Human platelets produced in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice upon transplantation of human cord blood CD34(+) cells are functionally active in an ex vivo flow model of thrombosis.
Xenotransplantation systems have been used with increasing success to better understand human hematopoiesis and thrombopoiesis. In this study, we demonstrate that production of human platelets in nonobese diabetic/severe combined immunodeficient mice after transplantation of unexpanded cord-blood CD34(+) cells was detected within 10 days after transplantation, with the number of circulating human platelets peaking at 2 weeks (up to 87 x 10(3)/microL). This rapid human platelet production was followed by a second wave of platelet formation 5 weeks after transplantation, with a population of 5% still detected after 8 weeks, attesting for long-term engraftment. Platelets issued from human hematopoietic stem cell progenitors are functional, as assessed by increased CD62P expression and PAC1 binding in response to collagen-related peptide and thrombin receptor-activating peptide activation and their ability to incorporate into thrombi formed on a collagen-coated surface in an ex vivo flow model of thrombosis. This interaction was abrogated by addition of inhibitory monoclonal antibodies against human glycoprotein Ibalpha (GPIbalpha) and GPIIb/IIIa. Thus, our mouse model with production of human platelets may be further explored to study the function of genetically modified platelets, but also to investigate the effect of stimulators or inhibitors of human thrombopoiesis in vivo.
Salles
Isabelle I
II
Laboratory for Thrombosis Research, Interdisciplinary Research Centre, KU Leuven Campus Kortrijk, E Sabbelaan 53, B-8500 Kortrijk, Belgium. isabelle.salles@kuleuven-kortrijk.be
Thijs
Tim
T
Brunaud
Christine
C
De Meyer
Simon F
SF
Thys
Johan
J
Vanhoorelbeke
Karen
K
Deckmyn
Hans
H
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001792:Blood Platelets / Q000166:cytology / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D036101:Cord Blood Stem Cell Transplantation / Q000379:methods*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D034061:Thrombopoiesis / Q000502:physiology*; D013927:Thrombosis / Q000503:physiopathology
D018952:Antigens, CD34