About the Neural stem cells lab group
Professor Jack Price leads the research group on neural stem cells.
My research group is primarily interested in stem cells, and we are studying their biology in four areas.
> First, we are interested in stem cells as therapeutic agents that can bring about functional improvement in the damaged brain.
> Second, we are interested in stem cell diversity.
> Third, we are using stem cells to model human neurodevelopmental disorders in vitro.
> Fourth, we are interested in endogenous neural stem cells, and their role in adult neurogenesis and its implications for human health.
In all these studies, we are working primarily with human stem cells, either neural stem cells derived from fetal or the adult nervous system, or induced pluripotent stem cells (iPSCs).
Stem cells as therapeutic agents
For some years, we have been studying the potential of neural stem cells to bring about repair in the nervous system. Neural stem cells are remarkable cells: if engrafted into the injured brain, they have the capacity to induce functional recovery (Price, 2001, 2011; Price and Williams, 2001).
For many years, we believed this property reflected the multipotentiality of the stem cells; that is, their ability to differentiate into multiple different neural types (Morgan et al., 2010; Pollock et al., 2006; Uwanogho et al., 2010). It transpires, however, that engrafted cells rather work to improve the brain’s own response to injury. Together with Dr. Mike Modo, we have engrafted neural stem cells into models of stroke and other neurodegenerative disease. We have used MRI, behavioural and histochemical assays to follow the behaviour of the cells and the progression of disease (Bible et al., 2009a, b; El-Akabawy et al., 2011; Johansson et al., 2008; Modo et al., 2009). With Prof Eva Sykova and Dr Pavla Jendelova, we have studied the impact of neural stem cell engraftment on spinal cord injury (Kubinova et al., 2010).
In this area of stem cell therapeutics, we collaborate with ReNeuron Ltd, a UK biotech company developing stem cells for therapeutic and drug discovery applications. I act as a consultant for ReNeuron.
Stem cell diversity
Stem cells are not all the same. Clones of neural stem cells, for example, differ from one another, even if they are genetically identical, and are derived even from the same area of brain. This diversity is important, partly because it is likely to have consequences developmentally, but also because it impacts on their utility. If stem cell lines are to be created to treat brain disorders, which lines should we choose from among the diverse types that emerge?
We are studying whether part of this diversity arises from mono-allelic gene expression. The genome typically carries two copies of each gene, one derived from each parent. Generally it is believed that both copies are expressed concurrently, though there are a number of documented exceptions, such as imprinted genes, and X-inactivation. We now have evidence that a particular subset of genetic loci show ‘stochastic’ monoallellic expression, meaning that a small proportion of genes expressed by human neural stem cells, are monoallelic in some cells and biallelic in other cells (Jeffries et al., Submitted). We also know that this choice is associated with differential DNA methylation, and with differential histone modifications, so we believe this is a novel epigenetic developmental control mechanism. We are now interested in the implications of this mechanism for human disease.
Stem cells as models of neurodevelopmental disorders
Human neural stem cells allow us to study molecular and cellular aspects of human brain development in a tissue culture dish. By manipulating their gene expression, or manipulating their environment, we can study the molecular basis of developmental events. We have taken advantage of this to establish models of neurodevelopmental disorders in culture. In collaboration with Dr Nick Bray and Dr. Matthew Hill, we have used human neural stem cells to investigate the biology of ZNF804A and DISC1, two risk genes for schizophrenia (Bray et al., submitted; Hill et al., 2011).
Our current strategy in this area concentrates on human induced pluripotent stem cells (iPSCs). We are currently part of EU-AIMS, a collaborative project funded under the European Communities ‘Innovative Medicines Initiative’, which seeks to use human iPSCs derived from autistic patients to study the pathophysiology of this disorder, and to enable drug-discovery studies into novel therapeutics in this area. We are specifically collaborating with Prof. David Collier and Dr. Sarah Curran to investigate the impact of copy number variations (CMVs) at synaptic genetic loci on autism.
Endogenous neural stem cells
The adult human brain contains neural stem cells, most conspicuously in the dentate gyrus, a region of the hippocampus. This population of stem cells generates the granule neurons that populate this brain region, and normal tissue homeostasis is dependant on this ongoing adult neurogenesis. There is accumulating evidence that failures in neurogenesis are associated with several human diseases, most prominently depression and dementia. We are interested in both these disorders. Together with Prof Carmine Pariante and Dr. Sandrine Thuret, we have modeled the reduction in neurogenesis that accompanies chronic depression (Anacker et al., 2011; Zunszain et al., 2012). This reduction appears to be caused at least in part by chronic stress, mediated by the hormone corticosterone. We have reproduced this effect on human hippocampal stem cells in vitro, and demonstrated that it is mediated by the glucocorticoid receptor. We show also that antidepressants work via this same pathway (Anacker et al., 2011).
Human neurogenesis may also be compromised in dementia. In collaboration with Prof. Simon Lovestone and Prof Clive Ballard, we are looking for factors associated with dementia that might be involved in this process. We hope this might lead to possible therapeutic programmes for this disorder.