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.

Foetal myogenesis is crucial for muscle growth and generation of adult satellite cells. One research axis is to understand the molecular mechanisms underlying limb fœtal myogenesis and the interactions that muscles have with adjacent tissues, using the chick, mouse and zebrafish models.

We have shown that Bmp and Notch signalling pathways regulate the number of foetal muscle progenitors in chick limbs. Moreover, Foetal muscle progenitors are not all equivalent. Foetal muscle progenitors displaying active Bmp signalling are regionalised inside muscles (Wang et al., 2010).

A second axis of research is to identify genes able to drive the tendon program, since surprisingly we know very little about tendon development, in vertebrates. Tendon formation and repair rely on specific combinations of transcription factors, growth factors, and mechanical parameters that regulate the production and spatial organization of type I collagen. Tendon and ligament injuries are common clinical problems during aging or following accident. No satisfying treatment currently exists to restore injured or defective tendon to its normal condition. The global strategy of this research is to use the knowledge that we are currently acquiring concerning tendon development in order to understand tendon repair.

We have shown that the ZN finger transcription factor EGR1 is involved in tendon formation during chick and mouse development (Lejard et al., 2011), and also in adult tendon repair (Guerquin et al., 2013). EGR1 is also sufficient to drive Mesenchymal Stem Cells towards the tendon lineage (Guerquin et al., 2013).

More...

Skeletal muscle formation is based on successive and distinct waves of myogenesis: primary/embryonic, secondary/foetal, perinatal and adult myogenesis. Foetal myogenesis is an important step for muscle growth and the generation of satellite cells. The source and the nature of the signals regulating the proliferation of muscle progenitors remain to be determined. Foetal muscle progenitors are not equivalent in limb muscles. There is a sub- population of foetal muscle progenitors that display specific active signaling pathways, at muscle tips, close to tendons. 

We aim to define the involvement of signalling pathways and the link with the cell cycle in foetal muscle growth in an in vivo context. The influence of tendon and muscle connective tissue on foetal myogenesis will also be studied.

The molecular aspect of tendon development is poorly understood. We established the transcriptome of tendon cells in mouse limbs during development. We plan to analyse the function of the novel genes identified in the transcriptome, during tendon development in vivo using animal models. The ability to trigger or inhibit the tendon program will also be analysed on cellular models and ex vivo. The mesenchymal stem cells will be used, cultured either in 2D or 3D (mimicking tendon formation in vitro). 

We also plan to establish the relationship between the mechanical parameters, transcription factors and signalling pathways during tendon differentiation.

Highlights

  • We have shown that the Bmp and Notch signalling pathways are important for foetal muscle progenitor proliferation 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.
  • We established the transcriptome of tendon cells, during limb development in mice.
  • We have shown the transcription factor EGR1 is important for tendon differentiation during chick and mouse development, mainly by regulating the transcription of the main tendon-associated collagen genes, the Cola1a1 and Col1a2 genes.
  • EGR1 is involved in tendon postnatal formation and repair
  • EGR1 is sufficient to activate the tendon program from mouse mesenchymal stem cells.

Future directions

  • Feotal myogenesis

Our goal is to define the involvement of the BMP and FGF signaling pathways, in fetal muscle growth using the chick model. Gain and loss of function experiments will be performed in chick embryos using limb somite electroporation combined with stable and muscle-specific promoter.

  • Tendon

Tendon development

The molecular aspect underlying tendon formation during development is still not understood. We intend to increase our molecular knowledge of tendon development by analysing the function of novel tendon genes using animal models. Mesenchymal stem cells will be also used to study tendon formation

  • Tendon repair

We will also use the knowledge acquired on tendon biology to approach tendon repair in the adult. We have developed tendon injury mouse models, and 3D culture systems that mimick tendon formation, in which we intend to study the influence of movements and signalling pathways.

Collaborations

  • National Collaborations

Tristan BAUMBERGER, Institut des nanoSciences de Paris (INSP) UPMC, PARIS. www.insp.jussieu.fr/ Team: Multiscale Mechanics of Soft Solid

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

Gervaise Mosser, Laboratoire Chimie de la Matière Condensée de Paris(LCMCP)CNRS/UPMC, UMR 7574, PARISTeam: Materials and Biology

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

Helge AMTHOR, UVSQ, SAINT-QUENTIN EN YVELINES,

  • International Collaborations

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

Carmen Birchmeier, Professor, Max Delbrück Center for Molecular Medecine, Berlin, Germany

Ronen Schweitzer, Associate Professor, Shriners Hospital Portland Oregon, Research Dept. of Cell and Developmental Biology, Oregon Health & Science University, Portland, USA.