Muscle and tendon formation and repair

The team’s projects seek to discover the basic mechanisms underlying the development and repair of the musculo-skeletal system.

The musculoskeletal system is essential for body stability and movement. It is composed of bones, muscles and other supporting connective tissues.

Skeletal muscle development, growth and regeneration rely on muscle stem cells. A major goal of muscle research is to understand the signals that regulate the ability of muscle stem cells to self-renew and differentiate.

Muscle connective tissue is composed of specialized fibroblasts derived from mesenchymal stem cells. Connective tissue deregulation leads to fibrosis, a process attributed to excess deposition of extracellular matrix in response to injury, inflammation or aging. Fibrosis is also a major pathological feature of progressive myopathies.

Tendon and ligament repair remains a clinical challenge. One of the reasons of our inability to fully repair tendon and ligament is the lack of understanding tendon biology.

Research in our laboratory is focused on understanding the fundamental mechanisms underlying the development of skeletal muscles and associated connective tissues: tendon and muscle connective tissue. Musculoskeletal system formation is a coordinated process that requires the integration of different cell types. We focus on the cellular and molecular interactions between tendon, muscle and muscle connective tissue during development using animal models, as well as 2D and 3D in vitro culture systems.

In addition to classical signalling molecules, it is becoming clear that mechanical parameters play fundamental roles in the formation, homeostasis and repair of the musculoskeletal system. We are studying muscle mechanobiology and aim to identify the molecules that sense and respond to mechanical stimuli in order to control cell differentiation of muscle, tendon and fibroblast cells in an in vivo context.

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1) Skeletal muscle development, growth and regeneration rely on muscle stem cells. A major goal of muscle research is to understand the signals that regulate the ability of muscle stem cells to self-renew or differentiate. Skeletal muscle formation is based on successive and distinct waves of myogenesis. Foetal myogenesis is an important step for muscle growth and the generation of adult muscle stem cells, satellite cells. The source and the nature of the signals that regulate the proliferation and differentiation of muscle progenitors remain to be determined. Foetal muscle progenitors are not all equivalent in limb muscles. There is a sub- population of foetal muscle progenitors that display specific active signalling pathways at muscle tips, close to tendons. We aim to understand the function of this sub-population of muscle progenitors in muscle growth and patterning.

2) Skeletal muscles are formed of myogenic cells and fibroblasts of connective tissues. Classical surgical experiments in chicken embryos have shown that fibroblasts contain the positional information to drive spatial organisation of limb muscles and that muscle cells are naïve. We aim at identifying the molecular signature underlying connective tissue specification and differentiation during development and the molecular interactions between fibroblasts and myogenic cells that impact on muscle spatial organisation during limb development.

3) Tendon and ligament injuries have clinical importance since they can lead to disability affecting patient’s activities. Tendon/ligament repair remains a clinical challenge. One of the reasons of our inability to fully repair tendon or ligament is the lack of understanding of molecular aspects underlying tendon biology. Our objective is to identify the link between mechanical and molecular signals that regulate tendon cell differentiation. Tendon mechanobiology will be studied in vivo using animal models (chicken and zebrafish) but also in vitro using mesenchymal stem cells or primary tendon cells in a 3-dimensional (3D) culture system mimicking in vitro tendon formation. We aim to identify the molecular sensors of mechanical forces during tendon cell differentiation.

4) The absence of movement during development leads to severe developmental defects that mostly affect the musculoskeletal system. Similar symptoms are also observed in congenital myasthenic syndrome due to mutations in genes coding for proteins involved in the function of neuromuscular junction. The importance of mechanical activity has been largely studied for cartilage and bone development, but not for skeletal muscle and its attachments. Using chicken and zebrafish animal models, we aim to address the mecanobiology of skeletal muscle and draw a general scheme on the mechanical and molecular signals that operate during development.

Highlights

We established the molecular signature downstream of connective-tissue-associated transcription factors (Development 2018)

We found that the loss of EGR1 function leads to white fat browning (Scientific Reports 2017)

We identified the FGF and TGFbeta signalling pathways as acting downstream of mechanical parameters to regulate limb tendon development in chicken embryos (Development 2016)

We identified the YAP and NOTCH pathways downstream of muscle contraction and involved in the regulation of the equilibrium between proliferation and differentiation of muscle cells (eLife 2016)

We established the transcriptome of tendon cells during limb development in mice (Development 2014)

We identified the EGR1 transcription factor as being involved in tendon postnatal formation and repair and sufficient to activate the tendon program in mouse mesenchymal stem cells (Journal of Clinical Investigation 2013)

We have shown that the BMP signalling pathway controls the number of foetal muscle progenitors during chick limb development. Moreover, we observed that foetal muscle progenitors are not all equivalent and that BMP signalling is active in a subpopulation of foetal progenitors at the extremities of muscles, close to tendons (Developmental Cell 2010)

Collaborations

  • Collaborations

Francis BERENBAUM, CDR Saint-Antoine, UPMC, INSERM, PARIS. www.cdr-saint-antoine.fr/ Team: Age-related joint diseases and metabolism

Chantal PICHON, Centre de Biophysique Moléculaire (CBM), CNRS UPR4301, Orléans. www.crbm.cnrs.fr/Team: Nucleic acid transfert with non viral system

Sigmar StRICKER, Max Planck Institut for Molecular Genetics, Berlin, Germany

Ronen SCHWEITZER, Shriners Hospital, Portland Oregon, Dept. of Cell and Developmental Biology, USA.