Professor Meng Li
Chair in Stem Cell Neurobiology, Neurosciences & Mental Health Research Institute
Meng Li's group is interested in elucidating the molecular mechanisms underlining neural fate specification and the subsequent differentiation of neuroectoderm cells into defined neuronal subtypes.
We aim to exploit iPSC-derived neurons for elucidating the cellular basis of neuropsychiatric diseases and developing better strategies for cell therapies.
We employ an integrated experimental approach involving in vitro neural development of human and mouse embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), as well as contemporary genetic manipulation in model organisms.
We apply the resulting knowledge to devise novel strategies that drive pluripotent stem cells into clinically important neurons, such as midbrain dopamine neuron, striatal GABAergic neurons and cortical interneurons.
The primary research interest of our laboratory is to uncover the molecular mechanisms underlying neuronal subtype specification of pluripotent stem cells and during mammalian development. Our research over the years has contributed to the advance in understanding pluripotent stem cell (PSC) neural fate conversion and dopaminergic fate specification of PSCs and during normal mammalian development. These studies led to the establishment of valuable 'tool boxes' for lineage-specific marking of defined stem/progenitors and mature dopamine neurons, and efficient novel methods for directed neuronal differentiation. Recently, we have extended our interest into GABAergic cortical interneurons, a complex group of cells which dysfunction has been implicated in neuropsychiatric diseases and epilepsy.
Molecular mechanisms controlling neurogenesis and neuronal subtype specification
Our ability to control the differentiation fate choice of pluripotent stem cells is pivotal for realising their potential in disease modelling, drug screening and cell therapy. We have recently identified the Doublesex and mab-3-related transcription factor 5 (Dmrt5) as a key factor controlling ventral midbrain neural progenitor identity and dopamine neuron differentiation. Emerging evidence also indicated the involvement of Dmrt5 function in cortical neurogenesis. Using state-of-the-art molecular and cellular tools and genetically engineered animal models, we aim to gain in depth understanding the role of Dmrt5 in forebrain and midbrain development and the underlying molecular cascade.
Model neuropsychiatric diseases with patient iPSCs
Recent genomic 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. However, how the genetic variances cause dysfunction of the mind remain largely unknown. Our group has developed protocols to generate midbrain dopamine neurons and cortical interneurons, respectively, from hESCs and hiPSCs. These are two of the three major neurotransmitter phenotypes affected in psychiatric patients. We are developing cellular model to study the effects of genetic variants in neuronal development and pathophysiology using hiPSCs derived from patients with neuropsychiatric diseases.
Cell based therapy for neurodegenerative disorders
Neural transplantation remains a promising therapy to treat neurodegenerative diseases such as Parkinson's and Huntington's disease. These are characterised by preferential loss of dopamine neurons in the substantia nigra and GABAergic projection neurons in the striatum. Another objective of our group is to generate transplantable nigral and striatal progenitors from human pluripotent stem cells using culture media compatibles with clinical applications. In addition, we are using these culture systems as in vitro model of development to study the molecular mechanisms controlling neuronal specification during early mammalian development.
- European Commission (FP7)
- The Wellcome Trust
- Medical Research Council
- Lucia Cardo
- Marija Fjodorova
- Craig Joyce
- Zoe Noakes
- John Pflug
- Krishanthi Sinnadurai
- Claudia Tamburini
- Matthieu Trigano
- Fraser Young