Neural stem cells produce the neurons and glial cells that make up our nervous system. They can be expanded continuously in the laboratory, thereby providing an unlimited source of human cells for disease modelling and regenerative medicine.
Cells that have molecular hallmarks of neural stem cells drive human brain cancers, such as glioblastoma. A full understanding of the molecular and cellular events that control neural stem cell fate may therefore reveal new therapeutic strategies to treat this devastating disease.
We are exploiting the latest experimental tools of molecular and cellular biology to address the following questions: How do neural stem cells make the decision to make more copies of themselves (self-renew), or become specialised (differentiate)? Why do brain tumour stem cells display unconstrained self-renewal? Are those genes and pathways that initiate and maintain neural stem cell identity useful therapeutic targets for glioblastoma? Can we identify new drugs that can specifically block self-renewal of brain tumour stem cells?
The primary model system is a novel set of neural stem (NS) cell lines generated from rodent and human germinal tissues or from brain tumour biopsies. Genome editing, biochemical approaches and genome-wide profiling of transcription factor transcriptional targets are a current area of focus. These in vitro studies are complemented by in vivo assays (intracranial stereotaxic injection) and analysis of the developing mouse forebrain and primary tumour samples. We are also now exploring the zebrafish as a convenient model system to track neural stem cell behaviour in vivo.
There are currently four major areas of interest:
1. Lineage specific transcription factors.
We are using genetic and biochemical approaches to define the molecular mechanisms through which lineage-specific transcriptional regulators orchestrate self-renewal and differentiation, focussing on SOX, FOX and bHLH families. These lie at the heart of cell fate decision-making by neural stem and progenitor cells during development and within brain tumours.
2. Chemical and genetic screening
We are carrying out image-based small molecule screens to search for new agents and pathways that can modulate self-renewal and differentiation of normal and glioblastoma-derived neural stem cells.
3. Epigenetic programming and reprogramming
We are investigating whether changes to the epigenome within glioblastoma-derived cancer stem cells enable suppression of malignant properties. We are using both direct differentiation as well as nuclear reprogramming strategies to test this.
4. Genome editing
Designer transcription factors and nucleases (TALENs or CRISPR/Cas system) provide exciting new possibilities for sophisticated genetic and epigenetic manipulations of mouse and human neural stem cells. We are exploiting these tools with the goal of establishing efficient gene targetting in human neural stem cells and in directing stem cell fate.
- Axel Behrens, CRUK LRI and Francis Crick Institute
- Stephan Beck, UCL Cancer Institute
- Paul Bertone, European Bioinformatics Institute and EMBL, Cambridge/Heidelberg
- Paul Brennan, University of Edinburgh and NHS Lothian
- Patrick Cai, SynthSys, University of Edinburgh
- Neil Carragher, University of Edinburgh
- Peter Dirks, Hospital for Sick Children, Toronto
- Robin Grant, NHS Lothian
- Jeroen Krijgsveld, European Molecular Biology Laboratory, Heidelberg
- John Mason, Centre for Integrative Physiology, University of Edinburgh
- Patrick Paddison, Fred Hutchison Cancer Centre, Seattle
- Dirk Sieger, Centre for Neuroregeneration, University of Edinburgh
- Bill Skarnes, Wellcome Trust Sanger Institute