Extracellular vesicles from human saliva promote hemostasis by delivering coagulant tissue factor to activated platelets

Yu, Yiping; Gool, Elmar L.; Berckmans, René J.; Coumans, F.A.W.; Barendrecht, Arjan D.; Maas, Coen; Wel, Nicole N. van der; Altevogt, Peter; Sturk, Auguste; Nieuwland, Rienk

doi:10.1111/jth.14023

Cited by 22 publications

(20 citation statements)

References 42 publications

(62 reference statements)

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“…The effect is likely to be even stronger in an allogeneic or autologous setting. Similarly to our findings, other researchers have recently shown that EVs isolated from saliva can promote haemostasis, the first phase of wound healing [32].…”

Section: Discussionsupporting

confidence: 91%

Exosomes derived from clinical‐grade oral mucosal epithelial cell sheets promote wound healing

Sjöqvist

Ishikawa

Shimura

et al. 2019

J of Extracellular Vesicle

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The oral mucosa exhibits unique regenerative properties, sometimes referred to as foetal-like wound healing. Researchers from our institute have used sheets of oral mucosa epithelial cells (OMECs) for regenerative medicine applications including cornea replacement and oesophageal epithelial regeneration for stricture prevention. Here, we have isolated exosomes from clinical-grade production of OMEC sheets from healthy human donors (n = 8), aiming to evaluate the clinical potential of the exosomes to stimulate epithelial regeneration and to improve understanding of the mode-of-action of the cells. Exosomes were isolated from conditioned (cExo) and non-conditioned (ncExo) media. Characterization was performed using Western blot for common exosomal-markers: CD9 and flotillin were positive while annexin V, EpCam and contaminating marker GRP94 were negative. Nanoparticle tracking analysis revealed a diameter of ~120 nm and transmission electron microscopy showed a corresponding size and spherical appearance. Human skin fibroblasts exposed to exosomes showed dose-dependent reduction of proliferation and a considerable increase of growth factor gene expression (HGF, VEGFA, FGF2 and CTGF). The results were similar for both groups, but with a trend towards a larger effect from cExo. To study adhesion, fluorescently labelled exosomes were topically applied to pig oesophageal wound-beds ex vivo and subsequently washed. Positive signal could be detected after as little as 1 min of adhesion, but increased adhesion time produced a stronger signal. Next, labelled exosomes were added to full-thickness skin wounds in rats and signal was detected up to 5 days after application. cExo significantly reduced the wound size at days 6 and 17. In conclusion, exosomes from OMEC sheets showed pro-regenerative effects on skin wound healing. This is the first time that the healing capacity of the oral mucosa is studied from an exosome perspective. These findings might lead to a combinational therapy of cell sheets and exosomes for future patients with early oesophageal cancer.

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Section: Discussionsupporting

confidence: 91%

Exosomes derived from clinical‐grade oral mucosal epithelial cell sheets promote wound healing

Sjöqvist

Ishikawa

Shimura

et al. 2019

J of Extracellular Vesicle

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“…EMVs, secreted by MSCs, mimic and recapitulate some of the parent cell functions, such as self-guidance into the target/injured site, immunomodulation and reprogramming of cells required for the tissue regeneration [71]. Remarkably, exosomes were shown to possess procoagulatory activity, essential for healing the bleeding wounds [72]. In the wound healing process, EMVs take part at all stages of wound healing [69,73].…”

Section: Extracellular Membrane Vesicles Of Stem Cells and Progenitormentioning

confidence: 99%

Regenerative therapy for the nonhealing cutaneous wounds

et al. 2018

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Regenerative medicine therapy is inspired by current research advances in cellular biology, genetic engineering, synthetic biology, material sciences and so far contributes to the traditional therapy, making resistant diseases curable. Nowadays, chronic wound healing is possible due to cell-based regenerative technologies and recent non-cell therapeutic approaches. Here we review clinical applications of human stem cells, as well as cellular and tissue products as alternatives to the traditional therapy of non-healing wounds. The cell-based technologies for tissue regeneration and bioengineering utilize stem cells that are either injected into bloodstream or positioned directly into the target area. Cell-free regeneration technologies require either stem cell products, i.e., secretomes or their separate components, extracellular membrane vesicles, or tissue products. The stem cell therapies are designed to replace critically absent components of wounded or degenerative tissue. The stem cell secretome can promote the repair of damaged tissues independently of parent cells. Extracellular membrane vesicles mimic and recapitulate the mechanisms of stem cells in tissue regeneration and therefore might be promising for chronic wound and severe burns healing. The tissue products traditionally remain efficient wound healing remedies along with emerging advanced technologies. K e y w o r d s: wound healing, cell and cell-free technologies, stem cells, secretomes, extracellular membrane vesicles, tissue products

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“…Saliva may affect (prolong) the time needed for the bleeding to stop by diluting blood and thereby diluting procoagulant factors in blood. On the other hand, salivary influence on haemostasis could be more specific as it has been demonstrated that saliva contains cell‐derived vesicles exposing procoagulant tissue factor (TF) . Berckmans et al .…”

Section: Introductionmentioning

confidence: 99%

Influence of saliva on the results of global laboratory coagulation tests

Špiljak

Šimunović

Lapić

et al. 2020

Australian Dental Journal

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Background Oral wounds inevitably come into contact with saliva which can affect the time needed for bleeding to stop. The influence of saliva can be non‐specific, related to dilution of blood, and/or mediated by salivary factors that affect haemostasis directly. The aim of this study was to assess if mixing blood with an individual's saliva would affect the rate of its coagulation measured by global coagulation tests, prothrombin time (PT) and activated partial thromboplastin time (APTT). Methods The study included 30 healthy non‐smoking volunteers. Paired blood and unstimulated saliva samples were obtained from each participant and PT and APTT were determined in blood, blood + saliva and blood + water mixtures. Coagulation tests were performed using the mechanical clot detection method. Results PT was significantly longer in both blood + saliva and blood + water mixtures compared to blood alone. APTT was significantly longer only in blood + water mixture compared to blood. Conclusions Similarly prolonged PT in both mixtures suggests that both saliva and water prolong coagulation evenly due to their non‐specific effect of blood dilution. The finding that APTT was significantly prolonged only when blood was mixed with water could indicate presence of tissue factor in saliva, however, in a concentration too low to influence the results of PT.

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Extracellular vesicles from human saliva promote hemostasis by delivering coagulant tissue factor to activated platelets

Cited by 22 publications

References 42 publications

Exosomes derived from clinical‐grade oral mucosal epithelial cell sheets promote wound healing

Exosomes derived from clinical‐grade oral mucosal epithelial cell sheets promote wound healing

Regenerative therapy for the nonhealing cutaneous wounds

Influence of saliva on the results of global laboratory coagulation tests

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