Haematological regeneration

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.

Specific aims:

1. To identify the complete transcriptome (RNA seq) of the first HSCs and the haemogenic endothelium from which they are generated;
2. 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;
3. 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.