Migrasomes: a promising extracellular vesicle-like novel organelle for bone regeneration

ABSTRACT

Bone regeneration represents a key objective in bone tissue engineering and involves a series of coordinated biological processes, including immunomodulation, neuroregulation, angiogenesis, and osteogenesis. Recent studies have underscored the therapeutic potential of extracellular vesicles (EVs) in promoting osteogenesis and facilitating the repair of bone defects, supporting their application as a promising cell-free strategy in regenerative medicine. Migrasomes, vesicle-like organelles anchored to retraction fibers and first identified in 2015, have emerged as key mediators in intercellular communication, lateral transfer of mRNA and proteins, and mitochondrial homeostasis. Through cell-free treatment, these functions support the activity and regenerative ability of stem cells during bone repair. This review provides an updated overview of migrasome-related research, emphasizing their roles in molecular delivery and regulation during bone regeneration. Moreover, the potential of migrasomes as innovative tools for bone tissue engineering is discussed, along with prospective strategies to enhance their utility through advances in understanding their biogenesis and cargo sorting. Despite their known biological functions, the therapeutic applications of migrasomes in bone regeneration remain largely unexplored, highlighting the need for further investigation in this emerging field.

1. Introduction

1.1. Challenges in bone regeneration

Bone is one of the few regenerative organs capable of continuous remodeling throughout adulthood. However, bone defects, resulting from trauma, pathological conditions, or surgical resection, often present with complications such as infection, irregular morphology, and poor tissue integration. These factors pose significant challenges to the efficacy of existing bone regeneration strategies, including scaffold-based approaches, mesenchymal stem cell (MSC) therapy, and the controlled delivery of growth factors or other bioactive agents [1,2]. Despite ongoing progress, current treatment modalities remain limited in their ability to fully restore structural and functional bone tissue [3,4]. The complexity of bone regeneration is influenced by defect size, anatomical location, and the mechanical requirements of the affected site, all of which contribute to variable clinical outcomes [5]. Although organoid and organ-on-a-chip technologies have emerged as promising models for studying tissue regeneration, their application to bone remains limited by the complex and time-consuming nature of experimental protocols [6–8].

In bone regenerative engineering, traditional scaffold fabrication methods include electrospinning and three-dimensional (3D) bioprinting, while additive manufacturing technology has emerged as an advanced technique offering distinct advantages [8–10]. For complex bone defect reconstruction, patient-specific bioactive scaffolds with controlled microstructural features are fabricated via additive manufacturing [8]. Clinically, ions and bioactive molecules are being explored as alternatives to traditional biologics, enabling extended release via modular delivery systems [9,11]. Through parametric design, topology optimization, and gradient modeling, additive manufacturing expands the functional capabilities of biomedical scaffolds and implants, achieving customized interconnected structures, tunable mechanical properties, and patient-specific compositions [10]. Although optimal biomaterial formulations are still under development, emerging tools such as artificial intelligence (AI) and deep learning are expected to advance regenerative medicine by enabling data-driven design and optimization of therapeutic strategies [12]. Recently, highly accurate prognostic models based on migrasome-related long non-coding RNAs were successfully constructed and validated for both colorectal cancer and renal cell carcinoma (the latter incorporating a risk assessment component) [13,14].

However, limited understanding of stem cell biology continues to restrict their effective clinical application [12]. Direct MSC transplantation is gradually being replaced by alternative approaches due to inconsistent outcomes and potential adverse effects [15]. In this context, extracellular vesicles (EVs), particularly exosomes, have gained attention as a cell-free therapeutic strategy capable of simulating the regenerative properties of stem cells [16].

While exosomes are widely recognized as effective natural delivery vehicles for growth factors and other regulatory molecules [8], advances in artificial modification and scalable isolation techniques have enhanced their therapeutic potential [17,18]. Furthermore, subcellular vesicles, including exosomes, may function independently of scaffolds or donor cells as targeted delivery systems [5]. For instance, aptamer-functionalized exosomes can bypass accumulation in the liver and lungs, selectively target bone marrow stem cells, and contribute to osteoporosis treatment [19].

This review explores the potential of migrasomes, EVs-like organelles, as novel tools for bone regeneration which have never been systemically summarized before. Large segmental bone defects pose a significant challenge as they cannot be effectively repaired without promoting bone cell activity and reconstructing the internal vasculature [17]. Notably, the ability of migrasomes to coordinate angiogenesis has been demonstrated [20]. Migrasomes, when combined with advanced and personalized scaffold manufacturing technology, hold promise for overcoming this problem and restoring mechanical integrity. Similarly, hydrogels extend their therapeutic effects to accelerate skin wound healing, thus demonstrating the potential of migrasome applications for bone regeneration [21]. Since migrasomes possess biological behaviors similar to their parent cells, studying them provides a novel perspective that could enhance our understanding and utilization of MSCs for bone regeneration. Therefore, our work is significant for understanding the current status of migrasome research, highlighting the clinical relevance of migrasomes, and providing a novel direction for regulating MSCs in bone regeneration. To our knowledge, this represents the first comprehensive review focusing on the role of migrasomes in bone regeneration, potentially offering benefits to patients with bone defects, particularly complex cases.

1.2. Migrasome essentials

This review explores the potential of migrasomes, organelle-like structures resembling EVs, as a novel tool for bone regeneration. Migrasomes form during cell migration along retraction fibers (RFs), which are extensions of the cellular cytoskeleton left behind by migrating cells [22]. These vesicle-like structures, typically ranging from 0.5 to 3 µm in diameter, preferentially develop at branch points of RFs and are then released via a process termed migracytosis [22]. Functionally, migrasomes contribute to mitochondrial quality control, mediate the lateral transport of mRNA and proteins, and participate in intercellular signaling [23,24]. Cai et al. classified migrasome functions into two distinct modes: the “waste bin” mode, which disposes of cellular debris, and the “information pocket” mode, which facilitates intercellular communication [25]. The RFs induce dynamic destabilization of migrasome size homeostasis [26]. While some researchers classify migrasomes as a subtype of EVs originating from migrating cells, this classification is debated [27]. The loss of the typical double-layer membrane structure resulting from connections to RF and the ability to split into multiple ones differentiates migrasomes from EVs [27,28].

Rather than being strictly categorized as EVs, both migrasomes and RFs are viewed as specialized components of the extracellular matrix (ECM), and their roles in tissue remodeling and signaling have attracted attention as potential targets for nanomedicine-based therapies [29]. It is also suggested that migrasomes become EVs once they detach from the RFs [30]. Similarly, migrasomes contain vesicles of varying sizes within their structure, leading scholars to describe their appearance as “pomegranate-like” [22,31]. The number of internal vesicles per migrasome varies widely, from fewer than 10 in most cases to as many as 300 in some instances [31]. Migrasomes serve as the primary secretory mechanism in migrating cells [32]. Migrasomes demonstrate active import capacity by translocating cytosolic constituents into their membrane-bound vesicles [31]. Their formation is closely associated with the extension of RFs (Figure 1(A)), and an increase in migrasome secretion can enhance the elongation of contraction filaments, therefore accelerating cell migration [33]. This reciprocal relationship creates a self-reinforcing mechanochemical loop, particularly under conditions favoring rapid and linear migration [30]. Recently, Li et al. reported a non-canonical migracytosis pathway in which migrasome formation occurs independently of cell migration but is induced by a small guanosine triphosphatases (GTPases) toxin [34].

Figure 1.

Biogenesis, functional mechanisms, and component distribution within migrasomes.

A. Migrasome biogenesis in relation to retraction fibers (RFs) elongation and cellular migration. B. Key functions and internal distribution of migrasome components. C. Crucial molecular regulators across the three primary stages of migrasome biogenesis. GTPases: guanosine triphosphatases. RFs: retraction fibers. SOX2: SRY-related HMG-box-2. ROCK1: Rho Associated Coiled-Coil Containing Protein Kinase 1. mtDNA: mitochondrial DNA.

The biogenesis of migrasomes follows three key stages: nucleation, maturation, and expansion, governed by the membrane microdomain assembly model and shaped by protein-dependent membrane tension [35–38]. However, the regulatory mechanisms of migrasome formation remain incompletely understood. During the nucleation phase, sphingomyelin synthase 2 (SMS2) localizes at the leading edge of migrating cells, initiating migrasome formation [39]. In the maturation phase, phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) signaling facilitates the recruitment of key molecules such as Rab35 and integrin α5 (ITGA5) [30]. Besides, proteomics studies have revealed that integrin family members are highly expressed in migrasomes [40]. These integrin heterodimers function as adhesion receptors, anchoring migrasomes to RFs and promoting cellular motility [30,41]. Key molecules involved in migrasome biogenesis include cholesterol and 14 tetraspanin (TSPAN) family members, such as TSPAN4. Further, TSPANs play a crucial role in maintaining migrasome stability [39,42] by preferentially accumulating in membrane regions exhibiting high positive curvature, including RFs [43]. Tetraspanins organize into tetraspanin-enriched microdomains (TEMs), which incorporate cholesterol and various tetraspanin-associated proteins within the membrane. These microdomains play a key role in organizing the membrane structure and influencing essential cellular functions, including adhesion, migration, and signal transduction [30]. TEMs undergo hierarchical assembly into larger membrane macrodomains, termed tetraspanin-enriched macrodomains (TEMAs) [30]. TEMAs support migrasome formation through two synergistic mechanisms: serving as physical scaffolds to drive migrasome expansion during growth and reinforcing structural integrity in mature organelles [38]. Moreover, calcium binding to its sensor, Synaptotagmin-1 (Syt1), facilitates migrasome precursor formation by inducing localized swelling at migrasome formation sites [37].

Recent studies have identified the mechanical stiffness of TEMAs as a critical driver for initiating local RF bulges, which then develop into mature migrasomes. These bulges emerge from dynamic shifts in membrane tension, with TEM-mediated stiffening representing a fundamental biophysical driver of migrasome biogenesis [42]. Elucidating the spatiotemporal dynamics of TEMAs is essential for understanding migrasome formation and advancing their therapeutic application in bone regeneration (Figure 1(C)).

Meanwhile, certain molecules indirectly regulate migrasome formation (Figure 1(A)). Partial loss of function of the migration-related CCCTC-binding factor (CTCF) in mouse melanoma cells has been shown to elevate cellular cholesterol levels while simultaneously decreasing migrasome formation [44]. Pretreatment with lipoprotein-deficient serum has been shown to reduce migrasome formation in H4 human neuroglioma cells, whereas hypo-osmotic stress stimulates their release [45]. The SRY-related HMG-box-2 (SOX2)-Rho Associated Coiled-Coil Containing Protein Kinase 1 (ROCK1) axis has been shown to enhance trophoblast cell migration and invasion while promoting migrasome formation [46]. Moreover, titania nanotube surfaces facilitate M2 macrophage polarization and contribute to increased migrasome production [47]. Zinc oxide nanoparticles (ZnO-NPs) promote migrasome formation, correlating with increased levels of PI(4,5)P2 and GTP-Ras homolog gene family, member A (RhoA), molecules essential for migrasomal biogenesis. Additionally, ZnO-NPs help removes lysosomes, lipid droplets, the ZnO-NPs themselves, and dysfunctional mitochondria through mitocytosis, thereby preserving cellular integrity [48]. Lysine-specific demethylase 1 (LSD1) and ERα activation facilitated cell migration by promoting migrasome generation through upregulation of fibronectin (FN) [49]. The vesicles within migrasomes are transported with the motor protein Myosin Va and the adaptor protein Rab-interacting lysosomal protein-like 2. This process is regulated by leucine-rich repeat kinase 2 (LRRK2), which phosphorylates Rab10 and activates Caveolin-1 [50]. During cell migration, most secretory carriers, driven by the actin-dependent motor protein Myosin 5a, transport secretory proteins, including signaling molecules, to the cell’s rear. These proteins are then actively delivered into migrasomes through constitutive and regulated secretion pathways and fuse with the migrasome membrane via soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-dependent mechanisms [32].

1.3. The potential value of migrasomes in bone regeneration

Like exosomes, migrasomes can transfer key signaling molecules to recipient cells, affecting cellular phenotypes and promoting regeneration through a cell-free strategy [51]. Emerging techniques such as genetic engineering, physical manipulation, chemical modification, and advanced screening have demonstrated success in enhancing exosome loading efficiency and optimizing fabrication processes for biomedical use, showing promising potential for application in migrasome engineering, potentially elevating their therapeutic efficacy in bone regeneration [52]. The documented affinity of nanoparticles for both migrasomes and RFs further support the development of engineering approaches aimed at improving the functionality and delivery capacity of migrasomes in regenerative applications [29].

Despite differences in origin, size, biogenetic pathways, and cargo profiles (Table 1), migrasomes and exosomes share a major clinical limitation: low production yields [57,58]. The emergence of affinity-based purification protocols, particularly wheat germ agglutinin (WGA)-coated magnetic beads and flow cytometry methods, has significantly enhanced migrasome isolation efficiency compared to centrifugation-dependent approaches [59]. However, optimizing secretion and culture conditions is also important for scalable production. The nanosurface offers another route by facilitating the generation of migrasomes suitable for bone regenerative medicine applications [47]. Experimental systems employing dynamic membrane reconstitution platforms and live-cell assays have successfully generated migrasome-mimetic giant unilamellar vesicles (GUVs) through electrofusion of proteoliposomes in vitro [42]. Similarly, a biomimetic system based on giant plasma membrane vesicles (GPMVs) was developed. An abrupt increase in GPMV tension led to the formation of migrasome-like bulges at the junctions of membrane tubules [35]. This suggests the potential for biomimetic migrasome generation in broader clinical applications. Stabilization of membrane bulging in branched tubular systems, along with identification of key molecular regulators of migrasome biogenesis, remains an important research focus [42,60]. Using an extrusion approach, researchers have developed high-yield exosome-mimicking nanovesicles for bone regeneration [18]. Moreover, perfusion bioreactors manufactured via 3D printing have increased the yield and bioactivity of macrophage-derived EVs [61]. 3D culture platforms also offer prolonged EV release and improved local bio-availability [62]. These approaches may be adapted to improve migrasome production, supporting their therapeutic application in regenerative medicine.

Table 1.

The comparasions between migrasomes and exosomes.

Characteristic	Migrasomes	Exosomes
Size	0.5–3 µm [22]	30–150 nm [30]
Origin	Plasma membrane [30]	The endosomal system [53]
Biogenesis machinery	Sphingomyelin synthase 2, phosphatidylinositol 4,5-bisphosphate, Rab35, integrin family, cholesterol, 14 members of the tetraspanin and Synaptotagmin-1 [30,37,39,40,42]	ESCRTs [30]
Cargo	Proteins, cholesterol, mRNA, miRNA, mtDNA, harmful substance and vesicles [30,54–56]	DNA, RNA, proteins and lipid, etc [30]
Spatial signaling regulates migration	Y [30,38]	Unreported
Membrane integrity	N [27]	Y [27]
Capability to divide	Y [28]	N [27]

ESCRT: endosomal sorting complex required for transport. mtDNA: mitochondrial DNA. TSPAN: tetraspanin. Y: Yes. N: No.

1.4. Migrasome-specific cargo delivery

To serve as an effective delivery vehicle for bone regeneration, migrasomes must achieve high payload retention and minimize cargo leakage, comparable to established EV systems [63]. They fulfill this requirement by releasing signaling molecules through controlled rupture or leakage [22]. During bone healing, chondrocytes transition into osteoblasts, facilitating endochondral ossification, essential for endochondral bone repair [64]. Osteochondral tissue regeneration requires well-defined gradients, such as mechanical support for cartilage rehabilitation [65]. Migrasomes generate localized gradients of signaling molecules at specific sites, serving as efficient delivery vehicles that could be used for tissue regeneration requiring precise spatiotemporal coordination [30].

Like EVs, which mediate intercellular communication and contribute to microenvironmental homeostasis, migrasomes have been recognized as specialized mediators of signal exchange among migrating cells [66]. Migrasomes facilitate intercellular communication, transfer cellular components such as mRNA and proteins, remove unwanted materials (e.g., damaged mitochondria), and integrate spatial, temporal, and biochemical information [22,67]. Proteins, mRNA, miRNA, and mitochondrial DNA (mtDNA) have been identified in migrasomes, with proteins being the primary focus of current research [30,54] (Figure 1(B)). Reported migrasome-associated mRNAs include BMP1, ITGB1, NDST1, TSPAN1, TSPAN18, TSPAN2, TSPAN4, TSPAN7, TSPAN9, and WNT8A [68]. Proteomic analysis by mass spectrometry reveals that membrane-associated proteins (60%) and cytoskeletal proteins (11%) constitute the predominant components of migrasomes when categorized by subcellular localization and functional classification, respectively [31]. TSPAN4 is a prominent membrane component, while actin polymerization is essential for migrasome biogenesis [31]. Although the secretory protein transport mechanism involving Myosin 5a-driven carriers and SNARE-mediated fusion has been characterized, the selective uptake and cargo sorting mechanisms in migrasome formation remain poorly understood [32,43]. Functionally, migrasomes act as “scavengers” helping to remove harmful substances and preserve cellular homeostasis and viability [55,56]. This role is particularly important during tissue regeneration, where initial cell survival is a prerequisite for successful outcomes [4]. Migrasome-mediated clearance of damaged mitochondria is a critical mechanism for maintaining cell survival under stress [23]. Furthermore, migrasomes may exert long-range effects on target cells through direct membrane fusion or alternative interactions with the ECM and neighboring cells [69,70]. Membrane fusion is the primary mechanism through which migrasomes interact with recipient cells, enabling direct molecular exchange [71]. However, migrasomes that are not engulfed may either adhere to the surfaces of neighboring cells and the ECM or remain in circulation for further transport [30]. Interestingly, Wu et al. reported that migrasomes attached to blood vessel walls may undergo fission, generating multiple vesicles from a single structure [28]. Given their role in cellular communication, migrasomes exhibit significant potential as delivery systems in tissue engineering. They are evolutionarily conserved and implicated in multiple physiological and pathological processes, including osteogenic differentiation, angiogenesis, cell migration, and proliferation, key elements of bone regeneration [72].

Significant differences in content composition have been observed between pancreatic cancer cells and their migrasomes, particularly in chemokines, cytokines, and proteins, with the presence of immunosuppressive factors [73]. The TSPAN family, especially TSPAN4, plays a key role in migrasome formation and has naturally emerged as a biomarker for migrasomes [42,74]. Silencing TSPAN4a and TSPAN7 in zebrafish embryos resulted in abnormal development, a defect that could be rescued by supplementing migrasomes from embryonic cells [75]. These findings underscore the essential role of migrasomes in developmental processes, including chemokine patterning and the coordination of long-range signaling gradients during gastrulation [75].

Migrasomes offer several advantages over exosomes and other EVs as signal delivery vehicles in bone regeneration. These include their larger size, which allows higher cargo capacity; ability to generate localized molecular gradients; role in maintaining mitochondrial homeostasis; and capacity to regulate spatiotemporal aspects of cell behavior. Together, these features highlight migrasomes as a promising platform for engineered regenerative strategies.

2. Migrasomal functions in bone regeneration

Bone regeneration is a complex, multi-phase biological process involving immunomodulation, neuroregulation, angiogenesis, and osteogenesis [11]. Initially, a favorable inflammatory microenvironment is established through macrophage polarization. Simultaneously, skeletal interoception regulates physiological responses crucial for initiating bone repair. This is followed by neovascularization, which ensures the supply of oxygen, nutrients, and cellular components to the regenerative callus. In the final stage, MSCs and other progenitor cell populations undergo osteoblastic differentiation, leading to osteogenesis.

2.1. Migrasomes and osteoimmunomodulation

Effective bone regeneration is influenced by the immune microenvironment, particularly through coordinated interactions between MSCs and macrophages. This MSC-macrophage crosstalk regulates stem cell recruitment, inflammatory resolution, and osteogenic differentiation, forming a key mechanism underlying fracture healing [76]. Migrasomes, mainly produced by immune cells within organisms, have been shown to interact with immune cells through cytokines and chemokines, playing a role in immunomodulation [77–79].

Recent studies have shown the involvement of migrasomes in various physiological and pathological processes, including immune surveillance and the maintenance of biological barrier integrity [25,80]. Migrasomes may facilitate osteoimmunomodulation through three key mechanisms: secretion by immune cells, delivery of immune-related chemokines, and establishment of an anti-inflammatory microenvironment, a key determinant for successful bone regeneration beyond mere osteogenic differentiation [77,81].

2.2. Migrasomes and neuroregulation

Communication between the immune and nervous systems plays a key role in skeletal interoception, affecting new bone formation. For instance, prostaglandin E2 (PGE2) secreted by macrophages can attenuate sympathetic nervous system activity, promoting osteogenesis. The skeletal interoceptive circuit consists of ascending neural pathways that convey internal body signals to the central nervous system (CNS) and descending neural pathways that provide processed interoceptive feedback to regulate bone remodeling in response [82]. Migrasomes derived from macrophages and enriched with CD5 antigen-like (C5L) have been observed adhering to blood vessel walls in both skin biopsies and brain tissues from patients with cerebral amyloid angiopathy (CAA) [71]. The widespread distribution of migrasomes in the CNS and peripheral tissues, combined with their diverse cargo of signaling molecules, strongly suggests a regulatory role in neurogenic signaling during bone regeneration.

2.3. Migrasomes and angiogenesis

Bone is a highly vascularized and dynamic tissue [83], and angiogenesis is essential for supporting bone remodeling and osteogenesis [84]. Coordinated angiogenesis and osteogenesis have been shown to significantly enhance bone regeneration, particularly in calvarial defect models under osteoporotic conditions [85]. Among vascular structures, Type H capillaries have gained attention due to their ability to promote osteogenic activity [86]. This specialized vesicular system plays a key role in facilitating this coupled angiogenesis – osteogenesis process during bone regeneration [38].

Recent studies have demonstrated that migrasomes promote endothelial cell tube formation, facilitating capillary development [20]. In particular, monocyte-derived migrasomes enriched with vascular endothelial growth factor A (VEGFA) and CXCL12 establish a positive feedback loop during capillary morphogenesis. These vesicles simultaneously activate angiogenesis and stimulate monocyte recruitment, promoting vascular development through dual signaling pathways, a mechanism validated in chicken embryo models [20]. Furthermore, evidence indicates that sustained migrasome release modulates tissue levels of CXCL12 and interleukin-6 (IL-6), thereby enhancing wound healing [21]. These findings suggest that migrasomes may contribute to osteogenesis through their angiogenic properties. However, the precise mechanisms underlying this interaction remain to be elucidated.

2.4. Migrasomes and Osteogenesis

2.4.1. Osteoblastic differentiation

Migrasomes regulate signaling in a spatiotemporally coordinated manner by generating bioactive molecule gradients, including chemokines, growth factors, and morphogens, offering new avenues for bone regeneration therapies [38]. Migrasomes derived from M2 macrophages cultured on titania nanotube surfaces have been shown to promote the osteogenic differentiation of MSCs [47]. Ti implants coated with these migrasomes significantly enhanced osteogenesis in vivo [47]. Given the known role of osteoclast activity in promoting early osteogenesis and bone healing, migrasomes may also affect pre-osteoclast migration and fusion through their function as mediators of cellular movement [87,88]. In the tumor metastatic microenvironment, migrasomes facilitate cytoplasmic transfer between osteoclasts and other cell types, further highlighting their potential role in bone cell interactions [89].

MSC-derived migrasomes have been found to contain the chemokine CXCL12, highlighting their potential role in recruiting stem cells for bone defect repair [30]. During hyperthermia-enhanced osteogenic differentiation, the increased mitochondrial activity and elevated metabolism are accompanied by the expression of osteogenesis-related genes, while migrasomes can eliminate damaged mitochondria to maintain cellular homeostasis, suggesting their potential protective role in hyperthermia-mediated bone regeneration strategies [90,91].

The biological functions of migrasomes are determined by their cargo, which affects their capacity for encapsulation and transport [35]. Several biomolecules relevant to osteoblastic differentiation have been identified in migrasomes. ITGA5, a key regulator of osteogenesis, is present in migrasomes [40,70]. ITGA5 expression is upregulated in pericranium-derived spheroids cultured in 3D environments or under osteogenic induction, where it serves as a metabolic pathway regulator [92]. ITGA5 enhances the expression of runt-related transcription factor 2 (RUNX2) and Bone morphogenetic protein (BMP) promoting the synthesis of type I collagen (COL-I) [93]. Tauroursodeoxycholic acid has been shown to promote osteogenesis and inhibit adipogenesis in MSCs by regulating ITGA5 expression [94]. Furthermore, BMP2, another osteogenic factor, has been identified within migrasomes via quantitative mass spectrometry [75]. These findings underscore the potential of migrasome-associated cargo in promoting osteoblastic differentiation.

Migrasome-mediated directional transport may contribute to bone regeneration by constructing spatially defined signaling domains that regulate osteogenic differentiation through spatial zoning, temporal modulation, and mitochondrial homeostasis. Moreover, in the context of early bone metastasis, migrasomes may play dual mechanistic roles: (i) by facilitating intercellular communication that reprograms osteoclast differentiation, and (ii) by serving as vehicles for selective mitochondrial clearance through migracytosis, therefore preserving cell viability and function [89].

Subsequent sections will address two additional cellular processes critical for osteogenesis, which are also closely related to migrasomes: cell migration and proliferation.

2.4.2. The crosstalk between migrasomes and migration

Sequential processing of migrasomes, involving recognition, endocytosis, and elimination, has been implicated in enhancing the migratory potential of tumor cells [29]. Certain stimuli can trigger migracytosis and may simultaneously influence migrasomal cargo remodeling. For instance, adipose-derived stem cell-derived migrasomes enriched with CXCL12 promote stem cell migration and tissue regeneration via the C-X-C motif chemokine receptor 4 (CXCR4)/RhoA signaling axis, underscoring their therapeutic potential in regenerative medicine [95]. Brain-derived neurotrophic factor (BDNF), a known promoter of tumor invasion and metastasis, has also been shown to increase migrasome production in correlation with its upregulation [66]. Cadaverine has been reported to disrupt leukocyte migration by interfering with cellular signaling in periodontitis pathogenesis [96]. Interestingly, this molecule activates the trace amine-associated receptor 8 (TAAR8)-mediated protein kinase A signaling pathway in retinal pigment epithelial cells, promoting migrasome production [67]. In contrast to canonical migration-dependent pathways, an alternative, non-canonical mechanism of migrasome formation was recently identified, regulated by small GTPases, and facilitated by SMS2 and microtubules during a specific time window, resulting in the generation of RhoA-rich migrasomes [34].

Migrasomes also function as carriers of ECM proteins, such as p21-activated kinase 4 (PAK4) and laminin alpha 4 (LAMA4), which enhance glioblastoma cell migration [97]. Upregulation of the ECM protein FN promoted cell migration by enhancing migrasome generation [49]. Integrin – ECM pairings (e.g., fibronectin-α5) play essential roles in migrasome formation [90]. Recent research highlights the dynamic regulatory effect of the ECM on migrasome biogenesis through both biomechanical and biochemical signals [31]. Cellular adhesion to the ECM not only initiates cell migration but also serves as a key mechanism for migrasome production by facilitating microenvironmental interactions [72,98].

Migrasomes transport distinct molecular signals compared to exosomes and other EVs and play a crucial role in guiding cellular movement [99]. In summary, while migration promotes migrasome formation, migrasomes, in turn, influence both the direction and speed of cell migration.

2.4.3. Migrasomes and proliferation

Migrasomes can mediate mitocytosis and establish their role in mitochondrial quality control. Low-intensity pulsed ultrasound (LIPUS) has been shown to induce migrasome formation by activating filamentous actin (F-actin), which then promotes yes-associated protein (YAP) nuclear translocation and increases expression of kinesin family member 5B (KIF5B) and dynamin-related protein 1 (Drp1), therefore enhancing mitocytosis [100]. In the tumor micro environment, pancreatic cancer cells secrete migrasomes that modulate immune responses by inducing macrophages to suppress T-cell proliferation and activation, thus promoting immunosuppression [73]. Moreover, migrasomes can affect tumor cell proliferation through the lateral transfer of mRNA and proteins, suggesting a broader role in regulating proliferative activity [90] (Figure 2).

Figure 2.

Migrasome-derived signaling promotes bone regeneration.

VEGFA: vascular endothelial growth factor A. CXCL12: C-X-C motif ligand 12. BMP2: Bone morphogenetic protein 2. ITGA5: integrin alpha 5. BNDF: Brain-Derived Neurotrophic Factor. PAK4: p21-activated kinase 4. LAMA4: laminin alpha 4. CNS: central nervous system.

3. Present situation, limitations, and future

3.1. Current challenges

Although EVs have been successfully derived from 3D cell aggregates, most migrasome research remains confined to two-dimensional-cultured cell lines [101]. To advance this field, future studies should adopt dynamic membrane reconstitution systems and live-cell imaging platforms, particularly those that replicate branched tubular membrane geometries. Addressing clinical limitations in bone regeneration, especially in terms of defect size and mechanical integrity restoration, requires transitioning from conventional in vitro models to more sophisticated systems, such as organ-on-chip platforms and organoid-based models. While recent data emphasize the role of migrasomes in osteoimmunomodulation, neuroregulation, angiogenesis, and osteogenesis (including cell migration and proliferation), direct experimental validation in bone defect repair models remains limited. In conclusion, this review identifies migrasomes as emerging players in regenerative medicine with promising applications in bone repair (Figure 2). However, direct evidence establishing migrasomal roles in healing bone defects of diverse etiologies and their contributions to different phases of bone regeneration remains limited. The field now requires dedicated attention to realize the full therapeutic potential of these evolutionarily conserved organelles.

3.2. Future directions

Systematic investigation into the roles of migrasomes in skeletal repair, alongside the development of standardized methodologies for migrasome research, is essential. One key avenue involves determining whether migrasomes derived from distinct cellular sources differentially regulate MSC functions, particularly osteoblastic differentiation, and elucidating the molecular mechanisms underlying these effects. Moreover, the potential involvement of migrasomes in mediating cellular crosstalk (e.g., paracrine signaling between MSCs and macrophages) and inter-organ communication presents a critical frontier for osteoimmunomodulation research [54,102]. The establishment of standardized operating procedures (SOPs) for animal models and the utilizing the transgenic and gene targeted mice are also warranted to construct robust preclinical platforms for the evaluation of migrasome-based therapeutics.

Migrasomes hold diagnostic value in various diseases. For example, migrasome-associated cargoes also serve as potential therapeutic targets and biomarkers in diseases such as cerebral amyloid angiopathy [71]. They have also been identified as biomarkers for kidney disease associated with podocyte injury due to their enrichment in phospholipase A2 receptors. Furthermore, their presence has been associated with acute myocardial infarction and other pathological conditions [68,103].

Translational research directions may include the development of diagnostic reagents based on migrasome-associated biomarkers for early or subtype-specific disease detection, as well as therapeutic strategies employing migrasomal secretion promoters/inhibitors and engineered migrasomes.

To improve migrasome production yields, it is important to elucidate the molecular mechanisms underlying migrasome biogenesis. As the biogenesis is mechanistically coupled with cargo sorting, mechanistic insights into this process will establish a conceptual framework for translating these discoveries into clinical applications, ultimately enabling precision delivery in therapeutic contexts [104].

While the “one-size-fits-all” paradigm does not exist in regenerative medicine, migrasomes possess underexplored potential in drug delivery systems despite their relatively large size compared to conventional nanoscale carriers [104]. Their ability to mediate nanoparticle-assisted intercellular communication distinguishes them from other vesicular or synthetic delivery systems [105]. Elucidating the mechanisms underlying migrasome transport and secretion is essential for optimizing their application for specific therapeutic purposes [50]. From one perspective, the migrasomal secretion of specific cells can be regulated; from another, migrasomes can be utilized as tools by modifying their surface and contents [79].

4. Conclusions

Above all, tissue regeneration requires precise spatiotemporal coordination. This is particularly evident in bone regeneration, where diverse etiologies contribute to distinct phases of the process. Addressing critical-sized bone defects poses a significant challenge, as they necessitate not only defect repair but also the restoration of mechanical integrity.

Migrasomes integrate spatial, temporal, and biochemical information. They generate gradients of bioactive molecules – including chemokines, growth factors, and morphogens – and may play a protective role in bone regeneration strategies, such as hyperthermia-mediated approaches [90,91]. Specifically: (i) Immune Modulation: Secreted by immune cells, migrasomes deliver immune-related chemokines and help establish an anti-inflammatory microenvironment [77,81]. (ii) Spatiotemporal Signaling: Through directional transport, spatial zoning, and temporal modulation, migrasomes facilitate intercellular communication that reprograms cellular differentiation. For example, they influence osteoclast activity during early bone metastasis [89]. Furthermore, these signals regulate both the direction and speed of cell migration.

Larger than exosomes, migrasomes function as vehicles for the selective clearance of harmful substances via migracytosis, thereby maintaining mitochondrial homeostasis and cell viability.

Migrasome-associated biomarkers hold promise for early or subtype-specific disease detection. Furthermore, therapeutic strategies may employ either the regulation of migrasomal secretion from specific cells (using promoters/inhibitors) or the engineering of migrasomes themselves (by modifying their surface and contents).

The therapeutic potential of migrasomes has gained recognition, particularly in the context of bone regeneration. Their integration with advanced experimental techniques and analytical tools may pave the way for clinical translation. However, their clinical application presents significant challenges. Progress in elucidating the biological functions and regulatory mechanisms of migrasomes will facilitate a more systematic exploration of their therapeutic applications. These insights will enable the development of rational engineering strategies aimed at designing patient-specific migrasomal platforms tailored to individualized clinical requirements.

5. Future perspective

More detailed research is expected to reveal further details of migrasomal biology, promoting a deeper understanding of their physiological and pathological roles. Advancing migrasome research requires convergent expertise and advanced technical approaches – from bulk omics research to precision imaging and tissues engineering – to decode their biological roles and clinical promise [106]. With the accumulation of mechanistic data and functional insights, migrasomes will likely emerge as a novel therapeutic modality in regenerative medicine. Future clinical strategies may be developed based on specific etiological factors and disease stages, enabling more personalized and precise interventions. As foundational knowledge expands, the clinical translation of migrasome-based therapeutics may become a reality.

Funding Statement

This work was supported by The First People’s Hospital of Lianyungang City under Grant [QN22–01], Grant [BS202303]  and Grant [YXQNJYRC007]  and health commission of Lianyungang City under Grant [L202303] . The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Article highlights

• This review provides an updated overview of migrasome research, summarizing their functions in orchestrating bone regeneration. Key roles include immunomodulation, neuroregulation, angiogenesis, and osteogenesis (via osteoblastic differentiation, migration, and proliferation). These functions are mediated through intercellular communication, lateral transport of mRNA/proteins, and maintenance of mitochondrial homeostasis.

• As natural carriers of directional signaling molecules that promote cell migration—and with potential for modification/scaffold fusion—migrasomes represent promising therapeutic vectors. They hold significant potential for overcoming critical-sized bone defects and restoring mechanical integrity.

• This study also outlines current limitations in fundamental migrasome research and suggests future clinical translation directions, drawing on insights from published disease-related reports.

Author contributions

Conceptualization, Investigation, writing – original draft preparation, funding acquisition, Chaoting Yan; writing – original draft preparation,Yueguang Gu; writing – review and editing, funding acquisition, Kunpeng Wang; Conceptualization, writing – review and editing, supervision, funding acquisition, Geng Wu. All authors have read and agreed to the published version of the manuscript.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.