In healthy adults, blood cells are continuously being replaced through the daily production of hundreds of millions new blood cells from stem cells. These blood stem cells reside in the bone marrow and are used clinically in transplantations of patients suffering from blood-related diseases and cancer (leukemia). The supply of blood stem cells for clinical use is limited and thus, there is a need for developing novel methods to produce more of these valuable cells. My research is aimed at understanding how blood stem cells are made so as to develop molecular methods by which we can generate and regenerate a complete, long-lived healthy adult blood system.
Haematopoietic stem cells (HSC) are the basis for regeneration of the haematopoietic system in clinical transplantations for blood related genetic disease and leukemias. However, the number of histocompatible donors is limited and HSC numbers in compatible donor samples, particularly umbilical cord blood, are too few to meet clinical requirements. There is an ever-increasing need for novel sources of, and expansion protocols for HSCs that are preferably patient-matched. Current developments in cell transdifferentiation and genetic reprogramming, together with our recent discoveries of haemogenic endothelium as the source of all HSCs, offer an opportunity for ex vivo generation and expansion of patient-specific HSCs. Using our unique combination of transgenic models, cell lines and differentiation protocols, the fundamental and translational goals of our research will yield important information on the genetic program that drives HSC production and expansion.
- To identify the complete transcriptome (RNA seq) of the first HSCs and the haemogenic endothelium from which they are generated;
- To use genetically engineered ES cells expressing haemogenic endothelial and HSC reporters to determine the optimal culture conditions for the generation/expansion of hemogenic endothelial cells and HSCs;
- To test the ability of pivotal molecules (particularly transcription factors and developmental growth factors) to augment programming/reprogramming to HSC fate.
We will use this information to generate human (patient-specific) HSCs from ES/iPS cells and/or to program/reprogram other cell types (endothelial) to haemogenic endothelial and HSC fate.
- European Research Council Advanced Grant Award
- National Institutes of Health MERIT Award
- ZonMw-TOP Award (Netherlands Medical Research Council)
- FES-Netherlands Institute of Regenerative Medicine Award
- Landsteiner Society for Blood Research
- Ruud Delwel, Erasmus Medical Centre,NL
- Lesley Forrester, U of Edinburgh, CRM
- Chris Gregory, U of Edinburgh, CIR
- Kamil Kranc, U of Edinburgh, CRM
- Alexander Medvinsky, U of Edinburgh, CRM
- Christine Mummery, Leiden University, NL
- John Pimanda, U of New South Wales, AU
- Nancy Speck, U of Pennsylvania, USA