Migrasomes, critical players in intercellular communication

Abstract

Migrasomes are a newly discovered type of extracellular vesicle (EV) formed during cell migration, playing a pivotal role in intercellular communication. These vesicles are generated by retracting fibers of migrating cells and encapsulate various molecules, such as proteins, lipids, and RNA, allowing the transfer of biochemical signals to neighboring cells. Current evidence suggests that migrasomes are involved in a wide range of physiological processes such as embryogenesis, angiogenesis, immune modulation, and mitochondrial quality control. Moreover, migrasomes are implicated in pathological conditions, including cancer metastasis, cardiovascular diseases, and viral infections. To fully understand their significance, it is critical to first explore the molecular mechanisms underlying their formation and function. Recent studies have shed light on the biogenesis, release, and biological properties of migrasomes, all of which are key to understanding their role in cell-to-cell communication. In this review, we provide an up-to-date summary of migrasome biogenesis, release, characterization, and their biological activities in intercellular communication, while also proposing potential new functions for these vesicles.

Introduction

Intercellular communication, a crucial feature of multicellular organisms, is mediated through direct cell–cell contacts or the transfer of secreted molecules. Emerging evidence highlights the role of extracellular vesicles (EVs) in this process. EVs are released by cells under both normal and pathological conditions, serving diverse biological functions and being found in various body fluids. These vesicles are essential for maintaining physiological balance, and their release often increases in response to homeostatic challenges [1]. EVs refer to a heterogeneous group of membrane-bound structures that vary in size, origin, and biological function. All cells, from bacteria to humans and plants, secrete different types of EVs or nanoparticles, a process conserved through evolution. EVs can be classified into various subtypes based on their characteristics, including exosomes, ectosomes, migrasomes, apoptotic bodies, retractosomes, exomeres, and oncosomes (Fig. 1). Each subtype has distinct mechanisms of synthesis and release, contributing to their role in intercellular communication (Table 1) [2,3,4].

Fig. 1

Timeline of key discoveries leading to migrasome identification. In 1945, initial observations identified filaments associated with cell retraction [16]. By 1963, these were further characterized as long tubular structures known as retractile fibers [17]. In 2012, pomegranate-like structures were observed attached to these fibers [18]. The formal naming of these migratory, pomegranate-like structures as “migrasomes” occurred in 2015, linking them explicitly to cell migration [19]. This progression highlights the gradual unveiling of migrasomes’ unique morphology and their role in cellular dynamics

Table 1 Characteristics of common extracellular vesicles

Among these, exosomes, ranging in size from 50 to 150 nm, are EVs that originate from the endocytic pathway. They result from the fusion of late endosomes/multivesicular bodies (MVBs) with the plasma membrane and are enriched with endosomal sorting complex proteins required for trafficking, such as ALG-2 interacting protein X (Alix) and tumor susceptibility gene 101 protein (TSG101), as well as tetraspanins such as CD63 and CD81 [5]. Exosomes can carry proteins, RNAs, miRNAs and other substances, mediating intercellular communication without direct cell-to-cell contact [5]. In contrast, microvesicles, ranging from 100 to 1000 nm in size, bud from the plasma membrane and contain specific proteins such as annexin A1 and annexin A2 [6]. Apoptotic bodies, which range from 50 to 5000 nm, are released from dying cells by vesiculation and rupture of the cell membrane [3], carrying fragmented proteins, lipids, and nucleic acids. And retractosomes range in size from 50 to 250 nm. They are formed by the breakage of retraction fibers produced by migrating cells. Cholesterol is much less enriched on retractosomes than on migrasomes. This suggests that retractosomes may form by mechanisms other than the assembly of tetraspanin-enriched macrodomains, which is different from migrasome formation. Currently, their specific functions remain unclear, but they may have potential roles in intercellular communication and other aspects [7]. Additionally, large oncosomes (1000 to 10000 nm) contain abnormal and transformed macromolecules, such as oncoproteins, that play a role in cancer progression [8]. The newly discovered exomeres, typically smaller than 50 nm, also contribute to intercellular communication and potentially influence target cell metabolism, particularly glycolysis [9].

In recent years, migrasomes have emerged as a distinct subtype of EVs, characterized by their formation during cell migration. These vesicles not only differ in size—ranging from 500 to 3000 nm—but also in their unique biogenesis and cargo loading mechanisms [10, 11]. Migrasomes form through the retraction of membrane tethers extended by the posterior region of migrating cells, creating vesicles that contain numerous smaller vesicles, with diameters between 50 and 100 nm, inside them [11]. Migrasomes have shown great potential in facilitating communication between cells by establishing complex gradients and conveying signals in a spatiotemporal manner [12, 13]. Moreover, they are involved in a wide array of cellular functions, including immune regulation, mitochondrial quality control, and the lateral transfer of materials between cells [12, 14]. Despite the significant progress in understanding migrasomes, a critical knowledge gap remains in terms of the precise molecular mechanisms that dictate how specific cargos-such as RNA and proteins-are selectively sorted into migrasomes, rather than other EVs, under different physiological conditions. It is well established that tetraspanin proteins, such as CD63 and CD81, play a role in stabilizing the structure of migrasomes, but how these vesicles selectively package their contents remains poorly understood [15]. Addressing this unresolved issue is particularly important in the context of cancer metastasis, where the differential sorting of molecular cargos could influence the behavior and fate of metastatic cells. This area of research holds the potential to provide new insights into how migrasomes contribute to disease progression and to uncover novel therapeutic targets.

Therefore, the objective of this study is to provide a comprehensive review of the current status of migrasome research, focusing on their formation mechanisms, physiological functions, and their significance in disease diagnosis and treatment. By exploring these aspects, we aim to highlight the critical areas that require further investigation, particularly the unresolved question of cargo sorting, which could have profound implications for understanding migrasome roles in health and disease.

The discovery of Retraction fibers and migrasomes

As early as 1945, Porter et al. [16] first observed filaments potentially associated with the retraction margins of cells. This initial observation set the stage for more detailed investigations, particularly by Taylor and Robbins in 1963, who employed optical and transmission electron microscopy (TEM) to document long tubular structures known as “retractile fibers.” These fibers appear when migrating cells retract from the underlying layer and are characterized by a non-uniform diameter, being anchored at the tip and remaining stationary when stretched. When relaxed or detached, they are passively disturbed by the movement of particles in Brownian motion [17]. In 2012, Yu et al. [18] utilized TEM to observe membrane-bound vesicular structures in the extracellular space surrounding normal rat kidney (NRK) cells. These structures were found to be connected to or closely associated with retraction fibers and exhibited diameters ranging from 0.5 μm to 3 μm, containing numerous smaller vesicles that resembled opened pomegranates. Further investigations using additional electron microscopy revealed that these pomegranate-like structures (PLSs) were indeed attached to contractile fibers. Subsequent studies indicated that the formation of PLSs could be inhibited by blocking cell migration, suggesting a strong correlation between PLS formation and cellular movement. Consequently, in a pivotal study published in 2015, these structures were named “migrasomes”, reflecting their association with cellular migration and their unique morphological characteristics (Fig. 2) [19].

Fig. 2

Extracellular vesicles (EVs) classifcation. This diagram provides a comprehensive overview of EV classification and biogenesis, emphasizing their size, cellular origin, and mechanisms of formation. EVs are categorized into small vesicles, including exomeres (<50 nm), exosomes (30–150 nm) derived from multivesicular bodies, and ectosomes (100–1000 nm) directly shed from the plasma membrane. The large vesicles comprise migrasomes (500–3000 nm) produced during cell migration, apoptotic bodies (1000–5000 nm) formed during apoptosis, and oncosomes (1000–10000 nm) associated with tumor cells. It emphasizes the distinct formation pathways for each EV type, including endosomal sorting, membrane budding, and cellular migration, demonstrating how these processes facilitate their release into the extracellular space

The biogenesis of migrasomes

During cell migration, the formation of migrasomes and retraction fibers (RFs) relies on the support of the extracellular matrix (ECM). For instance, researchers cultured L929 cells on fibronectin-coated microwell plates and, using WGA labeling and Opera Phenix system detection, observed that higher fibronectin concentrations enhanced migrasome formation, with an optimal concentration of 10 µg/ml. These findings highlight the critical role of ECM components, such as fibronectin, in migrasome formation and their close association with this process [20]. The formation of migrasomes is closely linked to the dynamic process of cell migration. As cells migrate, they deposit retraction fibers at the trailing edge, where localized plasma membrane protrusions give rise to migrasomes, particularly at the terminations and bifurcations of these fibers. As migration progresses, the connecting RFs gradually thin out and eventually rupture, exposing migrasomes to the surrounding ECM. At this stage, migrasomes may either be captured by neighboring cells or undergo rupture to release their contents. This process further underscores the essential role of the ECM in both the formation and dynamic regulation of migrasomes [19]. Recent research has revealed that membrane tension plays a pivotal role in migrasome formation, regulated by actin polymerization and the interaction of tetraspanin-enriched microdomains (TEMs) with Rab35 and PI(4,5)P2. This coordinated action ensures the stabilization and expansion of migrasomes, but the exact biophysical mechanisms that regulate membrane tension during migrasome formation remain underexplored. Membrane tension initiates localized swellings on the retraction fibers, which subsequently develop into migrasomes [20, 21].

Using quantitative mass spectrometry, Yu et al. discovered that the proteins enriched within the migrasomes are involved in various cellular processes including cell migration, cell-substrate adhesion, lipid catabolism, protein glycosylation and glycoprotein metabolism [22]. Additionally, they observed a high enrichment of tetraspanin (TSPAN) family members within the migrasome. The TSPAN family comprises 33 members, which are ubiquitously expressed in various cell types and possess four transmembrane domains [23, 24]. These proteins can segregate into tetraspaninenriched microdomains (TEMs) within the cellular membrane, contributing to diverse physiological processes such as cell adhesion, migration, immune response, fusion, and organ-specific signaling [25]. In vitro system simulation indicates that TSPAN4 and cholesterol alone are sufficient to generate migrasome-like structures [26]. In the realm of membrane biology, highlighting the role of certain tetraspanins, such as Tspan4, as curvature-sensing proteins is essential. Research on CD9 has shown that it can specifically accumulate on highly curved membrane structures. Similarly, Tspan4 has the ability to enrich membrane regions with high positive curvature, like retraction fiber nanotubes. These unique membrane structures are actively involved in various crucial cellular processes, including cell migration and signal transduction. Understanding the function of Tspan4 in this context may provide new insights into the complex membrane - related mechanisms within cells and open up novel avenues for future research [27]. The recent findings by Dharan et al. [28] have unveiled a two step process of migrasome formation through the utilization of live cell imaging and biomimetic model systems. The initial step is driven by membrane tension, leading to the development of localized swellings on tubular contractile fibers. Subsequently, specific proteins from the TSPAN family regulate the second step, facilitating the stabilization of these swellings and their eventual transformation into migrasomes. Subsequent studies have confirmed that TSPAN4 is overexpressed in the formation of migrasomes and has also been used as a marker for migrasomes [22].

The biogenesis of migrasomes is a tightly regulated process that encompasses three distinct stages: nucleation, maturation, and expansion (Fig. 3). Synthesis of sphingomyelin (SM) has been established as a prerequisite for the formation of migrasomes during the initial stages of migrasome formation. Liang et al. [29] discovered that migrasomes exhibit an enrichment of SM, and they identified sphingomyelin synthase 2 (SMS2) as a crucial protein involved in the biogenesis of migrasomes. In their study, firstly, SMS2 assembles into immobile foci that adhere on the basal membrane at the leading edge, where it determines the precise location for future migrasome formation sites; secondly, SMS2 foci remains localized on RFs and serves as the designated site for migrasome formation. Finally, ceramide undergoes conversion to SM at the SMS2 foci, thereby triggering the growth phase of migrasome formation. Furthermore, both CerS5, which is essential for long-chain ceramide synthesis, and CERT, responsible for transporting ceramides from the endoplasmic reticulum to the Golgi apparatus, are indispensable for migrasome formation.

Fig. 3

Stages of migrasome formation: nucleation, maturation, and expansion. Nucleation involves SMS2 catalyzing sphingomyelin formation at the cell membrane. Maturation is driven by PIP5K1A, PI(4)P, PI(4,5)P2, Rab35, and integrins, which promote membrane budding and protrusion development. Expansion involves the assembly of tetraspanin-enriched macrodomains (TEMs), extending the migrasome structure. Key molecular components like lipids, receptors, and integrins are crucial at each stage, emphasizing the pathways essential for migrasome development

Subsequent research has revealed that Phosphatidylinositol 4-phosphate 5-kinase (PIP5K1A) facilitates the re-synthesis of Phosphatidylinositol (4,5) bisphosphate (PI (4,5) P2) at the migrasomes formation site prior to its assembly [21]. Rab35, a PI (4,5) P2 binding protein localized within the migrasomes, is recruited to the migrasomes formation site through its interaction with PI (4,5) P2. Subsequently, via its interaction with integrin α5, Rab35 recruits integrin α5 to the migrasome formation site and primes it for tetraptransmembrane-dependent amplification [21]. Tropomyosin-1, a coiled-coil protein that stabilizes actin filaments, is a key regulator of tumor necrosis factor alpha (TNFα)-mediated migrasome formation in endothelial cells (ECs) [30]. Gagat et al. [31] note that angiogenic capacity and migrasome formation are augmented in TNFα-activated ECs with a knockout of tropomyosin-1, indicating the regulatory effect of tropomyosin-1 on migrasome formation. Moreover, the biogenesis of migrasomes is contingent on the cellular milieu, notably involving integrins and tetraspanins. Specifically, the integrin α5β1 is essential for anchoring migrasomes to the extracellular matrix, enabling their formation at designated cell migration sites [19].

Actin polymerization is another critical factor in migrasome biogenesis. Actin facilitates the membrane tension needed for migrasome expansion and stability. Yu et al. [19] demonstrated that inhibiting actin polymerization with Cytochalasin B and Latrunculin A, or disrupting the formation of branched actin networks with CK636, significantly diminishes migrasome formation. These findings indicate that actin polymerization plays a dual role, both in promoting cell migration and directly contributing to migrasome biogenesis. Using live cell imaging experiments, Fan et al. [32]observed a reduction in the formation of RFs and migrasomes when L929 cells exhibited discontinuous migration in one direction during rotation. Moreover, increased cell migration duration and velocity resulted in enhanced migrasome formation, suggesting that continuous and directional cell migration, coupled with proper membrane tension and actin dynamics, is essential for migrasome formation.

Detection and isolation of migrasomes

Currently, the most accurate method for identifying migrasomes is still through transmission electron microscopy (TEM). Research has shown that Tspan4, integrin, and pleckstrin homeodomains can serve as reliable markers for observing migrasomes using fluorescence microscopy [19, 33, 34]. However, due to the high abundance of TSPAN4 and integrin in exosomes, distinguishing migrasomes from exosomes solely based on the detection of TSPAN4 and integrin as markers may pose a challenge [10]. By tagging them with GFP or mCherry, the biogenesis of migrasomes can be visualized. There are also several markers that can be analyzed by protein blotting to rapidly determine the presence of migrasomes [10]. The binding ability of wheat germ agglutinin (WGA) to sialic acid and N-acetyl-D-glucosamine enables the staining of migrasomes, and efficiently labels cells, retractile fibers, and migrasomes in a very short period of time, offering significant advantages in tracking their trajectory. The migrasome is rich in many protein markers, such as carboxypeptidase Q (CPQ), EGF domain-specific O-linked N-acetylglucosamine transferase (EOGT), bifunctional heparin sulfate N-deacetylase/N-sulfotransferase 1 (NDST1), and phosphatidylinositol glycan anchor biosynthesis, class K (PIGK). These protein markers can be used to distinguish between migrasomes and other EVs [35].

The comprehensive protocol for migrasome isolation has been extensively elucidated in the study conducted by Yu et al. [22]. The isolation process for migrasomes, akin to that of other extracellular vesicles (EVs), involves extracting these structures from body fluids and conditioned cell culture media through a combination of ultracentrifugation and density gradient centrifugation [36]. Recently, Yang et al. introduced an innovative, straightforward, and efficient technique for the isolation and quantitative analysis of migrasomes. This method utilizes WGA-conjugated magnetic beads alongside flow cytometry (WBFC), enabling effective isolation of migrasomes from serum or urine samples. Furthermore, this technique facilitates the analysis of their lipid, protein, and RNA profiles, providing valuable insights into the molecular composition and potential functional roles of migrasomes in various biological contexts [37].

Biological functions of migrasomes

Migrasomes are enriched with a diverse array of signaling molecules, including cytokines, chemokines, and growth factors, which they transport to neighboring cells, thereby significantly influencing cellular behavior and fate. During embryonic development, migrasomes provide critical regional cues by delivering chemotactic factors, such as CXCL12, which guide cellular organization and tissue patterning. Moreover, migrasomes are integral to maintaining mitochondrial quality control by facilitating the expulsion of damaged mitochondria during mild stress. This process, known as mitocytosis, is essential for preserving cellular homeostasis, particularly in highly migratory cells like neutrophils and macrophages [12]. Additionally, migrasomes contribute to angiogenesis by delivering pro-angiogenic factors such as VEGFA, thereby promoting vascular development in both physiological and pathological contexts [38, 39]. These multifaceted roles of migrasomes underscore their importance in various biological processes, from development to immune responses, highlighting their potential as targets for therapeutic interventions (Fig. 4) [40].

Fig. 4

Mechanisms of migrasome-mediated intercellular communication. The diagram depicts various biological roles associated with migrasomes, including the release of signaling molecules, shedding of cellular contents, and lateral transfer of materials between cells. Migrasomes facilitate communication and material exchange, influencing processes such as immune response, tissue repair, and development. The functions highlighted underscore the diverse and dynamic contributions of migrasomes to cellular and physiological processes, with some aspects remaining to be fully elucidated

Regulation of embryonic development

Recent in vivo experiments have demonstrated that organ morphogenesis in zebrafish is dependent on migrasomes, which are enriched with signaling molecules that provide essential regional biochemical cues for accurate cellular localization [33]. Specifically, mesodermal and endodermal cells generate migrasomes rich in CXCL12. The interaction between CXCL12 within these migrasomes and its receptor, CXCR4, expressed on dorsal precursor cells (DFCS), triggers chemotaxis and facilitates the recruitment of DFCS. This interaction is crucial for ensuring the precise localization of DFCS and the subsequent processes of organ morphogenesis [33]. Additionally, polystyrene nanoplastics (PS-NPs, 50 nm) have been shown to inhibit ROCK1-mediated migration, invasion, and migrasome formation, leading to adverse reproductive outcomes such as miscarriage in pregnant mice [41]. Furthermore, ROCK1 has been implicated in regulating migrasome formation in zebrafish embryos, further emphasizing its importance in developmental processes. In essence, migrasomes represent a fundamental component of the cellular framework during embryonic development [19]. Their ability to transmit signals and engage with neighboring cells underscores their integral role in orchestrating the complexities of embryogenesis. Investigating the precise roles and mechanisms of migrasomes in these developmental processes could yield significant insights into the intricacies of developmental biology and its associated disorders.

Mitochondria quality control

Under conditions of mild mitochondrial stress, damaged mitochondria are transported into migrasomes, where they undergo processing and subsequent excretion from migrating cells [12]. This process positions migrasomes as crucial players in maintaining cellular homeostasis and ensuring mitochondrial quality control by facilitating the elimination of dysfunctional organelles. Notably, neutrophils and macrophages have been identified as primary sources of migrasomes [42]. When these immune cells experience mild mitochondrial stress, they can modulate their intracellular transport mechanisms, evading the binding of damaged mitochondria to dynein while enhancing their interaction with Kinesin Family Member 5B (KIF5B) through mitochondrial quality control pathways. This dynamic adjustment allows for the effective transportation of impaired mitochondria into migrasomes, which are then collectively excreted. By doing so, macrophages and neutrophils maintain their cell viability and functional capacity, illustrating the critical role of migrasomes in cellular stress responses and organelle homeostasis [12].

Promote angiogenesis

In the context of angiogenesis, Zhang et al. [39] discovered that monocytes play a significant role in capillary formation in chicken embryos through the production of migrasomes. These migrasomes, which are enriched with key signaling molecules such as vascular endothelial growth factor A (VEGFA) and CXCL12, not only facilitate capillary formation but also actively recruit additional monocytes to the site of angiogenesis within the chorioallantoic membrane of the chick embryo. This finding underscores the critical role of migrasomes in angiogenesis, a process essential for physiological development as well as pathological conditions, including tumor growth and peripheral nerve regeneration. The involvement of monocytes and macrophages in this process—highlighted by their secretion of pro-angiogenic factors via migrasomes—reveals a novel aspect of the cellular mechanisms driving blood vessel formation and tissue repair. Understanding these interactions may open new avenues for therapeutic interventions aimed at enhancing or inhibiting angiogenesis in various clinical settings.

Recruiting cancer cells

Mesenchymal stromal cells (MSCs), known for their multipotency and self-renewal capabilities, play a critical role in the bone marrow stem cell niche, significantly contributing to the process of hematopoiesis [43, 44]. Recent research by Deniz et al. [15] has illuminated the ability of MSCs to generate migrasomes, which are enriched with essential signaling molecules, including stromal cell-derived factor 1 (SDF-1 or CXCL12). These migrasomes facilitate the migration of hematopoietic cells, such as KG-1a cells and primary CD34 + hematopoietic stem and progenitor cells (HSPCs), underscoring their importance in cellular communication within the bone marrow microenvironment. Notably, Deniz et al. [15] found that leukemic cells exhibit a preferential uptake of migrasomes compared to primary CD34 + progenitors, suggesting a differential impact of these vesicles on various cell types within the bone marrow. This observation raises important implications: in pathological conditions like cancer, tumor cells may alter the normal exchange of material and information between healthy cells. Such modifications can lead to changes in the cellular microenvironment that promote tumor growth and metastasis, highlighting the potential role of migrasomes in cancer progression and offering insights into new therapeutic strategies targeting the tumor microenvironment.

Regulation of immunity

The immune system cells are the primary mobile cell types in organisms, and their function relies on the production of cytokines and chemokines. The immune response necessitates the involvement of diverse cell types, with migrasomes facilitating communication between immune cells to orchestrate the immune response [11]. Li et al. [45] discovered that upon bacterial stimulation, bone marrow mesenchymal stem cells (BM-MSCs) were loaded with the antimicrobial peptide dermcidin. In vivo tracking experiments revealed that these BM-MSCs rapidly penetrated into the lungs and disappeared within 24 h, leaving behind migration bodies rich in antimicrobial peptide dermcidin, which enhanced LC3-associated phagocytosis of macrophages and improved bacterial clearance. Therefore, the migrasomes of dermcidin-enriched MSCs can effectively reduce lung bacterial load and enhance LC3-associated phagocytosis, making it a promising therapeutic approach for the treatment of post-stroke pneumonia [45]. The study conducted by Hyun et al. [46] revealed the presence of membrane-covered structures measuring approximately 1 μm in diameter along the migratory path of neutrophils. These structures were found to release CXCL12 and serve as guidance cues for T cells, directing their movement along the same path as neutrophil migration. In contrast, Lim et al. [47] discovered that the depletion of neutrophil-derived CXCL12 and the antagonism of CXCR4 disrupted the guidance of T cell migration by neutrophils. This intricate interplay between migrasomes and immune cell functions holds promising implications for disease treatment.

The study conducted by Wang et al. [48] unveils a critical mechanism wherein Programmed Death-Ligand 1 (PD-L1), a molecule known for its immune checkpoint function, is abundantly present in the retraction fibers and migrasomes at the rear of migrating cancer cells. The presence of PD-L1-enriched migrasomes contributes to a suppressive immune microenvironment by potentially being internalized by neighboring cells, thereby upregulating PD-L1 expression and subsequently dampening the immune response. These migrasomes may also release chemokines, facilitating the migration of both tumor and stromal cells within the tumor microenvironment, thus enhancing metastatic capabilities [22]. Additionally, through the utilization of pan-cancer analysis and single-cell sequencing techniques, Qing et al. [49] discovered a strong correlation between genes associated with migrasomes and immune evasion as well as the tumor microenvironment. This finding suggests that these migrasomes hold potential as therapeutic targets for tumors, while their heightened expression levels serve as an indicator of unfavorable prognosis.

Lateral transfer of material between cells

The role of migrasomes in the lateral transfer of mRNA and protein is crucial, as they can regulate the physiological state and function of recipient cells through the transmission of genetic information and proteins. Migrasomes can transfer cellular contents into neighboring cells. Migrasomes are rich in PTEN protein, and upon addition of migrasomes to recipient tumor cells, PTEN protein can be translated into recipient cells, thereby reducing pAKT activity and inhibiting tumor cell proliferation [50]. The behavior of recipient cells can be influenced by migrasomes, which play a crucial role in mediating lateral transfer of mRNA and protein [51]. This phenomenon contributes to various physiological and pathological processes, offering novel opportunities for therapeutic intervention and enhancing our understanding of diseases. Cytosolic contents can be actively transported into and then released from the cell through the migrasome, a process called " migracytosis“ [19]. Many important physiological functions such as the formation of neuronal networks and innate and adaptive immune responses require material transport between cells, which also proved the important role of migracytosis in intercellular communication.

Migrasomes with disease

Migrasomes are increasingly recognized for their role in various diseases, acting as key mediators of pathological processes (Fig. 5). The dual role of migrasomes in health and disease presents both challenges and opportunities. In cancer, migrasomes may promote tumor progression by transferring pro-oncogenic molecules, aiding metastasis and tumor growth. In cardiovascular diseases, they contribute to thrombosis by delivering coagulation factors, increasing the risk of clot formation. Beyond these, migrasomes are also implicated in neurodegenerative diseases and other conditions characterized by inflammation and abnormal cell migration. Given their role in mediating intercellular communication, migrasomes hold significant potential as biomarkers for disease diagnosis, particularly in conditions such as acute myocardial infarction and cancer metastasis. Understanding how migrasomes function across different diseases is essential, as their ability to modulate cell signaling could lead to novel therapeutic approaches for treating diseases marked by dysregulated cell migration.

Fig. 5

Multifaceted physiological and pathological roles of migrasomes. Migrasomes are implicated in cardiovascular and cerebrovascular diseases (e.g., myocardial infarction, stroke), supporting cellular repair processes and influencing inflammatory pathways [67, 70]. They contribute to tumor progression in cancers such as gastric, liver, and glioma, and interact with viral pathogens like SARS-CoV-2, affecting immune responses and thrombosis [53, 56]. Additionally, migrasomes aid tissue regeneration, supporting fat and bone healing and providing early diagnostic potential for kidney injury, highlighting their pivotal role in intercellular communication and therapeutic applications [80]

Tumors with the migrasomes

The protein CD151 belongs to a family of four proteins and plays a crucial role in angiogenesis and cancer metastasis [52]. Zhang et al. [53]demonstrated that increased expression of CD151 upregulated the expression of migrasomes in hepatocellular carcinoma (HCC), thereby enhancing the invasive properties of HCC cells. Furthermore, migrasomes enriched with VEGF promotes angiogenesis, increasing the likelihood of HCC metastasis. The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein that plays a crucial role in the progression of Glioblastoma (GBM) by activating downstream signaling pathways [54]. TSPAN4, identified as a marker protein for migrasomes, has been confirmed by Dong et al.‘s study to promote GBM progression through the activation of the EGFR signaling pathway [55]. This suggests that targeted therapy against TSPAN4 could potentially offer significant clinical benefits to GBM patients. Qi et al. discovered a significant upregulation of TSPAN4 expression in gastric cancer tissues compared to adjacent normal tissues [56]. Suppression of TSPAN4 resulted in inhibited proliferation of gastric cancer cells both in vitro and in vivo, indicating its potential role in impeding the progression of gastric cancer. Through genome-scale CRISPR activation screening, Zhao et al. identified a correlation between TSPAN4 and resistance to chemotherapy in esophageal cancer. TSPAN4 is found to be upregulated in esophageal squamous cell carcinoma cell lines and significantly contributes to the development of paclitaxel resistance by inhibiting cellular apoptosis [57].The study conducted by Gu et al. [58]demonstrated a potential association between migrasomes and the underlying mechanism of early tumor metastasis to bone, suggesting that migrasomes could serve as one of the primary targets for intervention in secondary bone metastasis of malignant tumors.

Virus with the migrasomes

As a member of the EVs family, migrasomes also play a pivotal role in immune response and viral infection [59]. Tetraspanins contain four transmembrane domains and play a significant role in viral infections. They can mediate viral adsorption and invasion. For example, CD81, as a receptor for hepatitis C virus, binds to the viral envelope protein through its transmembrane domain to facilitate the virus’s entry into the cell. They also participate in viral assembly and release. For instance, TSPAN8 helps in the assembly of hepatitis B virus particles. Additionally, tetraspanins can regulate the host immune response and have an indirect effect on viral infections by influencing the activation of immune cells and the secretion of cytokines. Moreover, they can promote the spread of viruses between cells, creating a microenvironment conducive to viral spread and mediating the transfer of viruses between cells [60,61,62]. The interaction between viruses and platelets occurs through both ACE2-dependent and independent pathways, resulting in platelet activation, aggregation, and the subsequent release of various EVs, including migrasomes [63]. Notably, the release of migrasomes from platelets infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virions has been implicated in immune dysregulation and thrombosis, exacerbating the complications associated with COVID-19 [64]. In a significant finding, Lv et al. [65]demonstrated that the vaccinia virus (VACV) can induce migrasome formation, suggesting a potential mechanism for poxvirus transmission. However, further investigations are essential to elucidate the complex mechanisms underlying VACV-mediated migrasome formation and to explore the therapeutic potential of targeting migrasomes for antiviral drug development. Understanding these pathways could lead to innovative strategies for managing viral infections and their associated complications.

Migrasomes and cardiovascular system diseases

The involvement of migrasomes is essential in various physiological processes, including thrombosis, coagulation, angiogenesis, vascular injury response, and heart diseases [66]. The study conducted by Jiang et al. [67] revealed that migrasomes derived from neutrophils in the bloodstream exhibit a high concentration of adhesion molecules and coagulation factors, indicating a close association with cardiovascular homeostasis. This suggests that migrasomes may have implications for cardiovascular diseases. Zheng et al. [68]recently discovered a strong correlation between TSPAN4 expression and the occurrence of atherogenic plaque rupture and intraplaque hemorrhage. Furthermore, they observed an upregulation of TSPAN4 expression in a mouse model of spontaneous myocardial infarction (MI), indicating that both TSPAN4 and migrasomes could potentially serve as therapeutic targets for treating atherosclerosis and MI [68]. Zhu et al. demonstrated that migrasomes hold great potential as a biomarker for diagnosing acute myocardial infarction (AMI) [69]. Sun et al. [70] demonstrated that mechanical stimulation of low-intensity pulsed ultrasound (LIPUS) mitigated myocardial infarct size and myocardial ischemia-reperfusion injury (MIRI) by enhancing impaired mitochondrial excretion through migrasome-dependent mitosis. This may offer a novel, noninvasive, non-pharmacological approach for the treatment of MIRI.

Migrasomes and nervous system diseases

The accumulation of amyloid beta protein (Aβ) in cerebral amyloid angiopathy (CAA) compromises the integrity of the blood-brain barrier (BBB). Hu et al. [71]demonstrated a positive correlation between the Aβ40-induced macrophage-derived migrasomes and the severity of CAA. Furthermore, they found that these migrasomes were responsible for mediating BBB damage. Therefore, macrophage-derived migrasomes hold potential as both biomarkers and therapeutic targets for CAA [71]. A high-sodium diet promotes ischemic injury of the central nervous system and induces the generation of a substantial number of migrasomes in the ischemic brain tissue. Adjacent to these migratory cells, both atrophied and intact neurons were observed, along with the evidence of neuronal fragments within the migrasomes. This phenomenon may be attributed to two distinct mechanisms: firstly, migrasomes might infiltrate into intact neurons’ cytoplasm, leading to neuronal death and exacerbating ischemic cell damage; secondly, migrasomes could uptake debris from damaged neurons and thus serve as transporters [72]. Hence, migrasomes may play a role in the pathological process of acute stroke and represent potential targets for its treatment.

Migrasomes and kidney disease

Podocytes are specialized renal cells that play a crucial role in maintaining the glomerular filtration barrier. During the process of migration, particularly following podocyte injury, these cells release migrasomes—small extracellular vesicles that facilitate intercellular communication and tissue remodeling. Notably, this release of migrasomes is significantly enhanced in pathological conditions, as demonstrated in both mouse models of nephropathy and in patients experiencing renal injury [73]. Remarkably, elevated levels of migrasomes in urine have been detected prior to the clinical onset of proteinuria, indicating their potential utility as early biomarkers for diagnosing podocyte-associated renal diseases [74]. These findings highlight the promise of migrasomes not only as indicators of podocyte health but also as non-invasive biomarkers for the early detection of renal pathology, potentially allowing for timely intervention and improved patient outcomes.

Migrasomes and proliferative vitreoretinopathy

The occurrence of proliferative vitreoretinopathy (PVR) is a significant complication associated with rhegmatogenous retinal detachment, which can result in visual impairment [75]. The activation of retinal pigmented epithelium (RPE) by cytokines has been demonstrated to be associated with the development of PVR [76]. The migrasome marker TSPAN4 is highly expressed in clinical samples related to PVR, and subsequent investigations have demonstrated that the cytokine TGF-β1 upregulates TSPAN4 expression through activation of RPE, thereby promoting migrasome formation [77]. Migrasomes play a pivotal role in RPE activation and the progression of PVR. Therefore, the targeting of TSPAN4 or the inhibition of migrasome formation may represent innovative therapeutic strategies for the treatment of PVR [77].

Migrasomes and tissue regeneration

Adipose-derived stem cells (ASCs) are mesenchymal stem cells that reside in adipose tissue and actively participate in the regeneration of adipose tissue. It has been demonstrated that local upregulation of the chemokine CXCL12 following tissue injury can effectively recruit ASCs via their receptor CXCR4 [78, 79]. Chen et al. [80] reveals that ASCs produce migrasomes rich in CXCL12, which facilitate the recruitment of ASCs. By activating the CXCR4/RhoA signaling pathway, CXCL12 can attract stem cells and enhance adipose tissue regeneration. These findings suggest that utilizing ASC-derived migrasomes as novel therapeutic targets for ASC-mediated tissue regeneration holds great potential and may have broader applications in regenerative medicine. Li et al. [81]discovered that migrasomes derived from M2 macrophages on titania nanotubes array can enhance bone formation by promoting the osteogenic differentiation capacity of MSCs, indicating that nanosurfaces may serve as a promising platform for generating migrasomes and facilitating the advancement of regenerative medicine.

Perspective

The migration of cells is a crucial phenomenon in the growth and development of multicellular organisms. The discovery of migrasomes has introduced a new dimension to our understanding of cell–cell communication. Functionally, it plays an indispensable role in various biological processes, such as embryogenesis, immune response, wound healing, and cancer cell metastasis. During embryogenesis, cell migration facilitates the precise arrangement of cells into specialized tissues and organs. In adult animals, cell migration serves as a pivotal mechanism underlying numerous physiological and pathological processes [18]. The communication between cells is crucial in multicellular organisms, as it facilitates the exchange of information and coordinated responses. Intercellular communication occurs through various mechanisms, including direct physical contact, interactions between ligands and receptors, and the transfer of EVs [82]. Different biological processes regulate these modes of intercellular communication, and currently no single entity or process can comprehensively control all of them. At this juncture, the migrasome emerges as a critical player. As a novel type of EV associated with cell migration, it has garnered significant attention for its pivotal role in intercellular communication [35]. Notably, migrasomes possess the characteristics of “optimal” carriers for information transfer. They have demonstrated the ability to transmit information through all recognized modes of cell-cell communication. For instance, migrasomes can establish direct contact with other cells to facilitate contact-mediated communication, and they contain bioactive molecules or organelles that can be internalized by recipient cells for material and information exchange. Furthermore, migrasomes are abundant in signaling molecules and possess release mechanisms that enhance ligand-receptor mediated communication [11].

While the functional capabilities of migrasomes are evident, the biogenesis of migrasomes is a highly intricate process that undergoes precise regulation. Extensive research has been conducted on the occurrence process of migrasomes; however, there remain unresolved issues. Firstly, the clustering of SMS2 foci at the leading edge of the migrating cell basal membrane signifies the precise location where migrasome formation occurs [29]. However, the reasons for SMS2 foci clustering in this specific region and the exact mechanism underlying SMS2 foci assembly require further exploration. Secondly, it has been suggested that PIP5K1A is recruited to the site of migrasome formation before migrasome assembly [21], but the underlying mechanism remains elusive. Additionally, the study by Dharan et al. [28]has partially addressed the cellular mechanism underlying membrane tension and Tspan-based cluster formation of migrasomes; however, more comprehensive studies are needed to fully elucidate this mechanism.

Considering the role of migrasomes in intercellular communication, identifying reliable markers is crucial for their detection and analysis. The current study suggests that TSPAN4 may serve as such an indicator, prompting further investigation into specific markers associated with migrasomes. However, the existing methods for isolating migrasomes face challenges in ensuring their purity and yield. Validation studies are required to confirm the efficacy of Yang et al.‘s proposed technique [37], which offers a simple and efficient approach for isolating and quantitatively analyzing migrasomes.

Given that migrasomes are closely tied to cell migration, it is reasonable to explore their involvement in pathological processes, such as cancer. Malignant tumor cells exhibit a robust migratory capacity and migrasomes associated with tumors may arise during the migration of these cells [14]. Currently, research on migrasomes in tumors is still in its early stages, primarily focusing on TSPAN4, a known migrasome marker. Studies have shown associations between migrasomes and various cancers, including HCC, GBM, gastric, and esophageal cancers [53, 55,56,57]. However, the exact mechanisms through which migrasomes influence tumor progression or contribute to chemotherapy resistance remain largely unclear. Additional studies are necessary to elucidate these mechanisms and to explore the potential of migrasomes in cancer treatment and diagnosis. For instance, Gu et al. [58]revealed a potential link between migrasomes and secondary bone metastasis in tumors, suggesting that further investigations are needed to develop migrasome-targeted strategies for preventing bone metastasis. In addition to their roles in cancer, migrasomes play a pivotal role in maintaining mitochondrial quality control by eliminating dysfunctional mitochondria [12]. Given that tumor cells exhibit high metabolic efficiency, often leading to mitochondrial damage, an intriguing question arises: do tumor cells exploit migrasomes for their own benefit? This could be one of the mechanisms through which migrasomes facilitate tumor progression. Such possibilities require further investigation to fully understand the implications of migrasomes in both physiological and pathological contexts.

Beyond their direct involvement in tumor biology, migrasomes also interact closely with immune cells, influencing the immune microenvironment. For instance, migrasomes rich in PD-L1 can effectively suppress the immune microenvironment and facilitate tumor metastasis. Therefore, conducting an in-depth investigation into the correlation between migrasomes and PD-L1 will contribute to enhancing the efficacy of cancer immunotherapy. Furthermore, the study conducted by Lv et al. [65]suggests a potential association between migrasomes and VACA transmission, thereby indicating that inhibiting migrasome formation could be considered as a promising strategy for future development of anti-poxvirus drugs.

Conclusion

Migrasomes represent an exciting frontier in cell biology, offering insights into the intricate mechanisms of cell-cell communication and material transfer. This review highlights the emerging significance of migrasomes in mediating both physiological and pathological processes, underscoring their potential as valuable diagnostic biomarkers and therapeutic targets. Migrasomes offer a novel paradigm for understanding intercellular communication, with their involvement in diverse disease states such as cancer and cardiovascular disorders. However, many questions remain unanswered, particularly regarding the precise molecular mechanisms governing migrasome biogenesis, cargo sorting, and their interactions with other EVs. Future research should focus on elucidating these pathways, as well as exploring the therapeutic potential of modulating migrasome activity, which could open new avenues for personalized medicine.