Duchenne Muscular Dystrophy Patient iPSCs-Derived Skeletal Muscle Organoids Exhibit a Developmental Delay in Myogenic Progenitor Maturation
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Purification and Transplantation of Myogenic Progenitor Cell Derived Exosomes to Improve Cardiac Function in Duchenne Muscular Dystrophic Mice
Published on: April 10, 2019
Urs Kindler1,2, Lampros Mavrommatis1,3, Franziska Käppler1,3
1Department of Anatomy and Molecular Embryology, Institute of Anatomy, Faculty of Medicine, Ruhr University Bochum, 44801 Bochum, NRW, Germany.
Insights
This study demonstrates that 3D skeletal muscle organoids (SMOs) derived from Duchenne muscular dystrophy (DMD) patients reveal an immature developmental stage in myogenic progenitors (MPs) and activated fibro-adipogenic progenitors (FAPs), offering a new in vitro model for muscular dystrophy research.
Area of Science:
- Biomedical research
- Stem cell biology
- Regenerative medicine
Background:
- Duchenne muscular dystrophy (DMD) causes progressive muscle weakness and degeneration, linked to impaired muscle regeneration and fibrosis.
- Skeletal muscle stem cells (satellite cells) are crucial for muscle maintenance, but their function may be compromised in DMD due to dystrophin deficiency.
- Limited patient biopsies hinder research into DMD's cellular mechanisms.
Purpose of the Study:
- To establish and validate a 3D skeletal muscle organoid (SMO) system using DMD patient-derived induced pluripotent stem cells (iPSCs).
- To investigate the cellular and molecular characteristics of myogenic progenitors (MPs) and other cell types within DMD SMOs.
- To assess the utility of DMD SMOs as an in vitro model for studying muscular dystrophy.
Main Methods:
- Generation of 3D skeletal muscle organoids (SMOs) from three DMD patient-derived iPSC lines and two healthy control iPSC lines.
- Single-cell RNA sequencing (scRNA-seq) analysis of cells within DMD and healthy SMOs.
- Comparison of DMD SMO data with human myogenic reference atlas and primary satellite cell (SC) scRNA-seq data.
Main Results:
- DMD SMOs exhibited reduced myogenic progenitor (MP) populations with persistent activation and differentiation, trending towards embryonic and immature myotubes.
- scRNA-seq analysis indicated that DMD organoid-derived MPs are at a more immature developmental stage compared to controls.
- Activated fibro-adipogenic progenitors (FAPs) were observed in DMD SMO cultures.
Conclusions:
- The 3D skeletal muscle organoid (SMO) system provides a robust in vitro model for studying Duchenne muscular dystrophy (DMD), particularly for early-onset disease.
- This organoid approach effectively overcomes the challenge of limited patient material for skeletal muscle disease modeling.
- The findings highlight developmental immaturity and progenitor cell dysregulation in DMD, offering insights for therapeutic strategies.
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.
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