Research

Goal

• • Our research aims to leverage human pluripotent stem cells and optogenetic engineering to develop advanced, biologically relevant neuronal models. These systems enable us to explore fundamental mechanisms underlying human diseases and developmental processes, and facilitate the advancement of effective cell therapy strategies.

I. Modeling Human Diseases Using hPSC-Derived Neurons

• • Our laboratory generates human neurons derived from human pluripotent stem cells (hPSCs) to accurately model neurological diseases influenced by genetic factors, pharmaceuticals, neurotoxins, or pathogenic agents. Through these models, we specifically target diseases affecting critical areas of the nervous system, including the brain, dorsal root ganglion, and the enteric nervous system. Our previous research has successfully created models for Parkinson’s disease, peripheral neuropathies, and enteric nervous disorders. For instance, in Parkinson’s disease modeling, we have examined how genetic and environmental factors influence neuronal survival and function. By leveraging these advanced cellular models, we dissect molecular mechanisms underlying disease pathogenesis, evaluate potential therapeutic responses, and identify promising drug targets in clinically relevant human neuronal systems.

  • References: Oh, Y. et al., Nat. Neurosci., 2017; Oh, Y. BMB Rep., 2019; Mukherjee-Clavin, B. et al., Nat. Biomed. Eng., 2019; Choi, I.Y., et al., eLife, 2020; Lee, H. et al., Nat. Neurosci., 2021; Oh, Y., Front. Cell Dev. Biol., 2023

  • Supported by grants RS-2021-DD121219, KFRM-2021M3E5E5096744, RS-2023-00266171

       Neuropathological Brain Map of Lewy Body Dementia

• • Lewy body dementia (LBD) is the third most common dementia after Alzheimer's disease and vascular dementia, and it is hard to distinguish early symptoms from Alzheimer's disease or Parkinson's disease (PD). LBD patients also suffer from problems in thinking, movement, behavior, and emotion, which may be caused by the abnormal alpha-synuclein (α-syn) protein aggregation in the brain; its diagnosis is Lewy body disease. There are two main types of LBD: dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). Up to 80% of patients with PD progress to dementia, but there are no mechanistic studies at the brain region and cellular level with PD patients who do not progress to dementia.The Braak theory that abnormal α-syn aggregates, i.e., Lewy bodies (LB) lesions, begin in the olfactory bulb, spread synaptically like prions to the upper brain regions (brainstem, limbic system, cortex), and express various clinical symptoms, is widely accepted as the etiology of LBD. Identification of the brain map of propagation of LB lesions in the brain region and furthermore at the cellular level is important for the classification of LBD and for the establishment of a treatment strategy through novel target control. We are working to construct a neuropathological brain map of LB lesion propagation in LBD by effectively utilizing hPSC-derived neurons with α-syn aggregation-facilitating system (opto-α-syn aggregation system).

  • Reference: Kim. M.S. et al., Cell Stem Cell, 2023

  • Supported by a grant RS-2022-KH127042

II. Modeling Human Development using hPSC-Derived Neurons

• • Our team investigates critical aspects of human neuronal development by utilizing hPSCs. We employ directed differentiation techniques to generate neural progenitors from stem cells, subsequently guiding these progenitors to mature into fully functional neurons. Furthermore, we co-culture these differentiated neurons with target cell populations, such as other neural cells or myocytes, to study neuronal maturation, synaptogenesis, and neurotransmitter dynamics. Our studies reveal key insights into the pathways and mechanisms governing neuronal development and plasticity. Previous landmark studies from our group have demonstrated the ability to recapitulate developmental processes and synaptic interactions critical for understanding developmental disorders, providing foundational knowledge necessary for therapeutic advancements.

  • References: Kim, Y.J. et al., Cell Stem Cell, 2014; Oh, Y. et al., Cell Stem Cell, 2016

  • Supported by grants RS-2017-NR023376, RS-2018-NR031971

IIIa. Optogenetic Approaches for Biologically Relevant Modeling: Opto-Aggregation

• • We employ advanced optogenetic technologies to accelerate the aggregation of disease-relevant proteins, facilitating rapid and efficient modeling of neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. By harnessing optogenetic tools, we significantly shorten the aggregation timeframe from decades to mere hours, enabling rapid investigation into the pathogenic roles of aggregated proteins. This accelerated model allows us to analyze the biochemical and structural properties of protein aggregates, explore cellular responses, and evaluate therapeutic strategies designed to mitigate disease progression.

  • References: Yoo, H. et al., BMB Rep., 2022; Kim. M.S. et al., Cell Stem Cell, 2023

  • Supported by grants RS-2019-NR042310, RS-2020-NR048009, RS-2021-DD121219; RS-2022-KH127042

       Opto-α-syn system (OASIS) for Parkinson’s Disease Drug Discovery

• • We utilize the optogenetics-assisted alpha-synuclein aggregation induction system (OASIS; Kim et al., Cell Stem Cell, 2023) for Parkinson's disease drug discovery and development. OASIS rapidly induces alpha-synuclein aggregates and neuronal toxicity in human induced pluripotent stem cell (hiPSC)-derived midbrain dopaminergic neurons and organoids, effectively mimicking Parkinson’s disease pathology. Our lab leverages this advanced model to perform high-content compound screening, identifying promising drug candidates such as BAG956. BAG956 has shown efficacy by promoting the autophagic clearance of pathological alpha-synuclein aggregates both in vitro and in vivo, demonstrating significant potential as a neuroprotective agent. The OASIS model aligns with the FDA Modernization Act 2.0, emphasizing human-based models and providing a robust preclinical platform to accelerate the development of effective treatments for Parkinson’s disease.

  • Reference: Kim. M.S. et al., Cell Stem Cell, 2023

  • Supported by grants RS-2020-NR048009, RS-2021-DD121219

IIIb. Optogenetic Approaches for Biologically Relevant Modeling: Opto-Signaling

• • Our lab utilizes sophisticated optogenetic tools to precisely control cellular signaling pathways through photoactivatable proteins. We manipulate signaling pathways such as FGF, TGFβ, MAPK, PI3K/AKT, and SMAD, achieving precise spatial and temporal regulation. This approach allows detailed analysis of signaling dynamics, elucidating their roles in cellular functions like differentiation, proliferation, and apoptosis. These optogenetically engineered models provide critical insights into complex biological phenomena, significantly advancing our understanding of cellular signaling mechanisms and their implications in disease states and therapeutic intervention.

  • Reference: Choi, I.Y. et al., Biomaterials, 2021

IV. Development of Neuronal Progenitors for Cell Therapy

• • We are committed to developing therapeutic-grade neuronal progenitor cells derived from hPSCs aimed at clinical regenerative medicine applications. Our comprehensive protocols include progenitor cell generation, expansion, purification, and stringent quality control measures to ensure their safety, purity, and efficacy. These neuronal progenitors are formulated into injectable preparations for cell therapy, which are transplanted into animal models mimicking neurological conditions such as Parkinson’s disease and dementia. Our unpublished studies (manuscripts in preparation) have demonstrated significant functional restoration, effective neuronal integration, and improved neurological outcomes following transplantation in animal models of neurological disorders. These promising results support the potential clinical translation of our neuronal progenitors and pave the way toward therapeutic interventions for neurodegenerative diseases.

  • References: Kim, N.H. et al., Materials, 2020; Kim, N.H. et al., Anal. Chim. Acta, 2021; Moon, H. et al., Front. Cell Dev. Biol., 2023; Yong, S.H. et al., BMB Rep., 2024

  • Supported by a grant RS-2019-NR037362

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