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Dr Cedric Ghevaert

Research Interests

Platelet production from pluripotent stem cells for disease modeling and cellular therapy

Platelets are particles that circulate in the blood and participate in blood clotting in case of injury. However, platelets can also form clots in furred up arteries e.g. in the heart or the brain, leading to heart attack or stroke respectively. Understanding how platelets work, what influences their reactivity and how we can lower their clotting abilities is of great relevance in the treatment and prevention of heart attacks and strokes.

My research group has developed technologies to grow megakaryocytes (the platelet mother cells which usually lives in the bone marrow) in the laboratory from stem cells derived from either normal donors or patients with platelet disorders. This allows us to study in detail how platelets differ in health and disease and how their ability to clot and block blood vessels varies between donors and patients.

This technology also allows us to produce platelets in the laboratory for transfusion in humans. Platelets contain storage granules which they release upon activation. We can modify these platelets so that they can become delivery vehicles, their granules loaded with either clotting factors (to stop haemorrhages after heart surgery) or growth factors (to promote healing after a heart attack).

Keywords

iPSC ; platelets ; megakaryocyte ; iPS (induced pluripotent stem cells) ; stem cells

Topics

  • platelet disorders
  • in vitro production of platelets

Collaborators outside this directory

Key Publications

Gray platelet syndrome: proinflammatory megakaryocytes and α-granule loss cause myelofibrosis and confer metastasis resistance in mice. Guerrero JA, Bennett C, van der Weyden L, McKinney H, Chin M, Nurden P, McIntyre Z, Cambridge EL, Estabel J, Wardle-Jones H, Speak AO, Erber WN, Rendon A, Ouwehand WH, Ghevaert C. Blood. 2014 Dec 4;124(24):3624-35.

JAK2V617F homozygosity drives a phenotypic switch in myeloproliferative neoplasms, but is insufficient to sustain disease. Li J, Kent DG, Godfrey AL, Manning H, Nangalia J, Aziz A, Chen E, Saeb-Parsy K, Fink J, Sneade R, Hamilton TL, Pask DC, Silber Y, Zhao X, Ghevaert C, Liu P, Green AR. Blood. 2014 May 15;123(20):3139-51.

JAK2V617F leads to intrinsic changes in platelet formation and reactivity in a knock-in mouse model of essential thrombocythemia. Hobbs CM, Manning H, Bennett C, Vasquez L, Severin S, Brain L, Mazharian A, Guerrero JA, Li J, Soranzo N, Green AR, Watson SP, Ghevaert C. Blood. 2013 Nov 28;122(23):3787-97.

Recombinant HPA-1a antibody therapy for treatment of fetomaternal alloimmune thrombocytopenia: proof of principle in human volunteers. Ghevaert C, Herbert N, Hawkins L, Grehan N, Cookson P, Garner SF, Crisp-Hihn A, Lloyd-Evans P, Evans A, Balan K, Ouwehand WH, Armour KL, Clark MR, Williamson LM. Blood. 2013 Jul 18;122(3):313-20.

Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome. Albers CA, Paul DS, Schulze H, Freson K, Stephens JC, Smethurst PA, Jolley JD, Cvejic A, Kostadima M, Bertone P, Breuning MH, Debili N, Deloukas P, Favier R, Fiedler J, Hobbs CM, Huang N, Hurles ME, Kiddle G, Krapels I, Nurden P, Ruivenkamp CA, Sambrook JG, Smith K, Stemple DL, Strauss G, Thys C, van Geet C, Newbury-Ecob R, Ouwehand WH, Ghevaert C. Nat Genet. 2012 Feb 26;44(4):435-9, S1-2.

Dasatinib enhances megakaryocyte differentiation but inhibits platelet formation. Mazharian A, Ghevaert C, Zhang L, Massberg S, Watson SP. Blood. 2011 May 12;117(19):5198-206.

JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F-positive essential thrombocythemia. Li J, Spensberger D, Ahn JS, Anand S, Beer PA, Ghevaert C, Chen E, Forrai A, Scott LM, Ferreira R, Campbell PJ, Watson SP, Liu P, Erber WN, Huntly BJ, Ottersbach K, Green AR. Blood. 2010 Sep 2;116(9):1528-38.

Developing recombinant HPA-1a-specific antibodies with abrogated Fcgamma receptor binding for the treatment of fetomaternal alloimmune thrombocytopenia. Ghevaert C, Wilcox DA, Fang J, Armour KL, Clark MR, Ouwehand WH, Williamson LM. J Clin Invest. 2008 Aug;118(8):2929-38.

Immunologic and structural analysis of eight novel domain-deletion beta3 integrin peptides designed for detection of HPA-1 antibodies. Stafford P, Ghevaert C, Campbell K, Proulx C, Smith G, Williamson LM, Ranasinghe E, Watkins NA, Huntington JA, Ouwehand WH. J Thromb Haemost. 2008 Feb;6(2):366-75.

A nonsynonymous SNP in the ITGB3 gene disrupts the conserved membrane-proximal cytoplasmic salt bridge in the alphaIIbbeta3 integrin and cosegregates dominantly with abnormal proplatelet formation and macrothrombocytopenia. Ghevaert C, Salsmann A, Watkins NA, Schaffner-Reckinger E, Rankin A, Garner SF, Stephens J, Smith GA, Debili N, Vainchenker W, de Groot PG, Huntington JA, Laffan M, Kieffer N, Ouwehand WH. Blood. 2008 Apr 1;111(7):3407-14.

More publications available through PubMed.

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