Human induced pluripotent stem cells (hiPSCs) now provide unprecedented opportunities for cell replacement approaches, disease modeling and drug discovery in patient-specific manner. Particularly Lee lab is focusing on neural crest lineage (including peripheral neurons, Schwann cells, melanocytes) and skeletal muscle.
Neural crest, 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+ sympathetic neurons and their functional connection to target tissues (cardiac syncytia), which will lead us to investigate aberrant neuromodulation in patient-specific manner.
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+ nociceptive and MRGPRX1::GFP+ pruriceptive neurons.
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 the Lee 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.
Skeletal muscle cells, in vitro myogenesis, and muscular dystrophies
We developed a new methodology to directly derive and prospectively isolate thousands of millions of expandable and fusion-competent myoblasts from hESCs/hiPSCs. Using multiple genetic reporter hESC lines, we are recapitulating step-wise human myogenesis, comprising pluripotent stem cells, somite cells, adipomyocytes and putative satellite stem cells. Further, hiPSCs of Duchenne muscular dystrophy and facioscapulohumeral muscular dystrophy are providing us unique opportunities to learn more about the devastating muscular dystrophies.
Lab Website: Gabsang Lee Lab
Stem Cell Core Facility
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Lee G, Papapetrou EP, Kim HS, Chambers SM, Tomishima MJ, Fasano CA, Viale A, Tabar V, Sadlain M, Studer L. Modeling Pathogenesis and Treatment of Familial Dysautonomia using patient-specific iPSCs. Nature 2009 461: 402-406. PMID 19693009
Lee G*, Ramirez CN, KimH, Zeltner N, Liu B, Radu C, Bhinder B, Kim YJ, Choi IY, Mukherjee-Clavin B, Djaballh H, Studer L*. Large-scale screening using familial dysautonomia induced pluripotent stem cells identifies compounds that rescue IKBKAP expression. Nature Biotechnology 2012 30:1244-1280. PMID 23159879 * Corresponding Author
Kim YJ, Lim HT, Li Z, Oh Y, Kovlyagina I, Choi IY, Dong XZ, Lee G*. Generation of multipotent induced neural crest by direct reprogramming of human postnatal fibroblasts with a single transcription factor. Cell Stem Cell 2014 15:497-506. PMID: 25158936 * Corresponding Author
Choi IY, Lim HT, Estrellas K, Mula J, Cohen TV, Zhang Y, Donnelly CJ, Richard JP, Kim YJ, Kim HS, Kazuki Y, Oshimura M, Li HL, Hotta A, Rothstein J, Maragakis N, Wager K*, Lee G*. Concordant but varied phenotypes among patient-specific myoblasts of Duchenne muscular dystrophy revealed by a human iPSC-based model. Cell Reports 2016 15:2301-12. PMID: 27239027* Corresponding Author
Oh YH, Cho GS, Li Z, Hong I, Zhu R, Kim MJ, Kim YJ, Tampakakis E, Tung L, Huganir R, Dong X, Kwon C*, Lee G*. Functional coupling with cardiac muscle promotes maturation of hPSC-derived sympathetic neurons. Cell Stem Cell 2016 PMID: 27320040 * Corresponding Author