Specification, maintenance and elimination of stem cell progenitors for the mammalian anteroposterior axis

During embryo development, the spinal cord, vertebral column and muscles are laid down by stem cells. We have shown that these stem cells are unique for several reasons. Unlike embryonic stem (ES) cells, which can make any tissue in the body, or neural stem cells, which only make nervous tissue, these 'neuromesodermal' or 'NM' progenitors make two very distinct embryonic tissue types, the neural tube (which then generates spinal cord) and the mesoderm (which makes muscle, bone and cartilage). These stem cells are born very early during development and are active until the precursors of spinal cord and vertebral column are laid down. They then are completely removed from the embryo.

These cells would be a useful source of differentiated muscle, bone, and spinal cord if we could grow them in a culture dish. In fact, unlike ES cells, NM progenitors do not make malignant tumours when injected in adult mice. Recently, we have generated, in cell culture, NM progenitor-like cells and we plan to study how these cells are generated, how they make neural tube and mesodermal cell types, and how the embryo knows when to eliminate them. Several human birth abnormalities including caudal regression syndrome, a high risk for diabetic mothers, may arise because NM progenitors are not correctly eliminated, and we will use our knowledge of NM progenitors in the embryo to study whether this is the case. This programme therefore combines study of cells in embryos with cells in culture to understand development and disease, and to produce cell types that may be useful in the future for cell therapies.

The origin and maintenance of tissue stem cells in the embryo is not well understood. We have identified and characterised an in vivo stem cell population with novel characteristics, neuromesodermal (NM) progenitors, which produce the anteroposterior (AP) axis. Disruption of AP axis elongation occurs in a cluster of human syndromes (caudal regression syndrome, Currarino syndrome and sacrococcygeal teratoma). Our recent work has given new insight into the specification, maintenance and elimination of NM progenitors. In this programme, we plan to discover (i) what factors govern the specification of of NM progenitors from the pluripotent epiblast; (ii) the molecules that control NM progenitor maintenance and subsequent differentiation as neurectoderm or
mesoderm; and (iii) the hierarchy of events that lead to elimination of NM progenitors at the end of axis elongation. The experiments will make use of existing and new genetic modifications in ES and epiblast stem cells, physical micromanipulation of embryos and embryonic explants, imaging and cell sorting. This programme can therefore contribute significant understanding of an in vivo stem cell, shed light on the origin of common birth defects, and provide a novel, non-neoplastic source of spinal cord and mesoderm cell types that are currently refractory to in vitro isolation, such as skeletal muscle and intervertebral disc progenitors for therapeutic applications.

1. Research staff employed on this project will receive both highly specialist and generic/transferable skills training.
The skills set in this lab are not available anywhere else in the UK, and in very few labs worldwide. Training will therefore produce researchers with unique skills and qualities. In terms of career progression and diversification, the University of Edinburgh is recognised by the UK Research Council as a Centre of Excellence for generic and transferable skills training.

2. Students
I consider enthusing students about the research I do, and about stem cell and developmental biology research, one of my most important roles as a lecturer and researcher. Students will benefit by understanding why research is interesting, by entering research themselves, but at least by being aware of issues related to this research

3. Members of the public interested in stem cells
Through my webpage and a diverse range of outreach events organised by a dedicated team of outreach personnel in the Scottish Centre for Regenerative Medicine, the public will gain awareness of the scope of this research: what it does and does not do.

4. Patients in two categories:
Those affected by diabetic pregnancy leading to a high risk of caudal regression syndrome, those with familial Currarino syndrome, and sacrococcygeal teratoma will benefit by research that leads to an understanding of the causes of these developmental abnormalities, and, potentially, to identification of further risk factors and/or interventions that reduce risk

People suffering from a range of health problems for which neuromesodermal stem cells may be of therapeutic benefit, e.g. spinal cord injury, muscular dystrophy will benefit in the long term by a knowledge of whether it is feasible to generate cell types of therapeutic value.