Muscle wasting, caused by aging, genetic mutations, cancan-associated cachexia, or traumatic injury, can result in significant functional impairment, and is a challenging clinical problem with a significant socioeconomic burden on our healthcare system. We have shown that functional myoblasts are readily derived from human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), allowing us to begin to study Duchenne muscular dystrophy (DMD), the most common genetic disorder of muscle. However, we know little about i) how early myogenic events are genetically controlled during development, ii) whether embryonic PAX7 expressing myogenic stem/progenitor cells adopt postnatal `satellite-like' fate, and iii) how DMD is occurred in skeletal muscle stem/progenitor cell stage as well as their relevance for cell replacement therapy. First, using multiple genetic reporter lines to recapitulate human myogenic events, we will depict a time- course analysis of transcriptional landscape followed by `loss of function' analysis to address essential questions regarding which critical cell intrinsic/extrinsic component(s) govern the skeletal muscle specification process and stem cell maintenance. Secondly, by performing serial transplantation of human PAX7::GFP+ putative skeletal muscle stem/progenitor cells in mouse model, we will interrogate how the embryonic cells become to postnatal satellite-like cell fate. Thirdly, based on our observation on DYSTROPHIN expression in human skeletal muscle stem/progenitor cells, we will investigate stage-specific role(s) of DYSTROPHIN and its long intergenic non- coding RNAs (LincRNAs), in healthy and DMD condition. In addition, we will interrogate in vivo regeneration ability of patient-specific PAX7::GFP+ cells of genetically corrected DMD-hiPSC lines. Our proposed experiments are expected to expand and strengthen our current conception of myogenic specification events, and to accelerate a wide range of research on skeletal muscle disorders, e.g. traumatic muscle damages, genetic muscular dystrophies, neuromuscular diseases, type II diabetes and cancer-induced cachexia.
Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy, children with DMD suffer from extensive muscle loss, and they usually die in their late teens or early 20s. With our expertise on disease modeling with human induced pluripotent stem cells (hiPSCs) and our novel methodology to direct hiPSCs into myogenic lineage, we propose to study how the embryonic PAX7::GFP+ cells (derived from hESCs/hiPSCs) are shaped in transcriptional and functional aspects, and to investigate fundamental causes of DMD in with patient-specific myogenic stem/progenitor cells. These approaches will pave a way to deal with various skeletal muscle wasting conditions.
| Kim, Sangjune; Yun, Seung Pil; Lee, Saebom et al. (2018) GBA1 deficiency negatively affects physiological ?-synuclein tetramers and related multimers. Proc Natl Acad Sci U S A 115:798-803 |
| Oh, Yohan; Zhang, Feiran; Wang, Yaqing et al. (2017) Zika virus directly infects peripheral neurons and induces cell death. Nat Neurosci 20:1209-1212 |
| Kurapati, Sravya; Sadaoka, Tomohiko; Rajbhandari, Labchan et al. (2017) Role of the JNK Pathway in Varicella-Zoster Virus Lytic Infection and Reactivation. J Virol 91: |
