Research

Quality Control System for Parkinson's Disease Cell Therapy

• • Parkinson’s disease (PD) is a progressive, age-related neurodegenerative disease with noteworthy motor impairments, and is the second most common neurodegenerative disease after Alzheimer’s disease (AD). PD is primarily linked with the explicit loss of midbrain dopaminergic (mDA) neurons in the substantia nigra pars compacta (SNpc), and it physically displays as weakened movements in affected individuals. Because the key symptoms of PD result from the loss of the mDA neurons, transplanting the healthy mDA neural stem cells into the striatum region is one of powerful cell therapy strategies for PD. We are working on developing a novel real-time ultra-precision monitoring system for the quality control of human pluripotent stem cell (hPSC)-derived dopaminergic neural stem cells to treat neurodegenerative diseases, including Parkinson's disease. Funding source: NRF-2022M3A9H1014157, NRF-2019M3A9H1103783, HY-202100000000289

Optical Control of Signaling Pathways and Aggregation of Pathogenic Proteins in Human Stem Cells

• • Stem cell fate is largely determined by a complex cell signaling network. Our understanding and approaches to modulate such stem cell signaling networks is limited by the lack of precise control in single cells. In order to understand the operational principles of this network and physiological and pathological events, it is imperative to control signaling protein activities and subsequent cellular fates with great temporal and spatial precision. We have introduced light-sensing actuator modules into human pluripotent stem cells (hPSCs) to mimic fibroblast growth factor (FGF) signaling pathways via light illumination without using recombinant FGF protein. This method allowed us to maintain long-term stemness of the hPSCs. We are currently expanding this concept to the transforming growth factor beta (TGF beta) signaling pathway and the glial-derived neurotrophic factor (GDNF) signaling pathway, to control cellular fates and promote neuronal survival of hPSC-derived neurons. Furthermore, by utilizing the protein aggregation properties of light-sensing modules, we will accelerate the aggregation of pathogenic proteins , which will facilitate our understanding of the pathogenic mechanisms of proteinopathies. This project is expected to enhance our understanding of stem cell specification and utilization of stem cells in disease modeling, and ultimately lead to substantial advancements in modulation of transplanted cells in vivo. - adapted from the Lee lab homepage. Funding sources: KDDF-HN21C1258, NRF-2020R1A2C1009172, NRF-2019R1F1A1060296

Neuropathological Brain Map of Lewy Body Dementia

• • Lewy body dementia (LBD) is the third most common dementia after Alzheimer's disease (AD) 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. Funding sources: KDRC-HU22C0143, KDDF-HN21C1258, NRF-2020R1A2C1009172, NRF-2019R1F1A1060296

Neural Crest Cells, Autonomic Neurons, and Familial Dysautonomia

• • Previously, our group studied neural crest stem cells created from fibroblasts of patients with Familial Dysautonomia (FD), also known as Riley-Day syndrome, an inherited genetic condition that affects the peripheral nervous system. Although researchers know that FD is caused by a single point mutation in the IKBKAP gene, it is not clear  how symptoms, like inability to feel pain and changes in temperature, manifest. We found that FD-specific neural crest cells expressed low levels of genes needed to make autonomous neurons—the ones needed for the “fight-or-flight” response. The FD-specific neural crest cells also moved around less than normal neural crest cells. Moving forward, as an effort to discover novel drugs to treat FD, we performed high throughput screening with a compound library using FD patient-derived neural crest stem cells to look for compounds that increased gene expression and protein levels of autonomous neuron developmental components. These studies set a paradigm of hiPSC studies, including developing differentiation protocol, disease modeling with patient hiPSCs and high throughput drug screening. Now we are advancing from neural crest to autonomic neurons and multicellular system. Our PHOX2B::GFP+ve sympathetic neurons and their functional connection to target tissues (such as cardiac syncytia), which will lead us to investigate aberrant neuromodulation in patient-specific manner. - adapted from the Lee lab homepage. Funding sources: KFRM-2021M3E5E5096744, NRF-2018R1C1B5045395, NRF-2017R1A6A3A03010524, HY-201900000001678, HY-201800000001414, HY-201800000000616

Nociceptive/Pruriceptive Neurons and Congenital Pain Disorders

• • How our body can sense million of different stimuli with limited numbers of sensory neurons? How our ‘sensors’ can perceive specific stimulus?  The fate decision and physiological functions of individual sensory neurons should be choreographed by multiple molecular processes, which are closely related to the pathogenesis of many human pain disorders. Using iPSC lines of congenital sensory disorders, Congenital Insensitivity of Pain and Anhidrosis (CIPA) and Congenital Insensitivity of Pain (CIP), we are interrogating these questions with human TRPV1::GFP+ve nociceptive and MRGPRX1::GFP+ve pruriceptive neurons. - adapted from the Lee lab homepage. Funding sources: KFRM-2021M3E5E5096744, HY-201900000001678, HY-201800000001414

Schwann Cells and Charcot Marie Tooth 1A

• • Charcot-Marie-Tooth 1A (CMT1A) is one of the most common genetic diseases in peripheral nervous system. We have learned lots of information from animal models, but their genetics are yet exactly same as those of CMT1A patients. Recently, in our lab, the CMT1A-hiPSC-derived Schwann cells have provided us a new insight on the disease mechanism that is shared with Schwann cells derived from CMT1A-PDG-hESCs and induced neural crest of CMT1A fibroblasts. - adapted from the Lee lab homepage. Funding sources: KFRM-2021M3E5E5096744, HY-201900000001678, HY-201800000001414

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