Duchenne muscular dystrophy hiPSC-derived myoblast drug screen identifies compounds that ameliorate disease in mdx mice
Autor: | Shama R. Iyer, Congshan Sun, Richard M. Lovering, Gabsang Lee, Yazmin I. Rovira Gonzalez, In Young Choi, Kathryn R. Wagner, Peter Andersen, C. Conover Talbot |
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Rok vydání: | 2020 |
Předmět: |
musculoskeletal diseases
0301 basic medicine congenital hereditary and neonatal diseases and abnormalities Ginsenosides Myoblasts Skeletal Duchenne muscular dystrophy Induced Pluripotent Stem Cells Drug Evaluation Preclinical Mice Transgenic Mice 03 medical and health sciences 0302 clinical medicine Fenofibrate In vivo Animals Humans Medicine Myocyte Muscular dystrophy biology business.industry Skeletal muscle General Medicine medicine.disease Phenotype Muscular Dystrophy Duchenne 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Mice Inbred mdx biology.protein Cancer research Stem cell business Dystrophin Research Article |
Zdroj: | JCI Insight |
ISSN: | 2379-3708 |
Popis: | Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy. In the present study, when human induced pluripotent stem cells (hiPSCs) were differentiated into myoblasts, the myoblasts derived from DMD patient hiPSCs (DMD hiPSC–derived myoblasts) exhibited an identifiable DMD-relevant phenotype: myogenic fusion deficiency. Based on this model, we developed a DMD hiPSC–derived myoblast screening platform employing a high-content imaging (BD Pathway 855) approach to generate parameters describing morphological as well as myogenic marker protein expression. Following treatment of the cells with 1524 compounds from the Johns Hopkins Clinical Compound Library, compounds that enhanced myogenic fusion of DMD hiPSC–derived myoblasts were identified. The final hits were ginsenoside Rd and fenofibrate. Transcriptional profiling revealed that ginsenoside Rd is functionally related to FLT3 signaling, while fenofibrate is linked to TGF-β signaling. Preclinical tests in mdx mice showed that treatment with these 2 hit compounds can significantly ameliorate some of the skeletal muscle phenotypes caused by dystrophin deficiency, supporting their therapeutic potential. Further study revealed that fenofibrate could inhibit mitochondrion-induced apoptosis in DMD hiPSC–derived cardiomyocytes. We have developed a platform based on DMD hiPSC–derived myoblasts for drug screening and identified 2 promising small molecules with in vivo efficacy. |
Databáze: | OpenAIRE |
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