PI: Dr. Mirjam Belderbos
Hematopoietic stem cells
Hematopoietic stem cells are responsible for the production of all mature blood cell types throughout life, generating billions of mature blood cells each day. Aside from their role in homeostatic hematopoiesis, HSCs are crucial to regenerate the hematopoietic system upon myeloablative challenge, such as chemotherapy or transplantation.
Hematopoietic stem cell lineage tracing: from mice to humans
To understand how a relatively small number of HSCs (re-)generate the entire hematopoietic system, we use several innovative lineage tracing strategies. Lineage tracing relies on heritable markers to mark individual HSCs and to trace their clonal ancestry in vitro/in vivo (Belderbos et al, Blood 2017; Methods Mol Biol 2019). We have recently demonstrated that only a small fraction of human umbilical cord blood CD34+ cells generate offspring in murine xenografts (Belderbos et al, Biol Blood Marrow Transpl 2020). Importantly, the frequency of clonogenic cells differed up to 10-fold between umbilical cord blood donors, which may have important consequences for the selection of umbilical cord blood donors for HSCT.
The ambition of our lab is to translate these findings to humans. To this aim, in collaboration with the group of Ruben van Boxtel, we have adopted a novel lineage tracing method, using naturally occurring somatic mutations as “barcodes” to identify and trace individual HSCs in humans. Using this innovative approach in human HSCT recipients and their donors, we aim to unravel the clonal dynamics by which human HSCs (re-)generate blood, and identify novel features of human HSC “stemness”. Furthermore, we will define the impact of common HSCT-related complications (e.g. viral reactivations, bacterial infections, graft-versus-host disease) on the genomic and functional integrity of these cells.
Origins of pediatric bone marrow failure
Our group also focuses on the origins and mechanisms of HSC dysfunction in pediatric bone marrow failure, in particular Fanconi Anemia. Using single-cell technology and lentivviral rescue strategies, we aim to define which hematopoietic cell populations are involved in the pathogenesis of bone marrow failiure and myelodysplasia, and characterize the genomic pathways active within these cells. Ultimately, we envision that this will contribute to novel strategies to predict the occurrence of bone marrow failure/myelodysplasia, allowing for targeted intervention and preventive measures.
2. Belderbos ME, Jacobs S, Koster TK, Ausema A, Weersing E, Zwart E, de Haan G, Bystrykh LV: Donor-to-Donor Heterogeneity in the Clonal Dynamics of Transplanted Human Cord Blood Stem Cells in Murine Xenografts. Belderbos ME, Jacobs S, Koster TK, Ausema A, Weersing E, Zwart E, de Haan G, Bystrykh LV. Biol Blood Marrow Transplant. 2020 Jan;26(1):16-25.
3. Belderbos ME, Gennery AR, Dvorak CC, Blok HJ, Eikema DJ, Silva JMF, Veys P, Neven B, Buckley R, Cole T, Cowan MJ, Goebel WS, Hoenig M, Kuo CY, Stiehm ER, Wynn R, Bierings M; Inborn Errors Working Party of the European Group for Blood and Marrow Transplantation and the Primary Immune Deficiency Treatment Consortium: Outcome of domino hematopoietic stem cell transplantation in human subjects: An international case series. J Allergy Clin Immunol. 2018 Nov;142(5):1628-1631.e4.
4. Belderbos ME, Koster T, Ausema B, Jacobs S, Sowdagar S, Zwart E, de Bont E, de Haan G, Bystrykh LV.: Clonal selection and asymmetric distribution of human leukemia in murine xenografts revealed by cellular barcoding. Blood. 2017 Jun 15;129(24):3210-3220.
5. Bystrykh LV, Belderbos ME: Clonal Analysis of Cells with Cellular Barcoding: When Numbers and Sizes Matter. Methods Mol Biol. 2016;1516:57-89.
Our group consists of a multidisciplinary team, with fundamental biologists as well as clinical researchers. The group is led by dr. Mirjam Belderbos, MD, PhD. Next to her scientific activities, dr. Belderbos works as a pediatric oncologist in hematopoietic stem cell transplantation. Core values in our group are collaboration, curiosity and clinical impact.