Human Brain Organoid Models of Neurodegenerative Diseases
Given that obtaining live brain tissue from patients considered the ideal research material to understand underlying mechanisms of human neurological diseases is almost inaccessible, there is a growing interest in modeling neurological diseases with human neural cells derived from hPSCs. Our group has longstanding interest in stem cell biology, with a focus on leveraging stem cell differentiation capabilities for modeling human neurodegenerative diseases and establishing potential therapeutic intervention. Brain organoid, 3D structures recapitulating many aspects of the brain, is recently regarded as the most promising model that allows to study the fundamental properties of neuronal pathophysiology. We have developed a method to generate a human 3D midbrain organoid model derived from hPSCs and grown to mimic the structure of parts of the brain to study disease pathogenesis and allow examination of the progression of damage caused by Parkinson’s disease (PD).
The goal of our research is to understand the mechanisms underlying human neurodegeneration by applying state-of-the-art multidisciplinary approach including stem cell biology, CRISPR/Cas9 genome engineering, fluorescence probe-based live imaging system and neurophysiology techniques, and ultimately serve to drive work on new therapies.
Advance of brain organoid models
Understanding the fundamental mechanisms of apha-synuclein pathology and neuronal death
PD is a progressive movement disorder, characterized by a selective loss of DA neurons in SNpc. Numerous studies of PD genetics have identified genes associated with familial PD, many of which are involved in oxidative stress regulation, synaptic function as well as dysfunction of a lysosomal enzyme. The key pathophysiological hallmark of PD is the presence of intraneuronal protein inclusions named Lewy bodies (LBs) and aggregated forms of α-syn which are the main components of LBs. The pathogenesis of α-syn is considered the progressive conversion of soluble α-syn into insoluble aggregates through spontaneous nucleation. Suggested mechanism for this pathological conversion is the cell-to-cell transmission of α-syn under environmental and genetic perturbations. Transcellular transport of α-syn can occur through synaptic transmission or following the release of exosomes. We are working on finding the fundamental mechanisms of α-syn pathology associated to DA neuronal death. Our DA neuron tracing and α-syn monitoring dual reporter system allows us to observe the degree of α-syn aggregates and LBs formations as well as spatiotemporal monitoring of DA neuronal degeneration.
Preclinical research of brain organoid-based drug testing and screening platform
Preclinical research is the initial stage of therapeutic development to discover promising candidates for clinical trials. In this critical stage, disease models should faithfully recapitulate all key pathophysiological features of the human diseases. The aim is to show high reliability and efficacy of novel drugs that ameliorate the pathological condition. We have developed a robust method to generate midbrain organoids and successfully demonstrated that our midbrain organoids carrying PD-associated genetic perturbations recapitulated wide-ranging neurodegenerative phenotypes with α-syn pathologies, which are the key pathophysiological hallmarks of PD. This project is to establish a novel drug testing and screening platform by real-time tracing α-syn conjugated genetically encoded probes in fluorescently labelled dopaminergic neurons in the diseased midbrain organoid models. The overall purpose of this project is to elucidate the novel underlying mechanisms of synucleinopathy and enable the design of novel therapeutic strategies to reduce pathological a-syn aggregates, providing a more effective management of PD.
Generation of human microglia and investigation of their behaviour in the diseased milieu
Microglia are the innate immune cells in the CNS and lose their homeostatic molecular signature in the aging and neurodegenerative brains, showing increased basal levels of pro-inflammatory cytokines. This project initially focuses on incorporating hPSC-derived microglia to a PD brain organoid model that is clinically relevant and optimal for elucidating mechanisms pertaining to the pathogenesis of the disease. The overall purpose of this project is to investigate neuroinflammatory responses of hPSC-derived microglia and trace their morphologies and behaviors of genetically probed microglia in the disease milieu by a real-time monitoring system.