Stem cell biology
Our lab aims to identify the molecular mechanisms that control how hematopoietic stem cells emerge, expand or selfrenew. Hematopoietic stem cells ensure a balanced production of a wide variety of blood cells throughout life. Identifying the cellular and molecular signals that instruct these stem cells to divide, remain quiescent, or differentiate may allow to prevent the decline of stem cell function during aging, and generate functional blood cells that can be used for transplantation or transfusion purposes.
Research lines
1. Identification of molecular mechanisms that cause hematopoietic stem cell dysfunction.
During aging hematopoietic stem cells acquire properties that result in reduced functionality. In addition, the number of hematopoietic stem cells is altered in an aged organism, and a sizeable fraction of mature blood cells is derived from only a few stem cells, a process referred to as clonal hematopoiesis. We have previously identified multiple molecular mechanisms and altered expression of certain genes that contribute to stem cell dysfunction. Some of these mechanisms relate to an altered interaction of hematopoietic stem cells with their immediate surrounding, the stem cell niche. We aim to identify critical players that control the cross-talk between stem cells and their environment, with the ultimate aim to prevent age-associated stem cell decline and restore functionality.
2. In vitro derivation and expansion of hematopoietic stem cells
Hematopoietic stem cells have great clinical relevance as they are used in transplantation therapies that are aimed to restore blood cell production in patients with acquired or congenital blood diseases. These include patients suffering from malignancies such as leukemia, but also patients with hemoglobinopathies such as sickle cell anemia or thallasemia. In addition, genetic modification of hematopoietic stem cells can cure an increasing number of acquired diseases. Hematopoietic stem cells are very rare and require suitable donors, while the outcome of many transplant procedures is critically dependent on the number of stem cells transplanted. Thus, there is great interest to find ways to generate, donor-independently, hematopoietic stem cells from pluripotent stem cell sources or to expand hematopoietic stem cells in vitro.
We aim to develop novel methods that will allow to generate and expand hematopoietic stem cells in vitro.
Key publications
De Haan G, Weersing E, Dontje B, van Os R, Bystrykh LV, Vellenga E, Miller G. In vitro generation of long-term repopulating hematopoietic stem cells by FGF-1. Developmental Cell, 2003 4: 241-251
Bystrykh LV, Weersing E, Dontje B, Sutton S, Pletcher MT, Wiltshire T, Su AI, Vellenga E, Wang J, Manly KF, Lu L, Chesler E, Alberts R, Jansen RC, Williams RW, Cooke M, de Haan G. Uncovering regulatory pathways that affect hematopoietic stem cell function using ‘genetical genomics’. Nature Genetics, 2005, 37:225-232.
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.
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.
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
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.
Kim KM, Mura-Meszaros A, Tollot M, Krishnan MS, Gründl M, Neubert L, Groth M, Rodriguez-Fraticelli A, Svendsen AF, Campaner S, Andreas N, Kamradt T, Hoffmann S, Camargo FD, Heidel FH, Bystrykh LV, de Haan G, von Eyss B. Taz protects hematopoietic stem cells from an aging-dependent decrease in PU.1 activity. Nat Commun. 2022 Sep 3;13(1):5187. doi: 10.1038/s41467-022-32970-1
Natalia Skinder, Irene Sanz Fernández, Albertien Dethmers-Ausema, Ellen Weersing, Gerald de Haan. CD61 identifies a superior population of aged murine hematopoietic stem cells and is required to preserve quiescence and self-renewal. Blood Adv. 2024 Jan 9;8(1):99-111. doi: 10.1182/bloodadvances.2023011585. PMID: 37939263
Daozheng Yang, Natalia Skinder, Yun-Ruei Kao, Jiahao Chen, Victor Thiruthuvanathan, Arthur Flohr Svendsen, Chi Zhang, Bertien Dethmers-Ausema, Ellen Weersing, Maria Maryanovich, Britta Will and Gerald de Haan. Aberrant engagement of P-selectin drives hematopoietic stem cell aging. Nat Aging. 2025 Jun;5(6):1010-1024. doi: 10.1038/s43587-025-00880-8. Epub 2025 May 23. PMID: 40410559
Funding
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 €4,000,000, 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 €3,500,000, budget GdH €704,000).
2023-2029: Co-applicant. LargE SCALe eArly deTectIon Of caNcer (ESCALATION). NWO-KWF Partnership project. Total budget 2,500,000€, Sanquin budget 200,000€.
2025-2030: MakingBlood: Engineering an integrated platform for generation of human blood stem cells from pluripotent sources. European Research Council Synergy Grant (co-PIs: A Bigas, G de Haan, C Pina, C Sahlgren). €9,900,000 (€2,410.000 to Gerald de Haan).
Ancillary positions
Professor of Molecular Stem Cell Biology, Cancer Center Amsterdam, Department of Hematology University of Amsterdam/ Amsterdam University Medical Center.
Elected member Scientific Committee Danish Cancer Society
Member ZonMW Rubicon Programma
Ksenia (K.) Pavlova
