From Hematopoietic development towards generation of Hematopoietic stem cells

Haematopoietic stem cells (HSCs) give rise to the majority of cells in the adult haematopoietic system, however, their embryonic development is poorly understood. Embryonic stem (ES) cells can differentiate into all cells types of an adult animal. The recent successful generation of pluripotent ES-like (iPS) cells from cells of an adult organism has raised the hope of an effective treatment for tissue and organ deficiencies. As clonally-derived cell lines, pluripotent cells can be characterised, expanded, customised to meet needs of a patient, catalogued and stored in liquid nitrogen banks. Although ES and iPS cells can efficiently generate haematopoietic lineages in vitro they fail to generate transplantable long-term repopulating HSCs. The production of HSCs from pluripotent cells remains a considerable challenge for researchers around the world.
We have shown that mouse and human HSCs develop first in the AGM region and, more specifically, in the dorsal aorta. AGM-derived HSCs when transplanted into immunodeficient NSG mice can provide long-term high-level multilineage hematopoietic engraftment; the gold standard assay for functional HSCs. We have shown that these first HSCs have enormous regenerative potential and have put significant effort into the identification of secreted factors in the AGM region, which can drive development of the first HSCs.
The overall goal of this research proposal is to enhance haematopoietic differentiation from pluripotent cells with an ultimate goal of generating true human HSCs, based on our understanding of the early stages of embryonic HSC development.
Our studies have identified secreted factors in the mouse and more recently in the human AGM region. We hypothesise that some of these factors support HSC development from embryonic precursor cells by enhancing their self-renewal and differentiation potentials. Using human ES cell differentiation cultures, we will screen these factors for their capacity to elicit such an impact on ES-cell derived haematopoietic progenitors.
The student will master both ES cell differentiation techniques and experimental haematology methods . This will include in vitro assays, such as myeloid colony formation and T-cell differentiation as well as in vivo long-term transplantations. Other methods will include multi-colour flow cytometry (both analysis and sorting), confocal microscopy, qRT-PCR, RNAseq and genetic modification of ES cells.

This project is a collaboration between two laboratories: Prof. Alexander Medvinsky (an expert in early haematopoietic development) and Prof. Val Wilson (an expert in early embryo development).

http://www.crm.ed.ac.uk/research/group/ontogeny-haematopoietic-stem-cells
http://www.crm.ed.ac.uk/research/group/early-embryo-development