2025-08-15 オックスフォード大学
<関連情報>
- https://www.ox.ac.uk/news/2025-08-15-platelets-shown-store-dna-study-could-transform-cancer-screening
- https://www.science.org/doi/10.1126/science.adp3971
血小板は細胞外DNAを捕捉し、腫瘍由来のDNAと遊離胎児DNAを捕捉する Platelets sequester extracellular DNA, capturing tumor-derived and free fetal DNA
Lauren Murphy, Jeanne Inchauspé, Giampiero Valenzano, Pamela Holland, […] , and Bethan Psaila
Science Published:14 Aug 2025
DOI:https://doi.org/10.1126/science.adp3971
Editor’s summary
Although platelets are best known for their role in blood clotting, they also contribute to host defense and homeostasis. Murphy et al. found that platelets could acquire DNA from nucleated cells by internalizing extracellular vesicles and taking up DNA not enclosed in a membrane, called cell-free DNA (cfDNA) (see the Perspective by Tsui and Lo). In mice, depletion of platelets increased the concentration of cfDNA within blood plasma, indicating that platelets may help to remove cfDNA that has the potential promote inflammation. Human platelets isolated from pregnant individuals contain fetal DNA, and those from cancer patients contain DNA with tumor-associated mutations. Because there is a relatively low concentration of cfDNA in blood plasma, platelets might be an additional source to help overcome a current limitation in clinical diagnostics. —Sarah H. Ross
Structured Abstract
INTRODUCTION
Platelets are the smallest and second most abundant cell type in our blood, contributing to a range of physiological processes, including hemostasis, vascular maintenance, and innate immunity. Whereas megakaryocytes, the platelet-producing cells in the bone marrow, have a large, highly polyploid nucleus, platelets have no nucleus at all and have traditionally been assumed to be devoid of DNA. Platelets have a distinct cellular physiology with a series of surface-connected membrane channels, called the open canalicular system, mediating efficient internalization and release of biomolecules, including nucleic acids such as viral RNA and DNA, within the circulation.
RATIONALE
Given their known ability to sense and internalize exogenous nucleic acids, we hypothesized that platelets may sequester endogenous extracellular DNA during circulation. Conceivably, this process might contribute to physiological mechanisms that limit the abundance of cell-free DNA (cfDNA) in plasma, which is immunostimulatory. This phenomenon would be relevant to liquid biopsy approaches, many of which focus on cfDNA isolated from platelet-depleted plasma, in which platelet nucleic acids are discarded. cfDNA contained within platelets may offer an untapped, additional reservoir of clinically relevant genetic material to, for example, increase sensitivity in cancer screening to detect low–tumor burden disease.
RESULTS
By using high resolution imaging and flow cytometry, we confirmed that platelets contain fractional quantities of DNA. To test whether platelets can acquire DNA after their release from megakaryocytes, we performed live cell imaging and coculture experiments, demonstrating transfer of mutant DNA from malignant cells to healthy donor platelets in vitro. We confirmed that cfDNA sequestration by platelets occurs in vivo, corroborating both visually (with fluorescence in situ hybridization) and molecularly (with droplet digital polymerase chain reaction) that platelets from healthy pregnant females carrying male babies contained fragments of the Y chromosome.
Whole-genome sequencing of platelet DNA revealed a fragmentation pattern and nucleosome footprint that mirrored the attributes of cfDNA isolated from platelet-depleted plasma. The DNA fragments in platelets were histone-associated chromatin, with DNA methylation marks suggesting a similar cellular composition to cfDNA with contributions from blood leukocytes and megakaryocytes and a minor contribution from hepatocytes in healthy individuals.
Given our hypothesis that platelets clear cfDNA from plasma, we reasoned that plasma cfDNA would increase in the setting of thrombocytopenia. Indeed, acute platelet depletion in an immune thrombocytopenic purpura (ITP) mouse model led to a rise in plasma cfDNA, and patients with ITP and severely low platelet counts exhibited significantly higher plasma cfDNA levels than individuals with normal platelet counts.
We found that platelets could acquire DNA by internalizing both DNA-loaded extracellular vesicles released by apoptotic cells and membrane-free DNA fragments. Uptake and release of DNA could be pharmacologically manipulated. Platelet-encapsulated DNA was protected from external deoxyribonuclease (DNase) degradation, and inhibiting platelet exocytosis increased the abundance of DNA obtained from platelets.
Lastly, we demonstrated that tumor-derived DNA was present in platelets of patients with advanced cancer, where cfDNA was in high abundance; in low–tumor burden disease; and also in those with premalignant colonic polyps.
CONCLUSION
Platelets can acquire a repertoire of DNA fragments that map across the nuclear genome, including DNA derived from tumor cells and free fetal DNA. Prior work has shown that tumor cell–derived RNA is detectable within circulating platelets. Given their abundance, ease of isolation, and tissue-wide perfusion, platelets are ideally positioned to serve as biosensors for genetic perturbations across tissues. This finding has broad clinical relevance and sets the stage for future work to clarify the role of platelets in cfDNA homeostasis as well as the fate and physiological consequences of DNA fragments released at sites of platelet activation.
Platelets sequester cfDNA during circulation.
Bone marrow megakaryocytes release platelets into the bloodstream. During circulation, platelets encounter extracellular DNA—histone-bound nucleosome fragments—released by cells undergoing physiological apoptosis, including tumor cells and free fetal DNA. Platelets protect internalized DNA from external DNase degradation and release their DNA cargo in a dynamin-dependent manner upon platelet activation. [Figure created with BioRender.com]
Abstract
Platelets are anucleate blood cells vital for hemostasis and immunity. During cell death and aberrant mitosis, nucleated cells release DNA, resulting in “cell-free” DNA in plasma (cfDNA). An excess of cfDNA is deleterious. Given their ability to internalize pathogen-derived nucleic acids, we hypothesized that platelets may also clear endogenous cfDNA. We found that, despite lacking a nucleus, platelets contained a repertoire of DNA fragments mapping across the nuclear genome. We detected fetal DNA in maternal platelets and cancer-derived DNA in platelets from patients with premalignant and cancerous lesions. As current liquid biopsy approaches utilize platelet-depleted plasma, important genetic information contained within platelets is being missed. This study establishes a physiological role for platelets that has not previously been highlighted, with broad translational relevance.
