As the most tractable tissue system for regenerative medicine, research on the development of hematopoietic stem cells (HSCs), their molecular program, their interaction with the microenvironment, and their controlled growth and manipulation for use in clinical applications is a major focus of ESI. Considering the shortage in transplantable stem cells for the blood system, the main overall goal of the research program is to expand umbilical cord blood stem cells, find new tissue sources of stem cells (placenta, vascular endothelium) and produce patient specific hematopoietic stem cells from iPS cells. Collaborative interactions are widespread within ESI, fundamental research and clinical/translational laboratories.

Hematopoietic development - With an eye on using the signals triggering the development of HSCs during development for ex vivo manipulation of human HSCs for therapies, Dr. C. Robin has developed an innovative in vivo dynamic imaging that allows real time observation of HSC birth and behaviour. Her results confirm the origins of HSCs from embryonic endothelial cells, and raise hopes that molecular programming of these cells could lead to a new source of unlimited HSCs. Together with Prof. E. Dzierzak, who identified the aorta as the generator of adult HSCs, other new sources of HSCs are being characterized. The placenta is a particularly interesting source since it is a highly vascularized tissue that is readily obtained and usually discarded at birth. Dr. Cupedo collaborates with Dr. C. Robin and Prof. E. Dzierzak in these developmental studies and leads a research program in human lymphoid tissue development. Prof. J Cornelissen and Dr. T. Cupedo are directing efforts towards novel methods of generating thymic epithelium, to restore and direct lymphoid function in transplantation scenarios.

Molecular programming - Molecular programming of HSCs in development and differentiation programs is a strong and internationally recognized area of research in the ESI. The ability to manipulate the genetic and epigenetic program of HSCs or closely related cells greatly enhances our understanding of hematopoiesis but also provides new insights into possible molecular modulators for clinical use. Analysis of the pivotal HSC transcription factors such as Runx1, Gata2, etc. by Prof. E. Dzierzak has demonstrated a role for these factors in the generation of HSCs but not in their maintenance. Maintenance of stem cell fate most likely rests in the epigenetic program and is intensively studied by the group of Prof. F. Grosveld. Key biochemical and genetic technologies that allow the isolation of protein complexes have been developed in this laboratory. Prof. F. Grosveld has identified some of the major players in transcriptional activation and/or repression of the stem cell program. Collaborative studies between these groups and that of Prof. P. Verrijzer (Dept of Biochemistry) are beginning to provide insights into how to manipulate stem cell fate and hold future promise for clinical exploitation. Generation of human iPS cells from patients with blood-related disease will allow further insight into the correction of such defects and strategies for clinical treatment.

Stem cell-microenvironment interactions - Further lines of research involve the isolation and characterization of the supportive hematopoietic microenvironment. Prof E. Dzierzak and Dr. C. Robin have identified several of the microenvironmental factors that lead to development of HSCs and produced a panel of stromal cells from the embryonic aorta region and the placenta (both mouse and human) that support hematopoiesis ex vivo from a variety of mouse and human cell types including ES cells. The stromal cell lines are a valuable resource provided to the Erasmus MC and international research communities. In collaboration with Dr. R. Stam and Dr. M. den Boer, the stromal cells are being tested for their ability to expand leukemic cells in culture. Studies of cancer stem cells in leukemia have been hindered previously due to the inability of the cells to grow ex vivo.    

Cells of the bone marrow microenvironment in the osteoblastic and/or vascular niches are thought to play a role in the normal maintenance of HSCs. HSCs reside in close association with osteoblasts and the bone matrix. Prof H van Leeuwen has developed and fully validated a human pre-osteoblast-based in vitro bone formation model and has profiled these cells at all stages of differentiation. Studies in collaboration with Prof J Cornelissen are underway to study the impact of human osteoblasts on the survival, expansion and differentiation of human cord blood CD34+ cells. Results of a panel of stromal cell lines developed by the group of Prof. Dzierzak demonstrate that Wnt signaling increases HSC maintenance. Taking a more biochemical approach, Dr. ten Berge, in collaboration with Prof. Cornelissen is testing the effect of Wnt protein/liposomes on human cord blood CD34+ cells. HSC maintenance/expansion in these model systems will be tested for in the pre-clinical NOD-SCID xenotransplantation assay. With optimization of ex vivo manipulation and improved engraftment, Prof. J Cornelissen will coordinate clinical trials.