The research within our LUMC departments is conducted within departmental research programmes. The research programme below is embedded within the department of Chemical Cell Biology / Molecular Cell Biology.
- Research programme: Therapeutic cell differentiation
- Department: Chemical Cell Biology / Molecular Cell Biology
- Programme leader: Prof. Dr. R.C. Hoeben
- Principal investigators: Prof. Dr. M.J.T.H. Goumans, Dr. A. Zaldumbide, Dr. M.F.V. Goncalves, Dr. H.M.M. Mikkers, Dr. M.E. Ressing
- Biomedical research profile: Vascular and Regenerative Medicine
- Generic research profile(s): Ageing, Biomedical Imaging
This research program aims at understanding the molecular mechanisms that govern differentiation of normal and genetically-corrected stem cells. The mechanistic insights are used for developing new approaches for the treatment of acquired and inherited diseases. Embedded in the LUMC research profile “Vascular and regenerative medicine”, our research focuses on finding new stem-cell based treatment approaches for muscular, blood-borne, and cardiovascular disorders. The research has both technology-driven and application-driven aspects and we have state of the art technology for genetic modifications, e.g. TALENS, CRISPR/Cas9, viral vectors, iPS technology for disease modelling, for treatment, and for growth factor stimulation. In addition, we aim at developing new methods for moderating the innate and adaptive immune responses against diseased tissues and cellular grafts.
Aim and focus
Our toolbox has been used extensively within the LUMC and beyond for research purposes. We have intensify our efforts to seek employ of our tools in clinical projects, viz. to facilitate clinical translation of our viral technology, gene-editing technology, stem cells, exosomes, and TGFβ signalling in new treatment strategies. The disease targets include heart failure, pulmonary hypertension, type I diabetes, primary immune deficiencies, muscular dystrophy, and neurotrauma. For preclinical evaluation of our strategies we team up with clinically-oriented groups within the LUMC research profiles “Vascular and regenerative medicine”, “Aging”, “Cancer pathogenesis and prevention”, and “Immunity, infection and tolerance”.
Position in international context
We collaborate with international consortia such as IMGENE (H2020) and INNODIA (a private public partnership against type 1 diabetes), as well as with individual foreign groups such as MIT (Cambridge, MA, USA), and academic groups in Leeds, Cambridge and London (UK), Paris (France), Padua (Italy), Gothenburg (Sweden), Gottingen (Germany) and Singapore.
Content / highlights / achievementsSelected recent publications:
- Bao, X., Lian, X., Hacker, T.A., Schmuck, E.G., Qian, T., Bhute, V.J., Han, T., Shi, M., Drowley, L., Plowright, A., Wang, Q.D., Goumans, M.J., Palecek, S.P. 2016 Long-term self-renewing human epicardial cells generated from pluripotent stem cells under defined xeno-free conditions. Nat Biomed Eng 1:0003
- Chen, X., Janssen, J.M., Liu, J., Maggio, I., 't Jong, A., Mikkers, H.M., Goncalves, M.F.V. 2017. In trans paired nicking triggers seamless genome editing without double-stranded DNA cutting. Nat Commun, 8(1):657
- Dautzenberg, I.J., van den Wollenberg, D.J., van den Hengel, S.K., Limpens, R.W., Barcena, M., Koster, A.J., & Hoeben, R.C. 2014. Mammalian orthoreovirus T3D infects U-118 MG cell spheroids independent of junction adhesion molecule-A. Gene Ther, 21, (6) 609-617
- Gram,A.M., Oosenbrug,T., Lindenbergh,M.F., Bull,C., Comvalius,A., Dickson,K.J., Wiegant,J., Vrolijk,H., Lebbink,R.J., Wolterbeek,R., Adema,G.J., Griffioen,M., Heemskerk,M.H., Tscharke,D.C., Hutt-Fletcher,L.M., Wiertz,E.J., Hoeben,R.C., & Ressing,M.E. 2016. The Epstein-Barr virus glycoprotein gp150 forms an immune-evasive glycan shield at the surface of infected cells. PLoS Pathog 12, e1005550
- Holkers, M., Maggio, I., Liu, J., Janssen, J.M., Miselli, F., Mussolino, C., Recchia, A., Cathomen, T., & Goncalves, M.A. 2013. Differential integrity of TALE nuclease genes following adenoviral and lentiviral vector gene transfer into human cells. Nucleic Acids Res, 41, (5) e63
- Holkers, M., Maggio, I., Henriques, S.F., Janssen, J.M., Cathomen, T., & Goncalves, M.A. 2014. Adenoviral vector DNA for accurate genome editing with engineered nucleases. Nat Methods, 11, (10) 1051-1057
- Karkampouna, S., Kruithof, B.P., Kloen, P., Obdeijn, M.C., van der Laan, A.M., Tanke, H.J., Kemaladewi, D.U., Hoogaars, W.M., 't Hoen, P.A., Aartsma-Rus, A., Clark, I.M., ten, D.P., Goumans, M.J., & Kruithof-de, J.M. 2014. Novel Ex Vivo Culture Method for the Study of Dupuytren's Disease: Effects of TGFbeta Type 1 Receptor Modulation by Antisense Oligonucleotides. Mol Ther Nucleic Acids, 3, e142
- Kracht,M.J., van Lummel, M., Nikolic,T., Joosten,A.M., Laban,S., van der Slik,A.R., van Veelen,P.A., Carlotti,F., de Koning,E.J., Hoeben,R.C., Zaldumbide,A., & Roep,B.O. 2017 Autoimmunity against a defective ribosomal insulin gene product in type 1 diabetes. Nat Med 23, 501-507
- Mikkers, H., Freund, C., Mummery, C., & Hoeben, R.C. 2014. Cell-replacement therapies: is it time to reprogram? Hum Gene Ther 25,(10) 893-896
- Pelascini, L.P., Maggio, I., Liu, J., Holkers, M., Cathomen, T., & Goncalves, M.A. 2013. Histone deacetylase inhibition rescues gene knockout levels achieved with integrase-defective lentiviral vectors encoding zinc-finger nucleases. Hum Gene Ther Methods, 24, (6) 399-411
- Spijker,H.S., Ravelli,R.B., Mommaas-Kienhuis,A.M., van Apeldoorn,A.A., Engelse,M.A., Zaldumbide,A., Bonner-Weir,S., Rabelink,T.J., Hoeben,R.C., Clevers,H., Mummery,C.L., Carlotti,F., & de Koning,E.J. Conversion of mature human beta-cells into glucagon-producing alpha-cells. Diabetes 62, 2471-2480 (2013).
- Tijsen, A.J., van der Made, I., van den Hoogenhof, M.M., Wijnen, W.J., van Deel, E.D., de Groot, N.E., Alekseev, S., Fluiter, K., Schroen, B., Goumans, M.J., van der Velde, C., Duncker, D.J., Pinto, Y.M., & Creemers, E.E. 2014. The microRNA-15 family inhibits the TGFbeta-pathway in the heart. Cardiovasc Res 104, (1) 61-71
- van de Weijer, M.L., Bassik, M.C., Luteijn, R.D., Voorburg, C.M., Lohuis, M.A., Kremmer, E., Hoeben, R.C., LeProust, E.M., Chen, S., Hoelen, H., Ressing, M.E., Patena, W., Weissman, J.S., McManus, M.T., Wiertz, E.J., & Lebbink, R.J. 2014. A high-coverage shRNA screen identifies TMEM129 as an E3 ligase involved in ER-associated protein degradation. Nat Commun 5, 3832
- Moerkamp, A.T., Lodder, K., van Herwaarden, T., Dronkers, E., Dingenouts, C.K., Tengström, F.C., van Brakel, T.J., Goumans, M.J., & Smits, A.M. 2016. Human fetal and adult epicardial-derived cells: a novel model to study their activation. Stem Cell Res Ther 7 (1) 174.
- van den Wollenberg, D.J., Dautzenberg, I.J., Ros, W., Lipińska, A.D., van den Hengel, S.K., Hoeben, R.C. 2015 Replicating reoviruses with a transgene replacing the codons for the head domain of the viral spike. Gene Ther 22(3):267-79
- van der Bruggen, C.E., Happé, C.M., Dorfmüller, P., Trip, P., Spruijt, O.A., Rol, N., Hoevenaars, F.P., Houweling, A.C., Girerd B., Marcus, J.T., Mercier, O., Humbert, M., Handoko, M.L., van der Velden, J., Vonk Noordegraaf, A., Bogaard, H.J., Goumans, M.J., de Man, F.S. 2016. Bone Morphogenetic Protein Receptor Type 2 Mutation in Pulmonary Arterial Hypertension: A View on the Right Ventricle. Circulation 133(18):1747-60
- van der Veer, E.P., de Bruin, R.G., Kraaijeveld, A.O., de Vries, M.R., Bot, I., Pera, T., Segers, F.M., Trompet, S., van Gils, J.M., Roeten, M.K., Beckers, C.M., van Santbrink, P.J., Janssen, A., van Solingen, C., Swildens, J., de Boer, H.C., Peters, E.A., Bijkerk, R., Rousch, M., Doop, M., Kuiper, J., Schalij, M.J., van der Wal, A.C., Richard, S., van Berkel, T.J., Pickering, J.G., Hiemstra, P.S., Goumans, M.J., Rabelink, T.J., de Vries, A.A., Quax, P.H., Jukema, J.W., Biessen, E.A., & van Zonneveld, A.J. 2013. Quaking, an RNA-binding protein, is a critical regulator of vascular smooth muscle cell phenotype. Circ Res, 113, (9) 1065-1075
- Zaldumbide, A., Alkemade, G., Carlotti, F., Nikolic, T., Abreu, J.R., Engelse, M.A., Skowera, A., de Koning, E.J., Peakman, M., Roep, B.O., Hoeben, R.C., & Wiertz, E.J. 2013. Genetically engineered human islets protected from CD8-mediated autoimmune destruction in vivo. Mol Ther, 21, (8) 1592-1601
- Zhou, F., Drabsch, Y., Dekker, T.J., de Vinuesa, A.G., Li, Y., Hawinkels, L.J., Sheppard, K.A., Goumans, M.J., Luwor, R.B., de Vries, C.J., Mesker, W.E., Tollenaar, R.A., Devilee, P., Lu, C.X., Zhu, H., Zhang, L., & Ten Dijke, P. 2014. Nuclear receptor NR4A1 promotes breast cancer invasion and metastasis by activating TGF-beta signalling. Nat Commun 5, 3388
- Moerkamp, A.T, Leung, H.W., Bax, N.A.M., Holst, S., Lodder, K., Berends, T., Dingenouts, C.K.E., Choo, A., Smits, A.M. & Goumans, M.J. 2017. Glycosylated Cell Surface Markers for the Isolation of Human Cardiac Progenitors. Stem Cells Dev. 26, (21) 1552-1565
Several new themes focussed on translational research were initiated in the recent years. These include a translational program on gene editing in hemoglobinopathies, such as β-thalassemia and sickle-cell disease. This program is a collaboration of 5 departments within the LUMC (Paediatrics, Molecular Cell Biology, Human Genetics, Clinical Genetics, and Immunohematology and Blood Transfusion). This program was granted a PhD student by the Vascular and Regenerative Medicine Research Theme.
Also we initiated a translational program on oncolytic virus therapies in cancer that should bring one of our oncolytic reovirus variants to clinical evaluation. This research is performed within the OVIT consortium, an association of 12 departments in LUMC and EMC, Rotterdam, with further participation of groups at the Utrecht University and Sanquin in Amsterdam. Our work in OVIT is supported in part by the Technical Science Foundation STW and the foundation ’Support Casper’.
To stimulate cardiac repair, we are initiating a translational program to bring exosomes isolated from cardiac progenitor cells to a phase I clinical trial. In close collaboration with the departments of Immunohematology and Blood transfusion, cardiology and the NWO program Translation of adult stem cells (TAS) we are preparing an investigational medicinal product dossier (IMPD) and define release criteria. Our work is in collaboration with UMCU and supported by NWO and the Life Science and Health (LSH) foundation. Furthermore, in collaboration with VUmc as part of the CVON-PHAEDRA, we search for compounds that can restore TGFβ/BMP signalling in Pulmonary Arterial Hypertension (PAH). We identified two potential candidates and are initiating a clinical trial to test one of them.
Cohesion within LUMC
Our research is focussed on developing technology for personalized therapeutics. For preclinical evaluation of our strategies we team up with a variety clinically-oriented groups within the LUMC research profiles “Vascular and Regenerative Medicine”, “Ageing”, “Cancer Pathogenesis and Prevention”, and “Immunity, Infection and Tolerance”. Our collaborative projects focus on immune deficiencies (Mikkers, Hoeben, with Staal), hemoglobinopathies (Hoeben, Goncalves, outlined above), diabetes research (Zaldumbide and Hoeben, with IHB and Nephrology) bridging our activities with the Infection, Immunity and Tolerance profile. Also new projects on innate sensors (Ressing, Hoeben) with Chemical Immunology (Neefjes) were initiated and two PhD students were recruited to visualize and study these processes and further link our activities with the Infection, Immunity and Tolerance and the Biomedical Imaging profiles. In the oncolytic virus research, we collaborate with the dept. of Medical Oncology (Van de Burg, Van Hall), Urology (Van der Pluijm) and Hawinkels (Gastroenterology), linking our activities to the Cancer Pathogenesis and Therapy profile. For (pre)clinical validation of our research on cardiac regeneration (Goumans, Smits) and TGFβ signalling in cardiovascular disease (Goumans with ten Dijke) we collaborate with the Depts of Cardiology (Atsma), Thoracic Surgery (Klautz) IHB (Zwaginga), Surgery (Quax) and Anatomy and Embryology (Ruiter, Passier, Mummery).
Moreover, our group operates the LUMC Viral-Vector Facility, which provides research-grade lentiviruses, reoviruses, and adenoviruses to many research groups within Leiden University Medical Center and Leiden University. Annually, the facility produces over 400 research-grade batches of lentivirus vectors, hands out ca 1000 vector plasmids, and titres ca. 600 vector samples. Together with Prof Mummery’s (Anatomy and Embryology) we run the LUMC iPS Core Facility, which establishes and provided iPS clones to LUMC research groups, and capacity permitting, external users. The activities of the iPS Core Facility facilities will be expanded with the initiation of the iPS-Hotel.
Taken together, our program is strongly embedded in the Vascular and Regenerative Medicine profile with active interactions with the Biomolecular imaging, the Infection Immunity and Tolerance, and the Cancer Pathogenesis and Therapy profiles.