Stem Cells and Lymphocyte Development

At the Staal Lab we study blood forming stem cells and how these cells develop into lymphocytes, mostly into the main cells of the adaptive immune system, the T lymphocytes. We have a research interest in hematopoietic stem cells, their development into T cells and genetic defects that are associated with the loss of immune function.

Gene Therapy of Immunodeficiencies

Current research is focused on the optimization and clinical translation of gene therapy of RAG1 deficiencies. This project brings together over 10 years of preclinical work and should result in application of lentiviral gene therapy of a codon optimized RAG1 in hematopoietic stem cells. In preclinical pipeline, we have also developed lentiviral gene therapy vectors for BTK deficiency and RAG2 deficiency.

Molecular signals in HSC

The hematopoietic stem cell (HSC) and its progeny is another topic of interest. Without understanding what makes a HSC grow, resulting in repopulation of the bone marrow and generation of the hematopoietic system, either during development or after a bone marrow transplantation, the development of new therapies would be difficult. The HSC research group has an interest in understanding which molecular signals make HSCs do what they do, which cells provide these signals and how they can be manipulated to improve transplantation outcomes. The lab currently focusses on Wnt and Notch signals and their effect on hematopoietic differentiation.

T cell development

The development of T cells is closely linked to HSC differentiation. Different from other hematopoietic lineages, T cells develop in the thymus after it has been seeded with T cell progenitors from the bone marrow. Our focus is on the understanding of the dynamics of hematopoietic clones that seed the thymus and subsequently differentiate into mature T cells. Our current work also involves the analysis of human immunodeficiencies in a xenotransplant model to determine at which point during T cell development different mutations cause arrests in development. Human T cell development is studied using single cell RNA-seq, functional experiments, in vitro culture systems and in vivo transplantation into NSG mice. In addition, we are determining how interference with Wnt signals causes T cell development arrests and lymphoid leukemia.