A human in vitro model of Duchenne muscular dystrophy muscle formation and contractility

Nesmith, Alexander P.; Wagner, Matthew A.; Pasqualini, Francesco S.; O’Connor, Blakely B.; Pincus, Mark J.; August, Paul R.; Parker, Kevin Kit

doi:10.1083/jcb.201603111

Cited by 61 publications

(65 citation statements)

References 39 publications

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“…Using disease-specific iPS cell-derived myoblasts, and this approach, patient-specific customized tissue models are also possibly in the future. It is believed that creating a disease-specific model will be very useful for understanding the specific disease mechanisms and drug discovery for its treatment 47 – 49 . In order to effectively apply an engineered tissue construct as an in-vitro tissue model, a new analysis system will be important.…”

Section: Discussionmentioning

confidence: 99%

Engineered Human Contractile Myofiber Sheets as a Platform for Studies of Skeletal Muscle Physiology

Takahashi

Shimizu

Okano

2018

Sci Rep

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Skeletal muscle physiology and the mechanisms of muscle diseases can be effectively studied by an in-vitro tissue model produced by muscle tissue engineering. Engineered human cell-based tissues are required more than ever because of the advantages they bring as tissue models in research studies. This study reports on a production method of a human skeletal myofiber sheet that demonstrates biomimetic properties including the aligned structure of myofibers, basement membrane-like structure of the extracellular matrix, and unidirectional contractile ability. The contractile ability and drug responsibility shown in this study indicate that this engineered muscle tissue has potential as a human cell-based tissue model for clinically relevant in-vitro studies in muscle physiology and drug discovery. Moreover, this engineered tissue can be used to better understand the relationships between mechanical stress and myogenesis, including muscle growth and regeneration. In this study, periodic exercise induced by continuous electrical pulse stimulation enhanced the contractile ability of the engineered myofibers and the secretion of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) from the exercising myofibers. Since the physiology of skeletal muscle is directly related to mechanical stress, these features point to application as a tissue model and platform for future biological studies of skeletal muscle including muscle metabolism, muscle atrophy and muscle regeneration.

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Section: Discussionmentioning

confidence: 99%

Engineered Human Contractile Myofiber Sheets as a Platform for Studies of Skeletal Muscle Physiology

Takahashi

Shimizu

Okano

2018

Sci Rep

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“…Human pluripotent stem cells (hPSCs) 13 – 15 represent attractive cell sources for engineering biomimetic skeletal muscle due to unlimited proliferative potential, their ability to differentiate into myogenic cells 16 – 22 , maintain pathological phenotypes 21 , 23 – 26 , and their suitability for genome editing to study disease variants in same genetic background or correct underlying mutations. Skeletal muscle cells can be derived from hPSCs via small molecule differentiation 14 , 16 , 21 , 22 , 27 , 28 or direct reprogramming 17 , 18 , 20 , 29 , 30 .…”

Section: Introductionmentioning

confidence: 99%

Engineering human pluripotent stem cells into a functional skeletal muscle tissue

et al. 2018

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The generation of functional skeletal muscle tissues from human pluripotent stem cells (hPSCs) has not been reported. Here, we derive induced myogenic progenitor cells (iMPCs) via transient overexpression of Pax7 in paraxial mesoderm cells differentiated from hPSCs. In 2D culture, iMPCs readily differentiate into spontaneously contracting multinucleated myotubes and a pool of satellite-like cells endogenously expressing Pax7. Under optimized 3D culture conditions, iMPCs derived from multiple hPSC lines reproducibly form functional skeletal muscle tissues (iSKM bundles) containing aligned multi-nucleated myotubes that exhibit positive force–frequency relationship and robust calcium transients in response to electrical or acetylcholine stimulation. During 1-month culture, the iSKM bundles undergo increased structural and molecular maturation, hypertrophy, and force generation. When implanted into dorsal window chamber or hindlimb muscle in immunocompromised mice, the iSKM bundles survive, progressively vascularize, and maintain functionality. iSKM bundles hold promise as a microphysiological platform for human muscle disease modeling and drug development.

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“…To our knowledge, none of the existing human DMD in vitro models, either based on tissue-derived myoblasts (16) or on the differentiation of induced pluripotent stem cells (17–21), have been used for studying DMD during the ontogeny of the skeletal muscle lineage. Moreover, original protocols for in vitro myogenesis from human pluripotent stem cells (reviewed in (22)) use transgene overexpression or/and cell sorting procedures, and thereby, miss the steps preceding skeletal muscle commitment, e.g.…”

Section: Introductionmentioning

confidence: 99%

Myogenesis modelled by human pluripotent stem cells uncovers Duchenne muscular dystrophy phenotypes prior to skeletal muscle commitment

Mournetas

Massouridès

Dupont

et al. 2019

Preprint

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19Duchenne muscular dystrophy (DMD) causes severe disability of children and death of young men, with an 20 incidence of approximately 1/5,000 male births. Symptoms appear in early childhood, with a diagnosis made 21 around 4 years old, a time where the amount of muscle damage is already significant, preventing early 22 therapeutic interventions that could be more efficient at halting disease progression. In the meantime, the 23 precise moment at which disease phenotypes arise -even asymptomatically -is still unknown. Thus, there is a 24 critical need to better define DMD onset as well as its first manifestations, which could help identify early 25 disease biomarkers and novel therapeutic targets. 26In this study, we have used human induced pluripotent stem cells (hiPSCs) from DMD patients to model 27 skeletal myogenesis, and compared their differentiation dynamics to healthy control cells by a comprehensive 28 multi-omics analysis. Transcriptome and miRnome comparisons combined with protein analyses at 7 time 29 points demonstrate that hiPSC differentiation 1) mimics described DMD phenotypes at the differentiation 30 endpoint; and 2) homogeneously and robustly recapitulates key developmental steps -mesoderm, somite, 31 skeletal muscle -which offers the possibility to explore dystrophin functions and find earlier disease 32 biomarkers. 33Starting at the somite stage, mitochondrial gene dysregulations escalate during differentiation. We also 34 describe fibrosis as an intrinsic feature of skeletal muscle cells that starts early during myogenesis. In sum, our 35 data strongly argue for an early developmental manifestation of DMD whose onset is triggered before the 36 entry into the skeletal muscle compartment, data leading to a necessary reconsideration of dystrophin 37 functions during muscle development.Duchenne muscular dystrophy (DMD) is a rare genetic disease, but it is the most common form of myopathy 40 affecting approximately one in 5,000 male births and very rarely female. In this recessive X-linked monogenic 41 disorder, mutations in the DMD gene lead to the loss of a functional dystrophin protein, resulting in a 42 progressive -yet severe -muscle wasting phenotype (1). In patients, symptoms usually appear in early 43 childhood (2-5 years old) and worsen with age, imposing the use of wheelchair before 15 and leading to 44 premature death by cardiac and/or respiratory failure(s) mostly around 30 years of age (2). 45At the age of diagnosis, around 4 years old, muscles of DMD patients have already suffered from the pathology 46 (3,4). Several reviews pointed out the limitations of current disease biomarkers, which fail to detect the 47 development of DMD specifically and at an early age (5,6). Meanwhile, no treatment is available to stop this 48 degenerative disease yet. Developing therapies aim at restoring the expression of dystrophin in muscle cells 49 but, so far, the level stays too low to be beneficial to patients (7). The absence of both reliable biomarkers and 50 effective therapies stress the need o...

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A human in vitro model of Duchenne muscular dystrophy muscle formation and contractility

Abstract: Using a tongue-inspired in vitro platform, Nesmith et al. demonstrate that DMD myoblasts fail to align and polarize with respect to extracellular matrix cues in the same manner as healthy myoblasts, resulting in diminished myotube formation and weaker contractile strength.

Cited by 61 publications

References 39 publications

Engineered Human Contractile Myofiber Sheets as a Platform for Studies of Skeletal Muscle Physiology

Engineered Human Contractile Myofiber Sheets as a Platform for Studies of Skeletal Muscle Physiology

Engineering human pluripotent stem cells into a functional skeletal muscle tissue

Myogenesis modelled by human pluripotent stem cells uncovers Duchenne muscular dystrophy phenotypes prior to skeletal muscle commitment

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