Human mesenchymal stromal cells inhibit platelet activation and aggregation involving CD73-converted adenosine

Abstract

BackgroundMesenchymal stromal cells (MSCs) are promising cell therapy candidates. Clinical application is considered safe. However, minor side effects have included thromboembolism and instant blood-mediated inflammatory reactions suggesting an effect of MSC infusion on hemostasis. Previous studies focusing on plasmatic coagulation as a secondary hemostasis step detected both procoagulatory and anticoagulatory activities of MSCs. We now focus on primary hemostasis and analyzed whether MSCs can promote or inhibit platelet activation.MethodsEffects of MSCs and MSC supernatant on platelet activation and function were studied using flow cytometry and further platelet function analyses. MSCs from bone marrow (BM), lipoaspirate (LA) and cord blood (CB) were compared to human umbilical vein endothelial cells or HeLa tumor cells as inhibitory or activating cells, respectively.ResultsBM-MSCs and LA-MSCs inhibited activation and aggregation of stimulated platelets independent of the agonist used. This inhibitory effect was confirmed in diagnostic point-of-care platelet function analyses in platelet-rich plasma and whole blood. Using inhibitors of the CD39–CD73–adenosine axis, we showed that adenosine produced by CD73 ectonucleotidase activity was largely responsible for the LA-MSC and BM-MSC platelet inhibitory action. With CB-MSCs, batch-dependent responses were obvious, with some batches exerting inhibition and others lacking this effect.ConclusionsStudies focusing on plasmatic coagulation suggested both procoagulatory and anticoagulatory activities of MSCs. We now show that MSCs can, dependent on their tissue origin, inhibit platelet activation involving adenosine converted from adenosine monophosphate by CD73 ectonucleotidase activity. These data may have strong implications for safety and risk/benefit assessment regarding MSCs from different tissue sources and may help to explain the tissue protective mode of action of MSCs. The adenosinergic pathway emerges as a key mechanism by which MSCs exert hemostatic and immunomodulatory functions.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-0936-8) contains supplementary material, which is available to authorized users.

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“…However, minor side effects, including thromboembolism and immediate blood-mediated inflammatory response, do occur suggesting the effect of MSC infusion on hemostasis. 38 Adipose-derived mesenchymal stem cells seem to possess more stable pro-coagulant activity than bone marrow-derived MSCs, which raises potential safety concerns for its systemic administration into patients with clotting diseases. There are donor variants available among different cell populations, and the coagulation conditions can also be determined by the culture conditions used for treatment.…”

“…This study showed that BMSCs are dependent on their tissue of origin and inhibit platelet activation with the help of formation of adenosine from adenosine monophosphate due to the ecto-5ʹ-nucleotidase activity of CD73. 38 Hence, Na 2 SeO 3 may inhibit the coagulation mediated by BMSCs by affecting the differentiation of BMSCs. Consistent with previous studies, our study showed the inhibitory effect of Na 2 SeO 3 on the BMSC-mediated coagulation process.…”

Human Adipose Tissue-Derived Stromal Cells Suppress Human, but Not Murine Lymphocyte Proliferation, via Indoleamine 2,3-Dioxygenase Activity

“…The study was approved by the Mannheim Ethics Commission II (vote numbers 2015-520N-MA, 49/05 and 2006-192 N-MA, respectively). BM, CB and ASC were isolated and characterized as previously described [27]. Following isolation, ASC and BM were continuously cultured at a density of 200 cells/cm 2 and CB at 700 cells/cm 2 in DMEM (PAN Biotech; Aidenbach, Germany) supplemented with 10% pooled human allogeneic AB serum from healthy donors (German Red Cross Blood Donor Service Baden-Württemberg-Hessen, Mannheim, Germany), 1% penicillin/streptomycin (100,000 U/mL penicillin and 10 mg/mL streptomycin; PAN Biotech) and 2% L-glutamine (200 mM; PAN Biotech) (=DMEM-AB).…”

Thrombogenic Risk Induced by Intravascular Mesenchymal Stem Cell Therapy: Current Status and Future Perspectives

“…In contrast, recently, Netsch et al [67] published that MSCs from different origins (bone marrow, adipose and cord blood) express anticoagulant properties, affecting primary hemostasis. They showed that MSCS inhibit the agonist-induced activation and aggregation of platelets in platelet-rich plasma (PRP) and whole blood.…”