and ability to inhibit EndoMT. This review aims to systematically summarize the regulation of EndoMT by exosomes in different disease contexts and provide effective strategies for exosome-based EndoMT intervention.

Introduction

Endothelial-mesenchymal transformation (EndoMT) involves a series of cellular and molecular changes that cause endothelial cells(ECs) to lose their characteristics and acquire mesenchymal traits [1]. Initially, endothelial cells undergo morphological changes, shifting from an oval to a slender spindle shape. This process is accompanied by altered gene expression, characterized by the loss of endothelial markers (e.g., VE-cadherin, CD31) and the gain of mesenchymal markers (e.g., SM22α, α-SMA). Functional changes include enhanced cell migration and contraction, as well as increased invasive capabilities [1, 2]. EndoMT is increasingly recognized as a risk factor in cardiovascular diseases (e.g., pulmonary hypertension, atherosclerosis) [3, 4], and fibrotic diseases (e.g., heart and kidney fibrosis) [5, 6]. It also contributes to the breakdown of the endothelial barrier and increased vascular permeability, facilitating tumor cell invasion and metastasis [7, 8].

Exosomes, extracellular vesicles ranging from 30 to 150 nm in diameter, originate from endosomes, specifically multivesicular bodies (MVBs). When MVBs fuse with the plasma membrane, they release exosomes into the extracellular space [9,10,11]. Exosomes can deliver proteins, lipids, and nucleic acids (e.g., DNA, mRNA, microRNA, non-coding RNA) to target cells, regulating their functions [12, 13]. They can either promote or inhibit disease progression through the molecules they carry [14, 15]. Recent studies indicate that exosomal proteins and nucleic acids play critical roles in EndoMT regulation (Fig. 1). Therefore, this review systematically summarizes the regulatory effects and mechanisms of exosomes on EndoMT across different disease contexts, identifies the limitations of current researches, and outlines future directions to promote the translational application of exosome-mediated EndoMT regulation.

Fig. 1
figure 1

Schematic diagram of exosomes regulating EndoMT. Exosomes derived from tumor cells and immune cells in the tumor microenvironment may promote cancer metastasis by inducing EndoMT in microvascular endothelial cells. Additionally, in non-neoplastic diseases, exosomes from endothelial cells and immune cells can promote EndoMT, thereby damaging the barrier function of blood vessels

TAM, Tumor-related macrophages

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Exosomes can regulate EndoMT in pathological environment

Exosomes regulate EndoMT in tumor tissue

EndoMT induced by exosomes plays a crucial role in the malignant progression of tumor invasion and metastasis. Recent studies have concentrated on malignant tumors of the digestive system, including hepatocellular carcinoma, colorectal cancer, pancreatic cancer and adenoid cystic carcinoma [8, 16,17,18,19,20]. Additionally, exosomes have been shown to promote EndoMT in nasopharyngeal carcinoma [7]. On one hand, exosomes secreted by cancer cells can directly act on endothelial cells, compromising the vascular endothelial barrier [7]. On the other hand, exosomes secreted by tumor tissues can circulate in fluid environments, such as bile and ascites, inducing EndoMT in certain blood vessels, thereby accelerating tumor progression or distant metastasis [8, 21]. Moreover, even within the same type of tumor, the ability of exosomes to regulate EndoMT can be heterogeneous. For example, HMGA2 protein in exosomes secreted by nasopharyngeal carcinoma (NPC) cells can upregulate the expression of the EndoMT-related transcription factor Snail, disrupt tight junctions between endothelial cells, and increase vascular permeability. But compared to EBV-negative NPC cells, exosomes enriched in HMGA2 protein predominantly originate from EBV-positive NPC cells [7]. This may be due to the impact of the virus itself on cancer cell functions, as viral infection significantly alters the proteome and RNA profiles encapsulated in exosomes, facilitating the spread of cytokines and RNAs from infected to uninfected cells (Table 1) [22,23,24,25,26,27,28,29,30,31]. Therefore, elucidating the impact of different viral infections on exosome production and secretion can further clarify their regulatory role in EndoMT. Additionally, elevated levels of TGF-β in the tumor microenvironment(TME) not only promote EndoMT but also induce EMT in tumor cells [32, 33]. Exosomes derived from EMT-induced tumor cells can likewise trigger EndoMT, and the degree of cellular transformation may be more pronounced compared to tumor cells that have not undergone EMT induction [34].

Table 1 Viral infections alter Exosome Communication in the tumor microenvironment
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Additionally, previous studies have clearly demonstrated that the polarization state of macrophages affects cancer progression. M1 macrophages exhibit antitumor activity; in contrast, M2 macrophages promote tumor progression [35]. The tumor microenvironment (TME) skews macrophages toward a pro-tumor (M2) phenotype, regulating various stages of metastasis through the release of cytokines such as TGF-β, TNF-α, and IL-10 [36, 37]. The involvement of exosomes in tumor-associated macrophage (TAM)-mediated regulation of EndoMT, influencing cancer progression, has been increasingly recognized. M2 macrophage infiltration is closely associated with metastasis and poor prognosis in hepatocellular carcinoma (HCC). Exosomes from M2 macrophages are absorbed by HCC cells, promoting metastasis and epithelial-mesenchymal transition (EMT) [16]. These exosomes can also be internalized by endothelial cells, leading to the downregulation of tight junction proteins such as TJP-1, occludin, and claudin-5, thereby increasing vascular permeability and facilitating cancer cell metastasis [16]. Furthermore, miR-155 and miR-196a-5p are abundant in M2 TAMs and exosomes secreted by M2 TAMs. These microRNAs directly bind to the 3’-UTR of Ras association domain family member 4 (RASSF4), negatively regulating its expression and promoting the migration and invasion of non-small cell lung cancer (NSCLC) cells [38]. Although M1 macrophages are currently recognized for their antitumor activity, the role of exosome-mediated regulation in this process remains unclear. Further elucidation of how exosomes derived from different polarized macrophage types regulate EndoMT in various tumors is of critical importance for developing exosome-based interventions targeting distant metastasis in cancer.

Exosomes regulate EndoMT in non-tumor tissue

In non-tumor diseases, EndoMT is currently considered to be closely associated with disease progression, particularly in fibrosis and cardiovascular diseases such as atherosclerosis and vascular calcification [39,40,41,42]. Atherosclerosis is a widespread chronic inflammatory disease, and studies have shown that EndoMT is involved in the onset and development of atherosclerosis [39]. Various factors, including inflammation, shear stress, and oxidative stress, play roles in atherosclerosis and can also promote EndoMT [39, 43, 44]. In particular, inflammation involving cytokines such as TNF-α and IL-1β is a key factor in atherosclerosis, promoting EndoMT through both TGF-β-dependent and independent pathways [43]. Chronic inflammation caused by factors such as hypercholesterolemia or persistent stimuli can disrupt the protective cell signaling pathways of FGF signaling, thereby activating the EndoMT process. Once EndoMT is initiated, it exacerbates inflammation, creating a vicious cycle [45]. Vascular calcification (VC) is a pathological change in the atherosclerotic process that leads to arterial stiffening and reduced compliance [46]. Evidence suggests that BMP activation triggers EndoMT, leading endothelial cells transform into osteoblast-like cells, contributing to vascular calcification [47]. BMP is inhibited by matrix Gla protein (MGP), and the loss of MGP leads to rapid progressive calcification of vessels and abnormal endothelial cells [40]. The internal elastic lamina (IEL) is gradually degraded due to excessive proteolysis, causing ECs to lose their anchorage and become more susceptible to EndoMT [40, 48]. In MGP-deficient, diabetic, and atherosclerotic mice, enhanced BMP signaling triggers EndoMT, causing ECs to become more plastic and transition into osteoblast-like cells, thereby leading to vascular calcification [40,41,42]. Recent observations of EndoMT-related genes and molecular changes suggest that EndoMT also plays a critical role in the abnormal vascular development of cerebrovascular malformations. Increased EndoMT markers have been observed in cavernous malformations [49, 50]. Similarly, enhanced EndoMT-associated transcription factors (e.g., Snail, Twist) and mesenchymal markers have been shown in human brain arteriovenous malformations (bAVM) [51, 52]. Mutations may be involved in EndoMT and the development of bAVM. For example, a series of molecular analyses confirmed EndoMT characteristics in KRAS-overexpressing human umbilical vein endothelial cells (HUVECs), including increased mesenchymal markers and decreased EC markers [53, 54].

Significant progress has been made in understanding the impact of exosomes on EndoMT in non-tumor diseases, particularly in the context of diabetic complications such as diabetic retinopathy and diabetic nephropathy [55, 56]. By analyzing exosomes derived from the vitreous fluid of patients with proliferative diabetic retinopathy, it was found that these exosomes are enriched with long non-coding RNA LOC100132249. LOC100132249 functions as a competitive endogenous sponge for miR-199a-5p, thereby regulating the EndoMT process through the transcription factor SNAI1, leading to endothelial dysfunction [55]. Studies have confirmed that hyperglycemia itself can induce the EndoMT process by directly increasing both TGF-β-dependent and non-TGF-β signaling pathways. TGF-β signaling, as part of the EC metabolic memory, is activated by hyperglycemia and can lead to EndoMT in ECs even after the glucose levels are normalized in culture conditions [57]. Hyperglycemia can activate various pathways and pro-inflammatory factors that induce endothelial dysfunction. It triggers the non-canonical nuclear factor kappa-B (NF-κB) signaling pathway, resulting in the production of cytokines and chemokines that promote inflammation, which is a key factor in the occurrence of EndoMT [58]. However, research on the impact of hyperglycemia on exosome production and secretion is still lacking, and the precise mechanisms by which hyperglycemia regulates EndoMT progression via exosomes require further investigation.

In addition to the regulation by blood glucose, both direct physical trauma and secondary inflammatory responses can influence the EndoMT process through changes in exosomes [59, 60]. Oscillatory shear stress (OSS) can induce EndoMT in endothelial progenitor cells by promoting the release of exosomes enriched with circ-1199 [59]. These exosomes downregulate let-7 g-5p, which subsequently upregulates HMGA2, leading to the elevated expression of EndoMT-related transcription factors [59]. Research on spinal cord injury (SCI) has revealed the role of secondary injury in the development of EndoMT. After blood-spinal cord barrier disruption, M1-polarized macrophages accumulate at the injury site, playing a crucial role in the SCI process. In vitro studies have shown that exosomes from M1-polarized bone marrow-derived macrophages carry miR-155, which induces EndoMT in bEnd.3 cells through exosomal transport, exacerbating blood-spinal cord barrier damage [60]. In addition to acute injuries, chronic progressive cerebrovascular diseases of unknown etiology, such as Moyamoya disease, and congenital cerebrovascular anomalies, such as brain arteriovenous malformations (bAVMs), also involve EndoMT. Similarly, in these diseases, exosome-induced EndoMT is attributed to exosome-enriched RNA molecules [61, 62]. For example, a recent study reported that exosomal miR-3131 promotes EndoMT in KRAS-mutant bAVMs, suggesting that miR-3131 could be a potential biomarker and therapeutic target for KRAS-mutant bAVMs [62].

As mentioned above, exosomes derived from polarized macrophages carrying miR-155 exacerbate EndoMT in spinal cord injury, highlighting the critical role of macrophage-derived exosomes in the pathological process of vascular injury [60]. This mechanism differs from the regulation of EndoMT by polarized macrophages in tumor tissues, as discussed in Sect. 1.1. In the tumor microenvironment, M1 macrophages exhibit anti-tumor activity, negatively regulating the invasion and migration of tumor cells [36, 37]. However, in non-tumor tissues, M1 macrophages significantly promote the EndoMT process [63, 64]. Keith Q et al. demonstrated in their study on hemangioma regression mechanisms that M1-polarized, rather than M2-polarized, macrophages induce EndoMT in endothelial cells, promoting hemangioma regression, which could potentially serve as a novel therapeutic approach for this vascular anomaly [63]. Similarly, molecular studies on atherosclerosis have found that supernatants from M1 macrophage-derived foam cells (M1-FCs), but not from M2 macrophage-derived foam cells (M2-FCs), induce EndoMT. Specifically, M1-FCs upregulate CCL-4, which induces EndoMT, increases endothelial permeability, and promotes monocyte adhesion. This may further elucidate the pivotal role of EndoMT in the progression of atherosclerosis [65]. Therefore, a clearer understanding of the regulatory role of exosomes from polarized macrophages in vascular processes may contribute to the development of novel therapies for cardiovascular and fibrotic diseases.

Signaling pathways of exosomes regulating EndoMT

Signaling pathways of EndoMT

The signaling pathways involved in EndoMT are similar to those in epithelial-mesenchymal transition (EMT), with transforming growth factor-β (TGF-β) signaling being the most prominent [66,67,68,69,70]. TGF-β is a cytokine found in various cell types that regulates cell proliferation and differentiation, and its levels are elevated in immune diseases and inflammatory conditions [71]. Members of the TGF-β family, including TGF-β1, TGF-β2, and TGF-β3, bind to TGF-β receptors, initiating the EndoMT process in endothelial cells by activating downstream Smad-dependent and Smad-independent signaling pathways [72, 73] (Fig. 2). In the Smad-dependent pathway, Smad proteins, which are intracellular effectors of TGF-β signaling, are activated by the receptor and translocate to the nucleus to regulate transcription [73]. Besides TGF-β signaling, the Wnt/β-catenin signaling pathway also plays a role in the EndoMT process. Glycogen synthase kinase 3 beta (GSK3β) is a serine-threonine kinase that phosphorylates β-catenin. Wnt signal transduction inhibits GSK3β activity, thereby promoting the stability and function of the EndoMT transcription factor Snail1 [74]. Other pathways, such as the Notch pathway and the Hedgehog pathway, may also be involved in regulating the EndoMT process [75,76,77,78]. The signaling pathways involved in EndoMT are briefly summarized here, but they have been discussed in greater detail in previous reviews. For further information, refer to references [79,80,81].

Fig. 2
figure 2

Smad-dependent and Smad-independent TGFβ signaling in EndoMT. In the Smad-dependent signaling pathway, TGFβ binds to TGFβ receptor 1 or TGFβ receptor 2 on the cell membrane, promoting the phosphorylation of Smad2 and Smad3. Smad4 then forms a complex with phosphorylated Smad2 and Smad3, which is translocated into the nucleus, leading to the expression of EndoMT-related transcription factors and promoting the occurrence of EndoMT. In the Smad-independent signaling pathway, after TGFβ binds to its receptors, downstream signaling pathways such as PI3K, RAS, and MAPK are activated, resulting in the downregulation of endothelial-specific gene transcription and the upregulation of mesenchymal-specific gene expression, thereby promoting the occurrence of EndoMT

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Mechanisms of exosome-mediated regulation of EndoMT

Non-coding RNAs include microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). These non-coding RNAs influence EndoMT pathways during both developmental and pathological processes [82]. As previously mentioned, in both tumor and non-tumor diseases, exosome-mediated regulation of EndoMT is often driven by the non-coding RNAs contained within exosomes [19, 55, 60, 61]. Therefore, this section will analyze the mechanisms by which exosomes regulate EndoMT through miRNAs, lncRNAs, and circRNAs.

MiRNAs are small RNA fragments typically 20–25 nucleotides long, which bind to complementary sequences within mRNA targets, inhibiting the translation of mRNA into proteins [83]. MiRNAs that have been confirmed in exosomes to regulate EndoMT include miR-155, miR-30a-5p, miR-3131, miR-218, miR-122-5p, miR-92a-3p, miRNA151a-3p, and miRNA125b-5p [60,61,62, 84,85,86,87] (Table 2). Among these, miR-155 is upregulated in bone marrow-derived macrophages (BMDMs) during traumatic spinal cord injury, where it activates the NF-κB signaling pathway by targeting suppressor of cytokine signaling 6 (SOCS6), inhibiting SOCS6-mediated ubiquitination and degradation of p65, and thus regulating the EndoMT process in vascular endothelial cells [60]. However, the regulation of SOCS6 by miR-155 is not unique. In non-exosome studies, miR-155-5p has been shown to influence EndoMT progression via multiple targets or pathways, including SIRT1, SHIP-1, and c-Ski [88,89,90]. miR-155-5p modulates the expression of SIRT1 and downstream targets Nrf2 and HO-1, affecting the production of reactive oxygen species (ROS) in endothelial cells, thereby regulating endothelial-mesenchymal transition in a type 2 diabetes mouse model and impacting wound healing [88]. In pulmonary fibrosis models, endothelial miR-155 plays a key role in the fibrotic response through EndoMT, with SHIP-1 as its target. The regulation of EndoMT by endothelial miR-155 and SHIP-1 involves multiple signaling pathways, including PI3K/AKT, STAT3, and SMAD/STAT pathways [89]. In studies of cardiac fibrosis, miR-155 has been found to regulate TGF-β-induced EndoMT by targeting c-Ski, suggesting that the miR-155/c-Ski axis could be a novel biomarker and therapeutic target for cardiac fibrosis [90]. Similar to miR-155, other miRNAs in exosomes that regulate EndoMT are also associated with multiple targets or pathways. Therefore, the regulation of EndoMT by the same miRNA within exosomes is likely mediated through multiple targets and mechanisms, which increases the complexity of elucidating the mechanisms by which exosomes regulate endothelial injury and the challenges of developing therapeutic interventions.

Table 2 Exosomal molecules with proven regulatory effects on EndoMT functions
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When non-coding RNAs consist of more than 200 nucleotides, they are classified as lncRNAs. LncRNAs are involved in post-transcriptional regulation, controlling processes such as mRNA processing, stability, or translation. They can act as sponges to block the effects of miRNAs or serve as sources of other small RNAs [91]. Compared to miRNAs, there are fewer well-established lncRNAs that have been confirmed to regulate EndoMT via exosomes. Among them are SNHG7 and LOC100132249 [55, 92] (Table 2). LncRNA SNHG7 primarily functions in diabetic retinopathy. Specifically, Megakaryocytic leukemia 1 (MKL1), a transcription modulator, is highly expressed in high glucose-induced retinal epithelial cells and promotes EndoMT by activating TWIST1 [93, 94]. In 2022, Cao et al. discovered that SNHG7 can weaken MKL1 mRNA stability by interacting with the RNA-binding protein KHSRP. This SNHG7/KHSRP/MKL1 axis regulates endothelial-to-mesenchymal transition in diabetic retinopathy [95]. Consistently, MSC-derived exosomes highly express SNHG7, which can inhibit EndoMT and tube formation in diabetic retinopathy. However, unlike the mechanism targeting MKL1, exosomal SNHG7 from MSCs exerts its effects through the miR-34a-5p/XBP1 axis [92]. LncRNA LOC100132249, primarily derived from endothelial cells, is enriched in the vitreous of patients with proliferative diabetic retinopathy and has been shown to participate in angiogenesis. Mechanistically, LOC100132249 acts as a competitive endogenous sponge for miRNA-199a-5p, regulating the EndoMT initiator SNAI1 via activation of the Wnt/β-catenin pathway, ultimately leading to endothelial dysfunction [55].

CircRNAs represent another subclass of non-coding RNAs, typically formed by back-splicing. Similar to other lncRNAs, they function as miRNA sponges, RNA-binding protein sequestration factors, and can regulate gene expression by controlling mRNA transcription [96, 97]. As described in Sect. 1.2, oscillatory shear stress induces the release of circ-1199-enriched exosomes from endothelial progenitor cells, which downregulate let-7 g-5p, eventually activating p-Smad3/Smad3 and Snail to promote EndoMT in endothelial progenitor cells (Table 2) [59]. Beyond this, there are few circRNAs that have been directly confirmed to regulate EndoMT via exosomes. Notably, exosomal circDLGAP4 is involved in the pathological changes of vascular injury in diseases such as diabetic nephropathy and cerebral ischemia [98, 99]. Research on ischemic stroke has also revealed that circDLGAP4 regulates EndoMT related to blood-brain barrier integrity by targeting miR-143, thereby improving ischemic stroke outcomes [100]. Further research is needed to determine whether the effects of exosomal circDLGAP4 on vascular injury are mediated through the regulation of EndoMT in endothelial cells and to elucidate the specific mechanisms involved.

Exosome therapy for EndoMT

While EndoMT is an adverse factor in cardiovascular diseases, its reverse process plays an active role in repairing damaged myocardium. Exosomal miR-218-5p/miR-363-3p from endothelial progenitor cells improve myocardial infarction outcomes by targeting the p53/JMY signaling pathway. Further studies have shown that these microRNAs promote mesenchymal-to-endothelial transformation and inhibit myocardial fibrosis [101]. In the diseased state, exosomes can promote the progression of EndoMT and disrupt the barrier function of endothelial cells. However, exosomes from certain stem or progenitor cells can exert therapeutic effects by inhibiting the EndoMT process. Exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs) are rich in miR-218, which possesses anti-fibrotic properties and inhibits EndoMT through the MeCP2/BMP2 pathway, offering a novel approach to preventing pulmonary fibrosis [85]. In experimental models of pulmonary hypertension, hucMSC-Exos have been shown to effectively reduce right ventricular systolic blood pressure and right ventricular hypertrophy index, as well as inhibit pulmonary vascular remodeling and EndoMT processes [102]. Additionally, bone marrow-derived mesenchymal stem cells have demonstrated significant effects in inhibiting EndoMT. Exosomes derived from these cells, containing lncRNA SNHG7, negatively regulate miR-34a-5p and inhibit EndoMT in human retinal microvascular endothelial cells through the miR-34a-5p/XBP1 axis, providing new insights for the treatment of diabetic retinopathy [92].

Further modification of therapeutic exosomes or the construction of exosome-based drug delivery platforms as biocompatible carriers can achieve more precise regulation of EndoMT. Nintedanib, a triple tyrosine kinase inhibitor with anti-fibrotic and antioxidant properties, is used clinically to treat pulmonary fibrosis. Researchers have developed a system for delivering Nintedanib using adipose-derived stem cell exosomes, finding it effective in alleviating bleomycin-induced EndoMT and reducing oxidative stress levels in pulmonary fibrosis models, significantly enhancing therapeutic effects [103]. Moreover, modifying the surface of exosomes to improve their targeting in vivo is a promising research direction. For instance, exosomes from mouse aortic endothelial cells were cultured and extracted, then combined with DSPE-PEG and CD34 antibodies to form exosomal vectors (Exosome-DSPE-PEG-AbCD34) targeting endothelial cells. High expression of SMAD7 in endothelial cells can effectively reverse TGF-β1-mediated EndoMT. Loading a SMAD7 plasmid into Exosome-DSPE-PEG-AbCD34 achieved high targeting of exosomes to endothelial cells, significantly increased SMAD7 levels in these cells, decreased TGF-β1 expression, and effectively reversed TGF-β1-mediated EndoMT [104]. Therefore, the modifiability of exosome membranes enhances their advantages as delivery vectors and further boosts their ability to inhibit EndoMT.

Conclusions

Whether in the distant metastasis of tumor cells or in non-neoplastic diseases such as cardiovascular damage, the role of exosomes in stimulating endothelial cells to undergo EndoMT by transferring proteins and nucleic acids has become increasingly recognized by researchers. However, research on exosomal regulation of EndoMT remains relatively limited in recent years. Firstly, the techniques for isolating and purifying exosomes have not yet been standardized. Different methods can affect the purity and activity of exosomal components, thereby influencing research outcomes. The lack of a unified standard for exosome preparation presents obstacles for subsequent research and clinical applications. Secondly, in terms of the mechanisms by which exosomes regulate EndoMT, most studies focus on miRNA, with a lack of research on lncRNA and circRNA. Furthermore, how to achieve precise targeted delivery of exosomes, particularly across the blood-brain barrier (for brain diseases) or other organ barriers, remains a technical challenge. Current delivery technologies struggle to ensure the efficacy and stability of exosomes in vivo.

Thus, future researches need to promote the standardization of techniques for exosome isolation, purification, and qualitative analysis, particularly focusing on the stability and activity of exosomes to ensure reproducibility across different laboratories. Additionally, more attention should be paid to investigating changes in lncRNA and circRNA in exosomes and their mechanisms in regulating EndoMT, which could help identify new therapeutic targets and refine the functional models of exosomes. Furthermore, clarifying the safety, appropriate dosage, and delivery pathways of exosomes is essential to reduce risks in the drug development process and lay the foundation for future clinical translation. On the other hand, advances in exosome research rely on interdisciplinary collaboration, involving fields such as biology, nanotechnology, and drug delivery. Future studies should emphasize cross-disciplinary cooperation to explore new exosome modification technologies that enhance their targeted delivery efficiency and therapeutic effects in vivo. Through further investigation of the relationship between exosomes and EndoMT, new therapeutic strategies may emerge for cancer, cardiovascular diseases, fibrosis, and wound healing.

Data availability

Not applicable.

Abbreviations

EndoMT:

Endothelial-mesenchymal transformation

MVB:

Multivesicular bodies

EBV:

Epstein-Barr virus

KLF4:

Kruppel-like factor 4

MRPL23-AS1:

MRPL23 antisense RNA 1

TAM:

Tumor-related macrophages

SCI:

Spinal cord injury

TGF-β:

Transforming growth factor-β

GSK3β:

Glycogen synthase kinase 3 beta

hucMSC:

human umbilical cord mesenchymal stem cells

NPC:

Nasopharyngeal carcinoma

HCC:

Hepatocellular carcinoma

HBV:

Hepatitis B virus

HPV:

Human papillomavirus

NADCs:

Non-AIDS-defining cancers

BC:

Breast cancer

EGFR:

Epidermal growth factor receptor

TAR:

Transactivation response

ARID2:

AT-rich interactive domain

VAMP2:

Vesicle-associated membrane protein 2

SOCS:

Suppressor of cytokine signaling

TLR3:

Toll-like receptor 3

M1-BMDMs:

M1-polarized bone marrow-derived macrophages

BSCB:

Blood-spinal-cord-barrier

HG:

High glucose

GECs:

Glomerular endothelial cells

HPMEC:

Human pulmonary microvascular endothelial cells

ARDS:

Acute respiratory distress syndrome

MSCs:

Mesenchymal stem cells

HRMECs:

Human retinal microvascular endothelial cells

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Acknowledgements

The authors declare that they have not used Artificial Intelligence in this study.

Funding

This work was supported by the National High Level Hospital Clinical Research Funding(2022-PUMCH-C-032), the National Key R&D Program of China (2018YFA0108600), the CAMS Initiative for Innovative Medicine (2021-1-I2M-019), and National High Level Hospital Clinical Research Funding (2022-PUMCH-C-042).

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  1. Sun Sishuai and Gu Lingui are co-first authors.

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  1. Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China

    Sun Sishuai, Gu Lingui, Li Pengtao, Bao Xinjie & Wei Junji

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  1. Sun Sishuai
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Contributions

Data acquisition, analysis, and writing, SS and GL; review and editing, LP; project administration and funding acquisition, WJ and BX.

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Sishuai, S., Lingui, G., Pengtao, L. et al. Advances in regulating endothelial-mesenchymal transformation through exosomes. Stem Cell Res Ther 15, 391 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13287-024-04010-w

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Keywords

Stem Cell Research & Therapy

ISSN: 1757-6512