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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

megakaryocyte ; iPSC ; platelets ; stem cells

Topics

  • platelet disorders
  • in vitro production of platelets

Collaborators outside this directory

Key Publications

Please follow the link to PubMed for a full list of publications.

Mutant calreticulin knock-in mice develop thrombocytosis and myelofibrosis without a stem cell self-renewal advantage. Li J, Prins D, Park HJ, Grinfeld J, Gonzalez-Arias C, Loughran S, Dovey OM, Klampfl T, Bennett C, Hamilton TL, Pask DC, Sneade R, Williams M, Aungier J, Ghevaert C, Vassiliou GS, Kent DG, Green AR. Blood. 2017 Dec 27.

A high-throughput sequencing test for diagnosing inherited bleeding, thrombotic, and platelet disorders. Simeoni I, Stephens JC, Hu F, Deevi SV, Megy K, Bariana TK, Lentaigne C, Schulman S, Sivapalaratnam S, Vries MJ, Westbury SK, Greene D, Papadia S, Alessi MC, Attwood AP, Ballmaier M, Baynam G, Bermejo E, Bertoli M, Bray PF, Bury L, Cattaneo M, Collins P, Daugherty LC, Favier R, French DL, Furie B, Gattens M, Germeshausen M, Ghevaert C, Goodeve AC, Guerrero JA, Hampshire DJ, Hart DP, Heemskerk JW, Henskens YM, Hill M, Hogg N, Jolley JD, Kahr WH, Kelly AM, Kerr R, Kostadima M, Kunishima S, Lambert MP, Liesner R, López JA, Mapeta RP, Mathias M, Millar CM, Nathwani A, Neerman-Arbez M, Nurden AT, Nurden P, Othman M, Peerlinck K, Perry DJ, Poudel P, Reitsma P, Rondina MT, Smethurst PA, Stevenson W, Szkotak A, Tuna S, van Geet C, Whitehorn D, Wilcox DA, Zhang B, Revel-Vilk S, Gresele P, Bellissimo DB, Penkett CJ, Laffan MA, Mumford AD, Rendon A, Gomez K, Freson K, Ouwehand WH, Turro E. Blood. 2016 Jun 9;127(23):2791-803.

Large-scale production of megakaryocytes from human pluripotent stem cells by chemically defined forward programming. Moreau T, Evans AL, Vasquez L, Tijssen MR, Yan Y, Trotter MW, Howard D, Colzani M, Arumugam M, Wu WH, Dalby A, Lampela R, Bouet G, Hobbs CM, Pask DC, Payne H, Ponomaryov T, Brill A, Soranzo N, Ouwehand WH, Pedersen RA, Ghevaert C. Nat Commun. 2016 Apr 7;7:11208.

Brain-derived Neurotrophic Factor in Megakaryocytes. Chacón-Fernández P, Säuberli K, Colzani M, Moreau T, Ghevaert C, Barde YA. J Biol Chem. 2016 May 6;291(19):9872-81.

Circular RNA enrichment in platelets is a signature of transcriptome degradation. Alhasan AA, Izuogu OG, Al-Balool HH, Steyn JS, Evans A, Colzani M, Ghevaert C, Mountford JC, Marenah L, Elliott DJ, Santibanez-Koref M, Jackson MS. Blood. 2016 Mar 3;127(9):e1-e11.

Platelet-Associated Matrix Metalloproteinases Regulate Thrombus Formation and Exert Local Collagenolytic Activity. Mastenbroek TG, Feijge MA, Kremers RM, van den Bosch MT, Swieringa F, De Groef L, Moons L, Bennett C, Ghevaert C, Johnson JL, van der Meijden PE, Cosemans JM. Arterioscler Thromb Vasc Biol. 2015 Dec;35(12):2554-61.

Suppression of in vitro megakaryopoiesis by maternal sera containing anti-HPA-1a antibodies. Liu ZJ, Bussel JB, Lakkaraja M, Ferrer-Marin F, Ghevaert C, Feldman HA, McFarland JG, Chavda C, Sola-Visner M. Blood. 2015 Sep 3;126(10):1234-6.

Characterization of a human platelet antigen-1a-specific monoclonal antibody derived from a B cell from a woman alloimmunized in pregnancy. Eksteen M, Tiller H, Averina M, Heide G, Kjaer M, Ghevaert C, Michaelsen TE, Ihle Ø, Husebekk A, Skogen B, Stuge TB. J Immunol. 2015 Jun 15;194(12):5751-60.

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.

Low-affinity FcγR interactions can decide the fate of novel human IgG-sensitised red blood cells and platelets. Armour KL, Smith CS, Turner CP, Kirton CM, Wilkes AM, Hadley AG, Ghevaert C, Williamson LM, Clark MR. Eur J Immunol. 2014 Mar;44(3):905-14.

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.

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