Stem cell biology
Gerald de Haan has focused his entire scientific career on the identification of molecular mechanisms that control selfrenewal of hematopoietic stem cells. His early scientific contributions include papers in which the aging hematopoietic stem cell phenotype was described for the first time. He was the first to use the power of complex mouse genetics to identify genetic loci that regulate lifespan in mice and discover that these same loci were also controlling stem cell turnover rates. His lab was the first to use expression quantitative traits to search for loci that regulate stem cell-specific transcriptomes.
His lab was also one of the first to clonally study the behavior of single young and aged stem cells. His lab has used multiple genome-wide approaches to search for HSCs regulatory genes. This resulted in the identification of the Polycomb group proteins Ezh2 and microRNA125a, and led to functional studies in which these genes were shown to crucially regulate HSC selfrenewal and their leukemic derailment. The identification of the polycomb group gene Ezh2 spurred further efforts in establishing the role of the epigenetic machinery for HSC functioning, and identified Cbx7 as a key stem cell gene. These studies showed the importance of epigenetic modifications in hematopoietic stem cell selfrenewal. Only recently it has become apparent that a significant number of mutations in (elderly) patients with myelodysplastic syndromes and leukemia occur in epigenetic genes, and appear to confer a proliferative advantage to stem cells. His lab also developed technology to assess the fate of single (young and aged) HSCs, using either single cell transplants, or barcoding single HSCs and reading out clonal behavior using next generation sequencing approaches. His most recent studies have identified multiple novel HSC cell surface receptors that are specifically or preferentially expressed by aged HSCs, and current efforts in his lab aim to resolve the biological relevance of these novel HSC aging genes.
Research lines
1. Identification of molecular mechanisms that cause hematopoietic stem cell dysfunction.
2. The role of epigenetic modifiers in normal and leukemic stem cell selfrenewal.
3. In vitro derivation and expansion of hematopoietic stem cells
Key publications
Walasek MA, van Os R, de Haan G Hematopoietic stem cell expansion: challenges and opportunities. Ann N Y Acad Sci. (2012) Aug;1266:138-50.
Karin Klauke, Visnja Radulovic, Mathilde J.C. Broekhuis, Ellen Weersing, Erik Zwart, Sandra Olthof, Martha Ritsema, Sophia Bruggeman, Xudong Wu*, Kristian Helin*, Leonid Bystrykh, and Gerald de Haan (2013). Polycomb Cbx orthologs mediate the balance between Hematopoietic Stem Cell self-renewal and differentiation. Nat Cell Biol. 2013 Apr;15(4):353-62.
Verovskaya E, Broekhuis MJ, Zwart E, Ritsema M, van Os R, de Haan G, Bystrykh LV (2013). Heterogeneity of young and aged murine hematopoietic stem cells revealed by quantitative clonal analysis using cellular barcoding. Blood 122 (4): 523-32.
Evgenia Verovskaya, Mathilde J.C. Broekhuis, Erik Zwart, Ellen Weersing, Martha Ritsema, Lisette Bosman, Theo van Poele, Gerald de Haan#, Leonid V. Bystrykh# (2014). Asymmetry in skeletal distribution of murine hematopoietic stem cell clones and their equilibration by mobilizing cytokines. J. Exp.Med, 2014 Mar 10;211(3):487-97.
Edyta E. Wojtowicz, Eric R. Lechman, Karin G. Hermans, Erwin M. Schoof, Erno Wienholds, Ruth Isserlin, Peter A. van Veelen, Mathilde J.C. Broekhuis, George. M.C. Janssen, Aaron Trotman-Grant, Stephanie M. Dobson2, Gabriella Krivdova, Jantje Elzinga, James Kennedy, Olga Gan, Ankit Sinha, Vladimir Ignatchenko, Thomas Kislinger, Ellen Weersing, Mir Farshid Alemdehy, Hans W.J. de Looper, Bader, GD, Martha Ritsema, Stefan J. Erkeland, Leonid V. Bystrykh, John E. Dick and Gerald de Haan. Ectopic miR-125a Expression Induces Long-Term Repopulating Stem Cell Capacity in Mouse and Human Hematopoietic Progenitors. Cell Stem Cell. 2016 Sep 1;19(3):383-96. doi: 10.1016/j.stem.2016.06.008.
Mirjam E. Belderbos, Taco Koster, Bertien Dethmers-Ausema, Sabrina Jacobs, Sharlaine Sowdagar, Erik Zwart, Eveline de Bont, Gerald de Haan, Leonid V. Bystrykh. Clonal selection and asymmetric distribution of human leukemia in murine xenografts revealed by cellular barcoding. Blood. 2017 Jun 15;129(24):3210-20. PMID: 28396495.
Yang Han, Monika Eipel, Julia Franzen, Vadim Sakk, Bertien Dethmers-Ausema, Laura Yndriago, Ander Izeta, Gerald de Haan, Hartmut Geiger and Wolfgang Wagner. Epigenetic Age-Predictor for Mice based on Three CpG Sites. Elife. 2018 Aug 24;7. pii: e37462. doi: 10.7554/eLife.37462.
Jung J, Buisman SC, Weersing E , Dethmers-Ausema B1, Zwart E, Schepers H, Dekker MR, Lazare SS, Hammerl F, Skokova J, Kooistra SM, Klauke K, Poot RA, Bystrykh LV and de Haan G. CBX7 induces self-renewal of human normal and malignant hematopoietic stem and progenitor cells by canonical and non-canonical interactions. Cell Rep. 2019 Feb 12;26(7):1906-18.
Jacobs S, Ausema A, Zwart E, Weersing E, Kingma MJ, El Menshawi YAS, de Haan G, Bystrykh LV, Belderbos ME. Quantitative distribution of patient-derived leukemia clones in murine xenografts revealed by cellular barcodes. Leukemia. Epub 2019 Dec 18.
Simon Renders, Arthur Flohr Svendsen, Jasper Panten, Nicolas Rama, Maria Maryanovich, Pia Sommerkamp, Luisa Ladel, Seka Lazare , Bertien Dethmers-Ausema, Erik Zwart, Anna Rita Redavid, Benjamin Gibert, Manon Tourbez, Benjamin Ducarouge, Katharina Schönberger, Andreas Narr, Agnes Hotz-Wagenblatt, Dachuan Zhang, Claudia Korn Petra Zeisberger, Adriana Przybylla, Markus Sohn, Simon Mendez-Ferrer, Mathias Heikenwälder, Maik Brune, Daniel Klimmeck, Leonid Bystrykh, Paul S. Frenette, Patrick Mehlen, Gerald de Haan, Nina Cabezas-Wallscheid, Andreas Trumpp. Niche Derived Netrin-1 Regulates Hematopoietic Stem Cell Dormancy via its Receptor Neogenin-1. Niche derived netrin-1 regulates hematopoietic stem cell dormancy via its receptor neogenin-1. Nat Commun 12, 608 (2021). https://doi.org/10.1038/s41467-020-20801-0.
Svendsen AF, Yang D, Kim KM, Lazare S, Skinder N, Zwart E, Mura-Meszaros A, Ausema A, von Eyss B, de Haan G*, Bystrykh LV*. A comprehensive transcriptome signature of murine hematopoietic stem cell aging. Blood. 2021 Apr 19;blood.2020009729. doi: 10.1182/blood.2020009729.
Funding
2018-2022: Principal Investigator Landsteiner Foundation for Blood Transfusion Research grant: "Dissecting the role of Neogenin; a novel receptor required for hematopoietic stem cell proliferation and engraftment". (LSBR 1703: €440,000).
2018-2022: ARCH; Age-related changes in hematopoiesis. Marie Curie Innovative Training Network EUH2020 Contract number 813091 ((€265,619).
2019-2023: Principal Investigator Dutch Cancer Society grant 12621: Characterization and targeting CBX7 regulated self-renewal pathways in leukemia ("(€615,445).
2021-2027: ZonMW Program Grant “Pluripotent Stem cells for Inherited Diseases and Embryonic Research (PSIDER)” Using iPSCs to unravel hereditary anemias: from fundamental knowledge towards novel therapies TRACER. (total budget €4000,000, budget GdH €588,000).
2021-2027: ZonMW Program Grant “Pluripotent Stem cells for Inherited Diseases and Embryonic Research (PSIDER)” GREAT: 3D Gastruloid cultures to model normal and pathogenic human development. Total budget (total budget €3500,000, budget GdH €704,000).
2021-2024: Principal Investigator NWO Klein Identification and functional characrerizationof hematopoietic stem cell aging genes (€348,000).
Anne (A.) de Groot
