Duchenne Muscular Dystrophy Patient iPSCs—Derived Skeletal Muscle Organoids Exhibit a Developmental Delay in Myogenic Progenitor Maturation
Background: Duchenne muscular dystrophy (DMD), which affects 1 in 3500 to 5000 newborn boys worldwide, is characterized by progressive skeletal muscle weakness and degeneration. The reduced muscle regeneration capacity presented by patients is associated with increased fibrosis. Satellite cells (SCs...
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2025-07-01
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| author | Urs Kindler Lampros Mavrommatis Franziska Käppler Dalya Gebrehiwet Hiluf Stefanie Heilmann-Heimbach Katrin Marcus Thomas Günther Pomorski Matthias Vorgerd Beate Brand-Saberi Holm Zaehres |
| author_facet | Urs Kindler Lampros Mavrommatis Franziska Käppler Dalya Gebrehiwet Hiluf Stefanie Heilmann-Heimbach Katrin Marcus Thomas Günther Pomorski Matthias Vorgerd Beate Brand-Saberi Holm Zaehres |
| author_sort | Urs Kindler |
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| description | Background: Duchenne muscular dystrophy (DMD), which affects 1 in 3500 to 5000 newborn boys worldwide, is characterized by progressive skeletal muscle weakness and degeneration. The reduced muscle regeneration capacity presented by patients is associated with increased fibrosis. Satellite cells (SCs) are skeletal muscle stem cells that play an important role in adult muscle maintenance and regeneration. The absence or mutation of dystrophin in DMD is hypothesized to impair SC asymmetric division, leading to cell cycle arrest. Methods: To overcome the limited availability of biopsies from DMD patients, we used our 3D skeletal muscle organoid (SMO) system, which delivers a stable population of myogenic progenitors (MPs) in dormant, activated, and committed stages, to perform SMO cultures using three DMD patient-derived iPSC lines. Results: The results of scRNA-seq analysis of three DMD SMO cultures versus two healthy, non-isogenic, SMO cultures indicate reduced MP populations with constant activation and differentiation, trending toward embryonic and immature myotubes. Mapping our data onto the human myogenic reference atlas, together with primary SC scRNA-seq data, indicated a more immature developmental stage of DMD organoid-derived MPs. DMD fibro-adipogenic progenitors (FAPs) appear to be activated in SMOs. Conclusions: Our organoid system provides a promising model for studying muscular dystrophies in vitro, especially in the case of early developmental onset, and a methodology for overcoming the bottleneck of limited patient material for skeletal muscle disease modeling. |
| format | Article |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-07-01 |
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| spelling | doaj-art-0f0dccbf997d4a41bf8081ce1d588a0d2025-08-20T03:28:28ZengMDPI AGCells2073-44092025-07-011413103310.3390/cells14131033Duchenne Muscular Dystrophy Patient iPSCs—Derived Skeletal Muscle Organoids Exhibit a Developmental Delay in Myogenic Progenitor MaturationUrs Kindler0Lampros Mavrommatis1Franziska Käppler2Dalya Gebrehiwet Hiluf3Stefanie Heilmann-Heimbach4Katrin Marcus5Thomas Günther Pomorski6Matthias Vorgerd7Beate Brand-Saberi8Holm Zaehres9Department of Anatomy and Molecular Embryology, Institute of Anatomy, Faculty of Medicine, Ruhr University Bochum, 44801 Bochum, NRW, GermanyDepartment of Anatomy and Molecular Embryology, Institute of Anatomy, Faculty of Medicine, Ruhr University Bochum, 44801 Bochum, NRW, GermanyDepartment of Anatomy and Molecular Embryology, Institute of Anatomy, Faculty of Medicine, Ruhr University Bochum, 44801 Bochum, NRW, GermanyDepartment of Anatomy and Molecular Embryology, Institute of Anatomy, Faculty of Medicine, Ruhr University Bochum, 44801 Bochum, NRW, GermanyInstitute of Human Genetics, NGS Core Facility, Faculty of Medicine, University of Bonn, 53127 Bonn, NRW, GermanyMedical Proteom Center, Faculty of Medicine, Ruhr University Bochum, 44801 Bochum, NRW, GermanyDepartment of Molecular Biochemistry, Faculty of Chemistry and Biochemistry, Ruhr University Bochum, 44801 Bochum, NRW, GermanyDepartment of Neurology with Heimer Institute for Muscle Research, Faculty of Medicine, University Hospital Bergmannsheil, Ruhr University Bochum, 44789 Bochum, NRW, GermanyDepartment of Anatomy and Molecular Embryology, Institute of Anatomy, Faculty of Medicine, Ruhr University Bochum, 44801 Bochum, NRW, GermanyDepartment of Anatomy and Molecular Embryology, Institute of Anatomy, Faculty of Medicine, Ruhr University Bochum, 44801 Bochum, NRW, GermanyBackground: Duchenne muscular dystrophy (DMD), which affects 1 in 3500 to 5000 newborn boys worldwide, is characterized by progressive skeletal muscle weakness and degeneration. The reduced muscle regeneration capacity presented by patients is associated with increased fibrosis. Satellite cells (SCs) are skeletal muscle stem cells that play an important role in adult muscle maintenance and regeneration. The absence or mutation of dystrophin in DMD is hypothesized to impair SC asymmetric division, leading to cell cycle arrest. Methods: To overcome the limited availability of biopsies from DMD patients, we used our 3D skeletal muscle organoid (SMO) system, which delivers a stable population of myogenic progenitors (MPs) in dormant, activated, and committed stages, to perform SMO cultures using three DMD patient-derived iPSC lines. Results: The results of scRNA-seq analysis of three DMD SMO cultures versus two healthy, non-isogenic, SMO cultures indicate reduced MP populations with constant activation and differentiation, trending toward embryonic and immature myotubes. Mapping our data onto the human myogenic reference atlas, together with primary SC scRNA-seq data, indicated a more immature developmental stage of DMD organoid-derived MPs. DMD fibro-adipogenic progenitors (FAPs) appear to be activated in SMOs. Conclusions: Our organoid system provides a promising model for studying muscular dystrophies in vitro, especially in the case of early developmental onset, and a methodology for overcoming the bottleneck of limited patient material for skeletal muscle disease modeling.https://www.mdpi.com/2073-4409/14/13/1033skeletal muscleorganoidsmyogenesismyogenic progenitorssatellite cellsFAPs |
| spellingShingle | Urs Kindler Lampros Mavrommatis Franziska Käppler Dalya Gebrehiwet Hiluf Stefanie Heilmann-Heimbach Katrin Marcus Thomas Günther Pomorski Matthias Vorgerd Beate Brand-Saberi Holm Zaehres Duchenne Muscular Dystrophy Patient iPSCs—Derived Skeletal Muscle Organoids Exhibit a Developmental Delay in Myogenic Progenitor Maturation Cells skeletal muscle organoids myogenesis myogenic progenitors satellite cells FAPs |
| title | Duchenne Muscular Dystrophy Patient iPSCs—Derived Skeletal Muscle Organoids Exhibit a Developmental Delay in Myogenic Progenitor Maturation |
| title_full | Duchenne Muscular Dystrophy Patient iPSCs—Derived Skeletal Muscle Organoids Exhibit a Developmental Delay in Myogenic Progenitor Maturation |
| title_fullStr | Duchenne Muscular Dystrophy Patient iPSCs—Derived Skeletal Muscle Organoids Exhibit a Developmental Delay in Myogenic Progenitor Maturation |
| title_full_unstemmed | Duchenne Muscular Dystrophy Patient iPSCs—Derived Skeletal Muscle Organoids Exhibit a Developmental Delay in Myogenic Progenitor Maturation |
| title_short | Duchenne Muscular Dystrophy Patient iPSCs—Derived Skeletal Muscle Organoids Exhibit a Developmental Delay in Myogenic Progenitor Maturation |
| title_sort | duchenne muscular dystrophy patient ipscs derived skeletal muscle organoids exhibit a developmental delay in myogenic progenitor maturation |
| topic | skeletal muscle organoids myogenesis myogenic progenitors satellite cells FAPs |
| url | https://www.mdpi.com/2073-4409/14/13/1033 |
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