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Yichen Li

Postgraduate Student

Research summary

Schizophrenia is a devastating mental disorder that affects about 1% of the total population. Patients with adolescent-onset schizophrenia (AOS) suffer from more severe symptoms and have a worse prognosis. The aetiology of schizophrenia is largely unknown. However, it is accepted as a neurodevelopmental disorder with a multifactorial genetic and environmental (e.g. inflammation) basis. It has been difficult to produce adequate animal models. Therefore we use in vitro stem cell strategies to study neural development in AOS. The human olfactory mucosa harbours stem cells that give rise to neurons. Olfactory ecto mesenchymal stem cells (OE-MSCs) in vitro may provide an accessible resource for studying the molecular mechanisms that underlie the abnormal neurodevelopment seen in schizophrenia. Accordingly, we have isolated OE-MSCs from 13 patients and 9 age and gender matched healthy controls. Using this material, we assess the stem cell properties, and performing functional assays addressing proliferation and migration. From the same subjects, we also obtained skin biopsies for generating patient derived induced pluripotent stem cells (iPSCs) with the ultimate aim of differentiation of cortical projection neurons and microglia. The differentiation of iPSCs into cortical projection neurons has been shown to recapitulate neurodevelopment in vivo, and generates cerebral cortex layer specific neurons. We assess the timing, quantity, morphology, synaptogenesis and synaptic maturity of neural cells during differentiation with and without iPSC-microglia. We run whole exome sequencing on patients and their parents, and have discovered one of our reprogrammed patient carries a mutation in SYNGAP1. SYNGAP1 encodes a GTPase-activating protein and governs synapse development. We also collect NGN2 induced neurons to perform transcriptomic study longitudinally, derived from 3 patients and 3 controls. We 3D-print bioreactors in 24-well plate to culture cerebral organoids in order to study mature neurons. Our ultimate goal is to dissect out convergent molecular pathways shared between patients with different genetic predispositions. 

 

Bibliography

I obtained a BSc in Biochemistry in The Netherlands and MRes in Neuroscience in UK. After graduation I worked for a year to screen for therapeutic compounds on iPSC-derived motor neurons for the treatment of Amyotrophic Lateral Sclerosis. Currently I am a D.Phil candidate and a Clarendon scholar at DPAG, associated with St. Anne's College.