Profile pic 2014

Dr Rick Livesey

Human stem cell models of dementia

Email: rick@gurdon.cam.ac.uk

Laboratory Location:

Gurdon Institute

Departmental Affiliation:

Rick Livesey is a Wellcome Trust Group Leader at the Gurdon Institute and a member of the Department of Biochemistry, University of Cambridge.

Livesey Lab

Co-workers:

Laura Brightman • Phil Brownjohn • Tatyana Dias • Lewis Evans • Kirsty Ferguson • Alberto Frangini • Peter Kirwan • Teresa Krieger • Ayiba Momoh • Steven Moore • Tomoki Otani • Francesco Paonessa • Manuel Peter • Nathalie Saurat • Vickie Stubbs • James Smith • Philipp Berg

Rick Livesey did his preclinical medical studies in Cork, Ireland before joining the MB/PhD programme at the University of Cambridge Clinical School. He did his PhD at the MRC LMB in Steve Hunt's group and post-doctoral work with Connie Cepko at the Department of Genetics, Harvard Medical School.

Rick started his group at the Gurdon Institute in September 2001. He is currently a Wellcome Trust Senior Investigator.


Introduction

 

A major interest of the group is the use of stem cell-based models of Alzheimer’s disease to study the initiation and pathogenesis of neurodegeneration in dementia. Developing these models depends on our fundamental research in stem cell biology and neuroscience, together with associated technologies, such as genome engineering and imaging. This background enables us to generate in vitro cortical neural networks and to carry out functional studies of Alzheimer’s disease biology.

A challenge for modelling Alzheimer’s disease (AD), and developing therapies based on those models, is our incomplete understanding of the cell and molecular biology underlying the initiation and progression of the disease. Animal models continue to be critical to understanding the pathogenesis of Alzheimer’s disease. However, it is clear that no animal model completely recapitulates AD and there is an ongoing need for tractable systems for studying AD pathogenesis both in vitro and in vivo.

Building on our previous work using human ES and iPS cells to model Alzheimer’s disease pathogenesis in Down syndrome, we are carrying out functional studies of AD initiation and progression in human stem cell models, using genetic forms of dementia and AD.

Livesey Lab 2014

Human stem cell-derived neurons

Lab Information

The cerebral cortex, which makes up three quarters of the human brain, is the part of the nervous system that integrates sensations, executes decisions and is responsible for cognition and perception. Given its functional importance, it is not surprising that diseases of the cerebral cortex are major causes of morbidity and mortality. Understanding the biology of cortical neural stem cells is essential for understanding human evolution, the pathogenesis of human neurodevelopmental disorders and the rational design of neural repair strategies in adults.

During embryonic development, all of the neurons in the cortex are generated from a population of multipotent stem and progenitor cells. Much of the research in the lab centres on the cell and molecular biology of cortical stem cells, using mouse as a model system. We are particularly interested in the molecular mechanisms controlling multipotency, self-renewal and neurogenesis, and how these are coordinated to generate complex lineages in a fixed temporal order.

A number of ongoing projects in the group address the functional importance of transcriptional and epigenetic mechanisms in this system, including microRNAs and the polycomb chromatin-modifying complexes. In the other major strand of research in the group, we have used our understanding of murine cortical stem cells to develop methods for directing differentiation of human pluripotent stem cells to cortical neurons, via a cortical stem cell stage.We are using this system for basic studies of human cortical neurogenesis and to generate models of cortical diseases, with an initial focus on Down syndrome and Alzheimer’s disease.

R. Livesey Fig. 1

Fig. 1: Human stem cell-derived neuropithelial rosettes expressing cerebral cortex transcription factors

R. Livesey Fig. 2

Fig. 2: Layer-specific gene expression in neurons of different layers (red, green and yellow) of the cerebral cortex

R. Livesey Fig. 3

Fig. 3: A human cortical neural stem cell rosette, with stem cells (red) dividing at the apical surface (green)

Plain English

Making a brain depends on producing all of the different types of nerve cells in the correct places and at the appropriate times before wiring those nerve cells together to make functional circuits. We study how neural stem and progenitor cells build the executive centre of the mammalian brain, the neocortex. The neocortex is the part of the front of the brain that mammals, including humans, use to perceive physical sensations, sound and vision and where thoughts are generated and movement initiated. The consequences of mis-wiring in the cortex are neurological disease and disability, ranging from epilepsy to autism to major learning disabilities. An understanding of how stem and progenitor cells build the cortex is essential for understanding these neurodevelopmental disorders and also for the development of stem cell-based therapies for neurological repair. The cortex is a mammal-specific structure, so we also think that studying how genes are used to build the cortex will help us understand the evolution of uniquely human abilities, such as language.

Key Publications

Livesey, F. J. (2014). Human stem cell models of dementia. Human Molecular Genetics. doi:10.1093/hmg/ddu302.

• Shi, Y., Kirwan, P., Smith, J., Robinson, H.P., and Livesey, F.J. (2012). Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nature Neuroscience 15, 477-486.

• Shi, Y., Kirwan, P., Smith, J., Maclean, G., Orkin, S.H., and Livesey, F.J. (2012). A human stem cell model of early Alzheimer's disease pathology in Down syndrome. Science Translational Medicine 4, 124ra129.

• Alsiö, J.M., Tarchini, B., Cayouette, M., and Livesey, F.J. (2013). Ikaros promotes early-born neuronal fates in the cerebral cortex. PNAS, 110: E716–E725.

• Shi, Y., Kirwan, P. and Livesey, F.J. (2012). Directed differentiation of human pluripotent stem cells to cerebral cortex neurons and neural networks. Nature Protocols, 7:1836-1846.

R. Livesey Fig. 4

A single astrocyte (red) in a culture of human cortical neurons (green)

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