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From stem cells to skeletal muscle : the vital stages deciphered
A laboratory from the Institut Pasteur, associated with the CNRS has taken a determining step towards the understanding of the evolution of skeletal muscle stem cells. Using specific genetic markers, researchers have shown four characteristic stages that mark out the development of the muscle cells from a population of stem cells, which they have identified. This discovery has very important implications for the development of cellular therapies using muscle stem cells to ameliorate myopathic diseases.
Paris, june 15, 2005
Cellular therapies involve replacing abnormal or cells which have been lost with healthy cells. Over the last few years, new hope emerged with research on stem cells. The function of stem cells is to assure the development of organs and tissues, as well as their maintenance throughout the life of the organism. For therapeutic purposes it would be important that all stages of their maturation toward the differentiated state necessary to repair the lesion be well understood. With this prospect in mind, many laboratories have attempted to identify skeletal muscle stem cells and consequently try to determine their regenerative potential. Last year, studies directed by Shahragim Tajbakhsh in collaboration with Margaret Buckingham (Pasteur Institute – CNRS) deciphered very early genetic events which drive naïve skeletal muscle stem cells to make muscle (1).
As a follow up to these studies work published on June 15th in Genes and Development, Shahragim Tajbakhsh and his group (Stem Cells & Development, Institut Pasteur and CNRS) identified skeletal muscle stem cells by the expression of two genes, Pax3 and Pax7, and the lack of other muscle specific markers. Furthermore, they propose that skeletal muscle development is characterised by four distinct cell states in the embryo : stem, progenitor, precursor and differentiated cells. To demonstrate this relationship, they used a repertoire of genetic mutants involving the genes Pax3, Myf5, MyoD and Mfr4. These mutants allowed the engagement of cells in the muscle lineage to be blocked in space and time.
The researchers also showed that the evolution of these stem cells is tightly linked with the development of differentiating muscle itself: in mutant embryos deprived of skeletal muscle, the myogenic cells are eliminated by cell death (apoptosis) but only after having lost the expression of one of their markers, Pax7. The findings implicate Pax7 as a survival factor. One of the objectives for the future is to characterise the signals emitted by the differentiated muscle cells which drive stem cells to survive and self-renew. The identification of these signals will represent an important step for enhancing the self-renewal of engrafted cells, and thereby their regenerative potential in the context of cell therapies for myopathies.
These researches have been financed jointly by the integrated project EuroStemCell-FP6 (European research consortium on stem cells) and the AFM (French Association against Myopathies). The staff is a member of the European Network of Excellence MYORES-FP6.
"Pax3/Pax7 mark a novel population of primitive myogenic cells during development" Genes and development juin 2005.
Lina Kassar-Duchossoy’, Ellen Giacone, Barbara Gayraud-Morel, Aurélie Jory, Danielle Gomès, and Shahragim Tajbakhsh
Groupe Cellules Souches et Développement, CNRS-Institut Pasteur
" Mrf4 determines skeletal muscle identity in Myf5:Myod double-mutant mice" Nature septembre 2004 .
Lina Kassar-Duchossoy (1), Barbara Gayraud-Morel (1), Danielle Gomès (1), Didier Rocancourt (2), Margaret Buckingham (2), Vasily Shinin (1) et Shahragim Tajbakhsh (1)
1. Groupe Cellules souches et développement, CNRS-Institut Pasteur
2. Unité de Génétique moléculaire du développement, CNRS-Institut Pasteur