A decade of migrasome research: biogenesis, physiological functions, and disease implications

Abstract

Since their first report a decade ago, our understanding of migrasomes - specialized organelles initially identified in migrating cells-has advanced considerably. Researchers have elucidated key aspects of migrasome biology, including the mechanisms of their biogenesis, their roles in cellular physiology, and their implications in various diseases. Concurrently, the development of a robust toolkit for migrasome analysis has transformed these structures from mere microscopy curiosities into central players in an emerging field with significant impact on cell biology, developmental biology, immunology, and disease pathology. This review provides a comprehensive summary of current insights into migrasome biology, with a particular focus on the molecular mechanisms governing their formation and their established cellular and physiological functions. In addition, we highlight the current challenges and unresolved questions that continue to shape and propel future research in this exciting area of study.

Fig. 1. A collection of migrasomes.

a TSPAN4-GFP overexpressing MCA-205 cancer cell migrated on FN-coated surface. Scale bar, 5 μm. The enlarged box shows migrasomes and retraction fibers. Scale bar, 2 μm. b Neutrophil cells isolated from mouse bone marrow were activated with 1 μM fMLP and migrated on a confocal dish. Cells were stained with WGA-647 before imaging. Scale bar, 5 μm. The enlarged box shows migrasomes and retraction fibers. Scale bar, 1 μm. c Transmission electron microscopy image of the lowest ultra-thin section (in contact with the culture dish) of a L929 cell. Scale bar, 500 nm. Enlarged migrasome is shown in the down left panels. Scale bar, 500 nm. d Representative transmission electron microscopy images of L929 cell treated with 2 mM CCCP. Scale bar, 20 nm. e Neutrophil cells isolated from mouse bone marrow were activated with 1 μM fMLP and migrated on silicon surfaces and observed by field emission scanning electron microscopy. Scale bar, 2 μm. Boxed regions in the right down is an enlarged migrasome. Scale bar, 200 nm. f Intravital imaging of neutrophils in mouse liver. Neutrophils were labeled with PE-anti-Ly6G6C (green), and blood vessels were labeled with AF647-WGA (purple). The white arrow indicates the migrasome. Scale bar, 2 μm. g Intravital imaging of mouse circulating monocytes and monocyte-derived extracellular particles. LPS (12 mg/kg) was injected into mice by intraperitoneal injection. Monocytes were labeled with CCR2-PE antibody (yellow), and blood vessels were labeled with AF647-WGA (cyan). Scale bar, 5 μm. h Confocal image of migrasomes in zebrafish. A single blastomere of an embryo at the eight-cell stage was injected with tspan4a-GFP mRNA. Spinning disk microscopy was used to acquire 3D images of gastrula cells (6 hpf). i Transmission electron microscopy image of CAM of chicken embryos from day 9. Individual migrasomes are pointed by black arrows. Scale bar, 1 μm.

Fig. 2. Mechanism of migrasome biogenesis.

Migrasome biogenesis occurs in three distinct stages: the nucleation phase, triggered by the assembly of SMS2 foci; the maturation phase, orchestrated by the PIP5K1α-Rab35-integrin signaling axis; and the expansion phase, facilitated by the formation of TEMs.

Fig. 3. Cargoes of migrasomes.

The cargoes carried by migrasomes can be classified into five categories: secretory vesicles, damaged mitochondria, mRNA, viruses, and coagulation factors.

Fig. 4. Biological functions of migrasomes.

Migrasomes participate in diverse physiological processes through multiple mechanisms: a localized secretion of signaling molecules; b targeted delivery of signaling cues via detached migrasomes, contributing to the formation of spatially defined signaling centers and gradients during embryonic development, angiogenesis, and immune responses; c intercellular transfer of proteins and RNAs between neighboring cells, fostering cell–cell communication; d maintenance of cellular homeostasis under stress conditions by expelling damaged organelles; e absorption and targeted delivery of coagulation factors to promote clotting.