A Stem Cell Model to Study Human Cortical Interneuron Function

Neurological and psychiatric disease such as epilepsy and schizophrenia present a major burden to the modern society. Currently there are no effective treatments due to our limited knowledge on how the diseases are developed. It is clear however that a type of nerve cells called cortical interneurons are either lost or do not function properly in the brains of these patients. Abnormal cortical development has also been suggested as a major contributor to the cause of this disease.

Pluripotent stem cells (PSCs) are permanent cell lines capable of giving rise to all types of specialised cells, such as nerve cells, in the laboratory culture dish. In this study, we aim to develop ways to generate cortical interneurons from human PSCs. We will design cultures to contain essential identified connections that affected in the diseases. We believe that this model nerve cell culture will serve as a valuable experimental tool to help us to understand how neuropsychiatric diseases are caused. We are also interested in using these stem cell derived specialised cells for transplantation and to develop potential cell therapy for epilepsy.

Dysfunction of the cortical GABAergic interneurons has been identified as the core pathophysiology of epilepsy and neuropsychiatric disorders. Moreover, abnormal cortical development has been suggested as a major contributor to the development of these illnesses. However, due to our limited knowledge of human cortical development and a lack of defined aetiology and causal mechanisms of the pathogenesis, there is currently no effective treatment for these conditions.
Pluripotent stem cells (PSCs) are capable of generating all types of somatic cells in the laboratory culture dish and therefore offer a valuable tool to understand human cortical development. Moreover, the generation of induced pluripotent stem cells (iPSCs) from patient somatic cells carrying defined genetic variants offer iPSCs a unique path to investigate the underlying disease mechanisms. It is hoped that knowledge obtained from these studies would lead to the development of new, rational treatments for a variety of neurological diseases.
Substantial funding has been made available worldwide to create banks of iPSCs from healthy people and those with genetic diseases. In order realize the great promise of iPSCs in medicine, the next critical step will be the development of strategies that drive iPSCs towards somatic cell types targeted by a given disorder from hPSCs.
Therefore, the main aim of this proposal is to develop strategies that command hPSC differentiation towards cortical interneuron subtypes. This work will prove the principle that hPSCs can generate defined disease relevant units of neuronal network amenable to controlled activity perturbation, which serve as the foundation for exploiting patient-derived induced pluripotent stem cells in understanding aberrant human cortical development and neurobiology associated with neurological and psychiatric diseases.

The project is anticipated to impact on several intellectual and scientific fronts in stem cell neurobiology and regenerative medicine (see Academic Beneficiaries). A significant contribution will be the new knowledge on the molecular control of cortical neuronal fate specification. Understanding how cells acquire specific neuronal cell fate is of great importance in the growing field of stem cell research and translational medicine. This is of particular relevance to neuropsychiatric disorders and epilepsy where aberrant cortical development has been strongly implicated.

Neuropsychiatric diseases and epilepsy present a major burden to the modern society. There is no evidence that this burden is decreasing unless more effective approaches to treatment and prevention can be developed. However, the development of new, rational treatments has been limited both by our imperfect knowledge of the development and function of human cortical neurons and the lack of a defined aetiology and limited knowledge of the pathophysiology of these diseases. The project will help us to understand how extracellular signals interact to create a code that gives cells a specific identity related to regional position and time. This information directly impact on developing strategies for generating neurons with specific identity from hESCs and hiPSCs that could be used on transplantation studies. Cell replacement therapies can have a direct impact in the life of people with neurodegenerative diseases. Evidence from experimental studies in several models of temporal lobe epilepsy in rodents has provided "proof of concept" that fetal neural stem cell transplants or cell lines genetically engineered to release GABA at multiple sites in the brain reduce seizure severity and/or frequency, raising hope that cellular transplantation may be developed as a therapy for some forms of epilepsy.

We anticipate the project will also provide a valuable foundation for exploring disease iPSCs in modelling human diseases. Genetic studies have identified a number of genetic risk factors conferring susceptibility across a spectrum of clinical phenotypes including schizophrenia, autism, attention deficit hyperactivity disorder (ADHD), and intellectual disability. Neural differentiation of patient-derived iPSCs offer a unique opportunity to translate the genetics into a greater understanding of how the genetic variances cause dysfunction of the mind and how these disorders arise so that more effective interventions can be developed.

The themes of this proposal - regenerative and stem cell biology - are medically and economically important fields for the UK and are expected to undergo a large expansion as genomic data and stem cells are exploited and therapeutic interventions begin to rely on this knowledge. Thus, trained researchers with experience in appropriate fields of research are necessary. Specialised stem cell research is expanding at very high rate and requires highly trained personnel to support this. Personnel with skills in stem cell, developmental and molecular biology are likely to play a key role in the post-genomics era. This project will contribute to the training of such personnel and will allow the dissemination of this knowledge and skills.