Therapeutic potential of human myogenic reserve cells in Duchenne Muscular Dystrophy
Dr. Thomas Laumonier, University of Geneva
Abstract (lay summary see below)
Duchenne Muscular Dystrophy (DMD) is a severe and progressive neuromuscular muscle-wasting disorder that affects 1/3500 males and caused by the lack of dystrophin. Currently there is no cure to stop muscle degeneration in DMD. Muscle stem cells (MuSC)-based cell therapy holds great potential because it would allow muscle regeneration and genetic complementation for patients suffering from muscular diseases.
However, the strategy still needs to be improved as the culture conditions still impinge the regenerative capacities of amplified MuSC. We demonstrated that human myogenic reserve cells (RC) generated in vitro, are similar to quiescent MuSC with properties required for their use in cell therapy i.e. they survive, they form new myofibers and they generate Pax7+ MuSC in vivo. Moreover, as compared to other MuSC, RC hold the advantage to be generated in vitro in number compatible with therapeutic applications. However, their regenerative capacity has not yet been tested in a DMD model.
Recently, we showed that human myogenic reserve cells (RC) are heterogenous for Pax7, with a Pax7High and a Pax7Low subpopulation. We performed bulk RNA-Seq on human RC subpopulations and our results suggest that the Pax7High RC are less primed to myogenic differentiation and adopt a more stem-like state. Thus, Pax7High subpopulation may constitute an appropriate stem cell source for potential therapeutic applications in DMD. In this specific one-year project, we will assess the therapeutic potential of human RC subpopulations (Pax7High and a Pax7Low) after transplantation in immunodeficient dystrophic mice. For this purpose, we will first define strategies to isolate viable human RC subpopulations as intracellular staining for Pax7 is not compatible with in vivo injections. We will then evaluate their survival using non-invasive bioluminescent techniques and assess their function in vivo upon engraftment. The proposed project will bring new information on the regenerative capacity of human RC subpopulations in pathological DMD conditions and will open major perspectives for the possible clinical use of human RC.
Lay summary
La dystrophie musculaire de Duchenne (DMD) est une maladie neuromusculaire grave et progressive. Il n'existe actuellement aucun remède pour guérir cette dégénérescence musculaire. La thérapie cellulaire a un grand potentiel thérapeutique car elle pourrait améliorer la régénération musculaire et restaurer l’expression de dystrophine chez les patients. Cependant, cette stratégie doit encore être améliorée car les conditions de culture réduisent dramatiquement les capacités régénératives des cellules souches musculaires (MuSC) amplifiées. Nous avons démontré que des MuSC humaines dites « reserve cells » (RC), générées in vitro, ont les propriétés requises pour leur utilisation en thérapie cellulaire. Dans ce projet, nous allons évaluer le potentiel thérapeutique de sous populations de RC humaines (Pax7High and a Pax7Low) dans des conditions pathologiques chez la souris. Ces travaux ouvriront des perspectives majeures pour une éventuelle utilisation clinique de sous populations de RC humaines.
Progetti
- Nuovi progetti di ricerca dal 2024
- L'importanza della ricerca
- Progetti finanziati
- Unstructured proteins as therapeutic targets for neuromuscular diseases
- Open and reproducible pipeline for the acquisition and analysis of muscle MRI data in Facioscapulohumeral Muscular Dystrophy
- Dissecting lysosomal signals to fight Pompe disease
- Functional properties and epigenetic signature of quiescent and early activated human muscle reserve cells
- Activation of human skeletal muscle stem cells:role of Orai3 ans its partner AHNAK2 in physiological condition and in Duchenne Muscular Dystrophy
- Understanding the clinical spectrum associated with VMA21 deficiency
- ANTXR2 as a key player in Collagen VI signaling in muscle stem cells: new therapeutic perspectives for COL6-related myopathies.
- Molecular mechanisms of complement activation and neuromuscular disruption by combinations of autoantibodies from patients with Myasthenia Gravis
- From the investigation of the role of SRSF1 in ALS/FTD to its targeting as a therapeutic strategy
- Molecular crosstalk between muscles and motor neurons and its role in neuromuscular circuit formation
- Molecular Diagnosis and Coping Mechanisms in Mitochondrial Myopathies
- IPRIMYO: Immune-privileged, immortal, myogenic stem cells for gene therapy of Muscular Dystrophy
- Effect of RYR1 mutations on muscle spindle function and their impact on the musculoskeletal system
- Therapeutic potential of human myogenic reserve cells in Duchenne Muscular Dystrophy
- Glutamine metabolism as a potential target for Duchenne Muscular Dystrophy
- Targeting protein s-acylation during Tubular Aggregate Myopathy
- Aggravating the phenotype of dystrophic mice for improving preclinical research and clinical translation for Duchenne muscular dystrophy
- Characterization of autoreactive T cells in Guillain-Barré syndrome
- A vascularized human muscle-on-a-chip to elucidate the contribution of endothelial-mesenchymal transition on the progression of muscular dystrophies
- Characterization of a novel form of ALS associated with changes in the sphingolipid metabolism
- Pre-clinical treatment of mouse models carrying recessive Ryr1 mutations with HDAC/DNA methyltransferase inhibitors.
- New aspects of TGFβ signaling in muscle homeostasis and regeneration
- Inhibition of sphingolipid synthesis as a treatment strategy for Duchenne muscular dystrophy
- Tamoxifen in Duchenne muscular dystrophy (TAMDMD)
- DNA aptamers against the DUX4 protein reveal novel therapeutic implications for FSHD
- Facilitating diagnosis of critical illness myopathy using muscle excitability testing
- Rapid Exploratory Imaging for High-resolution and Whole Extremity Coverage in MR Neurography
- Deciphering novel mechanisms and effectors contributing to muscle dysfunction in Myotonic Dystrophy Type I
- Can HDAC/DNA methyltransferase inhibitors improve muscle function in a congenital myopathy caused by recessive RYR1 mutations?
- Identification of the critical regulators of protein synthesis and degradation in human muscle atrophy
- Exploring peripheral B-cell-helper T cell phenotypes in the blood of patients with Myasthenia gravis using mass cytometry (CyTOF)
- Molecular signature, metabolic profile and therapeutic potential of human myogenic reserve cells
- A multicenter cross-sectional and longitudinal study of the Swiss cohort of Merosin-negative congenital muscular dystrophy
- Targeting NADPH oxidase 4 in models of Duchenne muscular dystrophy
- Characterizing the role of ER stress in C9orf72-linked ALS pathology
- Inducing mitophagy with Urolithin A to restore mitochondrial and muscle function in muscular dystrophy
- Motor unit action potentials analysis in patients with myopathies with a new wireless portable and multichannel Surface EMG device (WPM-SEMG)
- Role and therapeutic potential of PLIN3 in neuromuscular diseases
- Changes in ventilation distribution in children with neuromuscular disease using the insufflator/exsufflator technique: An observational study
- Mechanism and function of genome organization in muscle development and integrity
- Role and therapeutic potential of NADPH oxidases in a mouse model of Duchenne Muscular Dystrophy
- Characterization of pathological pathways activated in muscles of patients with congenital myopathies with disturbed Ca2+ homeostasis
- Creation of a study team to conduct an SMA 1-clinical trial at the Centre for Neuromuscular Diseases of the University Children's Hospital Basel (UKBB)
- Novel treatment to stop progressive neuropathy and muscle weakness in multifocal motor neuropathy
- Understanding the pathomechanisms leading to muscle alterations in Myotonic Dystrophy type I
- Automated volumetry and quantitative MRI to diagnose peripheral nerve lesions – translational proposal for a new clinical diagnostic imaging tool
- Novel approaches against Spinal Muscular Atrophy by targeting splicing regulators
- Protective effects and mechanisms of action of tamoxifen in mice with severe muscular diseases
- Role of the receptor FgfrL1 in the development of slow muscle fibers
- Muscle velocity recovery cycles: A new tool for early diagnosis of critical illness myopathy
- Generation of uncommitted human IPSC derived muscle stem cells for therapeutic applications
- Transposable vectors for dystrophin-expression in a murine model for muscular dystrophy
- Cardiac involvement in patients with Duchenne/Becker Muscular Dystrophy; an observational study
- Deciphering the pathogenic mechanisms of C9ORF72 ALS
- Enhancing estrogenic signalling to fight muscular dystrophies: Mechanisms of action and repurposing clinically approved drugs
- Mechanisms and therapeutic potential of modulating PGC‐1α to alter neuromuscular junction morphology and function
- Triggering human myoblast differentiation: from EGFR to myogenic transcription factors
- Improving cellular therapies of muscle dystrophies by uncovering epigenetic and signaling pathways of muscle formation
- Protein engineering in an attempt to increase the mechanical, integrin dependent cytoskeleton-matrix linkage in muscle fibers
- Muscle velocity recovery cycles: a new tool for characterization of muscle disease in vivo
- Excessive neurotrypsin activation and agrin cleavage-a pathogenic condition leading to sarcopenia-like muscle atrophy?
- Evaluation of novel treatment strategies for dyspherlinopathies in mouse models
- Cell therapy of LGMD2D by donor HLA-characterized human mesoangioblasts (hMABs) produced in GMP conditions
- In search of small molecules targeting protein-RNA complex: a novel approach against Spinal Muscular Atrophy
- Restoration of autophagy as a new strategy for the treatment of congenital muscular dystrophies
- Development of magnetic resonance methods for functional imaging of the skeletal muscle
- Targeting ER stress response: a potential mechanism for neuroprotection in Amyotrophic Lateral Sclerosis
- Generation of uncommitted human IPSC derived muscle stem cells for therapeutic applications
- Opuscolo progetti
- SEAL Therapeutics AG
- Meeting e workshop
- Partecipazione ad altre organizzazioni
- Registri dei pazienti
- La rete Myosuisse
FSRMM
- Chemin des Saules 4B
2013 Colombier - +41 78 629 63 92
- philippe.rognon@fsrmm.ch