Research Scientist – NHSBT Programme Leader
Novel regulators of blood formation
Description of research
Dr Marloes Tijssen’s research group is based at the Cambridge Blood Centre, NHS Blood and Transplant (NHSBT). Her programme of research aims to identify and characterise novel regulators of blood formation with a particular interest in platelets and their parent cell, the megakaryocyte.
Understanding platelet formation
Platelets are the first cells to arrive at a site of injury. They stick to the damaged blood vessel wall and release proteins that help form a network of fibres to form a clot. Platelets also deliver signals to the damaged tissue to start the healing process. People with a reduction in functional blood platelets are at risk of severe bleeding.
With the demand for platelet transfusions to treat patients with a low platelet count growing yearly, there is an urgent need to produce platelets for transfusion in the laboratory. Current culture protocols do not generate sufficient functional platelets. A better understanding of platelet formation by megakaryocytes is required before in vitro produced platelets for transfusion can become reality.
However, the same platelets can also do harm if they are too large, too active or there are too many of them. A clot may be formed in arteries of the heart or the arteries bringing blood to our brain leading to a heart attack or stroke, respectively. An increased understanding of platelet formation may improve treatment of people at risk of developing a heart attack or stroke.
Dr Marloes Tijssen’s previous work characterised the genome-wide binding of 5 transcription factors, GATA1/2, RUNX1, FLI1 and SCL in primary human megakaryocytes (see the publication). Statistical analysis of the 17,263 regions bound by at least one factor demonstrated that simultaneous binding by all five factors was the most enriched pattern and often occurred near known haematopoietic regulators. She hypothesised that some of the highly regulated genes that were not previously described to play a role in haematopoiesis could be novel regulators of platelet formation. Recently, her group demonstrated that one of these genes, tropomyosin 4, dose-dependently regulates platelet formation and that variations in the gene can lead to a mild bleeding disorder (see the publication). Current research aims to define what the role of tropomyosin 4 is in the cytoskeletal changes necessary for platelet formation.
Producing platelets and red blood cells for transfusion
Human pluripotent stem cells (PSCs) can be maintained and expanded in vitro for prolonged periods and can be induced to differentiate towards virtually any cell type. Therefore, they offer huge opportunities for basic research and clinical applications. Platelets and red cells are enucleated and therefore can be irradiated prior to administration to patients. This opens the possibility of generating banks of genetically-modified PSCs from which advanced cellular therapies can be generated.
Dr Cedric Ghevaert’s group has in collaboration with Dr Marloes Tijssen developed a forward programming approach using three transcription factors for the efficient generation of mature megakaryocytes from PSCs (see the publication). Dr Marloes Tijssen uses this method to further unravel the differentiation of megakaryocytes with the aim to identify ways to improve in vitro platelet production.
The production of red cells from human PSCs is hampered by the fact that the cells produced have an embryonic phenotype, in particular expression of embryonic and foetal globins rather than adult globins and poor enucleation rate. We are part of the Novosang consortium, funded through a strategic initiative from the Wellcome Trust. Its aim is to produce red cells from PSCs for transfusion into humans and to carry out a first-in-man study with cells produced in the laboratory. Dr Marloes Tijssen and Dr Cedric Ghevaert’s teams collaborate in an effort to use the forward programming of PSCs to enforce an adult phenotype onto PSC-derived red cells.
Pleines I, Woods J, Chappaz S, Kew V, Foad N, Ballester-Beltrán J, Aurbach K, Lincetto C, Lane RM, Schevzov G, Alexander WS, Hilton DJ, Astle WJ, Downes K, Nurden P, Westbury SK, Mumford AD, Obaji SG, Collins PW, Delerue F, Ittner LM, Bryce NS, Holliday M, Lucas CA, Hardeman EC, Ouwehand WH, Gunning PW, Turro E, Tijssen MR, Kile BT. Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia. J Clin Invest. 2017 Jan 30. pii: 86154. doi: 10.1172/JCI86154.
Wijgaerts A, Wittevrongel C, Thys C, Devos T, Peerlinck K, Tijssen MR, Van Geet C, Freson K. The transcription factor GATA1 regulates NBEAL2 expression through a long-distance enhancer. Haematologica. 2017 Jan 12. pii: haematol.2016.152777. doi: 10.3324/haematol.2016.152777.
Kollmann K, Warsch W, Gonzalez-Arias C, Nice FL, Avezov E, Milburn J, Li J, Dimitropoulou D, Biddie S, Wang M, Poynton E, Colzani M, Tijssen MR, Anand S, McDermott U, Huntly B, Green T. A novel signalling screen demonstrates that CALR mutations activate essential MAPK signalling and facilitate megakaryocyte differentiation. Leukemia. 2016 Dec 2. doi: 10.1038/leu.2016.280.
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. Large-scale production of megakaryocytes from human pluripotent stem cells by chemically defined forward programming. Nat Commun. 2016 Apr 7;7:11208. doi: 10.1038/ncomms11208.
Shaham L, Vendramini E, Ge Y, Goren Y, Birger Y, Tijssen MR, McNulty M, Geron I, Schwartzman O, Goldberg L, Chou ST, Pitman H, Weiss MJ, Michaeli S, Sredni B, Göttgens B, Crispino JD, Taub JW, Izraeli S. MicroRNA-486-5p is an erythroid oncomiR of the myeloid leukemias of Down syndrome. Blood. 2015 Feb 19;125(8):1292-301. doi: 10.1182/blood-2014-06-581892. Epub 2014 Dec 22.
Wilkinson AC, Kawata VK, Schütte J, Gao X, Antoniou S, Baumann C, Woodhouse S, Hannah R, Tanaka Y, Swiers G, Moignard V, Fisher J, Hidetoshi S, Tijssen MR, de Bruijn MF, Liu P, Göttgens B. Single-cell analyses of regulatory network perturbations using enhancer-targeting TALEs suggest novel roles for PU.1 during haematopoietic specification. Development. 2014 Oct;141(20):4018-30. doi: 10.1242/dev.115709. Epub 2014 Sep 24.
Wilkinson AC, Goode DK, Cheng YH, Dickel DE, Foster S, Sendall T, Tijssen MR, Sanchez MJ, Pennacchio LA, Kirkpatrick AM, Göttgens B. Single site-specific integration targeting coupled with embryonic stem cell differentiation provides a high-throughput alternative to in vivo enhancer analyses. Biol Open. 2013 Oct 7;2(11):1229-38. doi: 10.1242/bio.20136296. eCollection 2013.
Goldberg L, Tijssen MR, Birger Y, Hannah RL, Kinston SJ, Schütte J, Beck D, Knezevic K, Schiby G, Jacob-Hirsch J, Biran A, Kloog Y, Marcucci G, Bloomfield CD, Aplan PD, Pimanda JE, Göttgens B, Izraeli S. Genome-scale expression and transcription factor binding profiles reveal therapeutic targets in transgenic ERG myeloid leukemia. Blood. 2013 Oct 10;122(15):2694-703. doi: 10.1182/blood-2013-01-477133. Epub 2013 Aug 23.
Tijssen MR, Ghevaert C. Transcription factors in late megakaryopoiesis and related platelet disorders. J Thromb Haemost. 2013 Apr;11(4):593-604. doi: 10.1111/jth.12131.
Macaulay IC, Thon JN, Tijssen MR, Steele BM, MacDonald BT, Meade G, Burns P, Rendon A, Salunkhe V, Murphy RP, Bennett C, Watkins NA, He X, Fitzgerald DJ, Italiano JE Jr, Maguire PB. Canonical Wnt signaling in megakaryocytes regulates proplatelet formation. Blood. 2013 Jan 3;121(1):188-96. doi: 10.1182/blood-2012-03-416875. Epub 2012 Nov 16.
Nürnberg ST, Rendon A, Smethurst PA, Paul DS, Voss K, Thon JN, Lloyd-Jones H, Sambrook JG, Tijssen MR; HaemGen Consortium, Italiano JE Jr, Deloukas P, Gottgens B, Soranzo N, Ouwehand WH. A GWAS sequence variant for platelet volume marks an alternative DNM3 promoter in megakaryocytes near a MEIS1 binding site. Blood. 2012 Dec 6;120(24):4859-68. doi: 10.1182/blood-2012-01-401893. Epub 2012 Sep 12.
Wilson NK, Tijssen MR, Göttgens B. Deciphering transcriptional control mechanisms in hematopoiesis:the impact of high-throughput sequencing technologies. Exp Hematol. 2011 Oct;39(10):961-8. doi: 10.1016/j.exphem.2011.07.005. Epub 2011 Jul 23.
Paul DS, Nisbet JP, Yang TP, Meacham S, Rendon A, Hautaviita K, Tallila J, White J, Tijssen MR, Sivapalaratnam S, Basart H, Trip MD; Cardiogenics Consortium; MuTHER Consortium, Göttgens B, Soranzo N, Ouwehand WH, Deloukas P. Maps of open chromatin guide the functional follow-up of genome-wide association signals: application to hematological traits. PLoS Genet. 2011 Jun;7(6):e1002139. doi: 10.1371/journal.pgen.1002139. Epub 2011 Jun 30.
Tijssen MR, Cvejic A, Joshi A, Hannah RL, Ferreira R, Forrai A, Bellissimo DC, Oram SH, Smethurst PA, Wilson NK, Wang X, Ottersbach K, Stemple DL, Green AR, Ouwehand WH, Göttgens B. Genome-wide analysis of simultaneous GATA1/2, RUNX1, FLI1, and SCL binding in megakaryocytes identifies hematopoietic regulators. Dev Cell. 2011 May 17;20(5):597-609. doi: 10.1016/j.devcel.2011.04.008.
Steevels TA, Westerlaken GH, Tijssen MR, Coffer PJ, Lenting PJ, Akkerman JW, Meyaard L. Co-expression of the collagen receptors leukocyte-associated immunoglobulin-like receptor-1 and glycoprotein VI on a subset of megakaryoblasts. Haematologica. 2010 Dec;95(12):2005-12. doi: 10.3324/haematol.2010.026120. Epub 2010 Aug 16.
Watkins NA, Gusnanto A, de Bono B, De S, Miranda-Saavedra D, Hardie DL, Angenent WG, Attwood AP, Ellis PD, Erber W, Foad NS, Garner SF, Isacke CM, Jolley J, Koch K, Macaulay IC, Morley SL, Rendon A, Rice KM, Taylor N, Thijssen-Timmer DC, Tijssen MR, van der Schoot CE, Wernisch L, Winzer T, Dudbridge F, Buckley CD, Langford CF, Teichmann S, Göttgens B, Ouwehand WH; Bloodomics Consortium. A HaemAtlas: characterizing gene expression in differentiated human blood cells. Blood. 2009 May 7;113(19):e1-9. doi: 10.1182/blood-2008-06-162958. Epub 2009 Feb 19.
Reems JA, Wang W, Tsubata K, Abdurrahman N, Sundell B, Tijssen MR, van der Schoot E, Di Summa F, Patel-Hett S, Italiano J Jr, Gilligan DM. Dynamin 3 participates in the growth and development of megakaryocytes. Exp Hematol. 2008 Dec;36(12):1714-27. doi: 10.1016/j.exphem.2008.08.010.
Tijssen MR, di Summa F, van den Oudenrijn S, Zwaginga JJ, van der Schoot CE, Voermans C, de Haas M. Functional analysis of single amino-acid mutations in the thrombopoietin-receptor Mpl underlying congenital amegakaryocytic thrombocytopenia. Br J Haematol. 2008 Jun;141(6):808-13. doi: 10.1111/j.1365-2141.2008.07139.x. Epub 2008 Apr 13.
Tijssen MR, Woelders H, de Vries-van Rossen A, van der Schoot CE, Voermans C, Lagerberg JW. Improved postthaw viability and in vitro functionality of peripheral blood hematopoietic progenitor cells after cryopreservation with a theoretically optimized freezing curve. Transfusion. 2008 May;48(5):893-901. doi: 10.1111/j.1537-2995.2008.01650.x. Epub 2008 Feb 21.
Tijssen MR, van Hennik PB, di Summa F, Zwaginga JJ, van der Schoot CE, Voermans C. Transplantation of human peripheral blood CD34-positive cells in combination with ex vivo generated megakaryocytes results in fast platelet formation in NOD/SCID mice. Leukemia. 2008 Jan;22(1):203-8. Epub 2007 Oct 18.
Gusnanto A, Tom B, Burns P, Macaulay I, Thijssen-Timmer DC, Tijssen MR, Langford C, Watkins N, Ouwehand W, Berzuini C, Dudbridge F. Improving the power to detect differentially expressed genes in comparative microarray experiments by including information from self-self hybridizations. Comput Biol Chem. 2007 Jun;31(3):178-85. Epub 2007 Mar 24.
Macaulay IC, Tijssen MR, Thijssen-Timmer DC, Gusnanto A, Steward M, Burns P, Langford CF, Ellis PD, Dudbridge F, Zwaginga JJ, Watkins NA, van der Schoot CE, Ouwehand WH. Comparative gene expression profiling of in vitro differentiated megakaryocytes and erythroblasts identifies novel activatory and inhibitory platelet membrane proteins. Blood. 2007 Apr 15;109(8):3260-9. Epub 2006 Dec 27.
Tijssen MR, van der Schoot CE, Voermans C, Zwaginga JJ. Clinical approaches involving thrombopoietin to shorten the period of thrombocytopenia after high-dose chemotherapy. Transfus Med Rev. 2006 Oct;20(4):283-93.
Bruin M, Tijssen MR, Bierings M, de Haas M. Juvenile cyclic amegakaryocytic thrombocytopenia: a novel entity. J Pediatr Hematol Oncol. 2005 Mar;27(3):148-52.
Gonçalves MA, van Nierop GP, Tijssen MR, Lefesvre P, Knaän-Shanzer S, van der Velde I, van Bekkum DW, Valerio D, de Vries AA. Transfer of the full-length dystrophin-coding sequence into muscle cells by a dual high-capacity hybrid viral vector with site-specific integration ability. J Virol. 2005 Mar;79(5):3146-62.
Hornberg JJ, Tijssen MR, Lankelma J. Synergistic activation of signalling to extracellular signal-regulated kinases 1 and 2 by epidermal growth factor and 4 beta-phorbol 12-myristate 13-acetate. Eur J Biochem. 2004 Oct;271(19):3905-13.
Tijssen MR, van der Schoot CE, Voermans C, Zwaginga JJ. The (patho)physiology of megakaryocytopoiesis: from thrombopoietin in diagnostics and therapy to ex vivo generated cellular products. Vox Sang. 2004 Jul;87 Suppl 2:52-5.