Résumé :
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Communication n° 91. In a recent study conducted in our laboratory we have identified and sorted "side population" (SP) cells from myoblast cultures. In addition to the presentation of the SP phenotype these cells presented other features in common with stem cells, including G0-cell cycle arrest and reduced expression of tissue-specific transcription factors (Benchaouir et al, 2004). The SP cells expressed several members of the ABC-transporter family, including mdr1a, mdr1b and ABCG2. Treatment of the myoblast cultures by FGF6, a muscle-specific growth and regeneration factor, resulted in about a 100 fold increased mdr1a expression, while the level of mdr1b and ABCG2 remained unchanged. Moreover, the FGF6 treated culture presented 20 fold increased in the proportion of SP cells (Israeli et al, 2004). mdr1 is expressed in a wide variety of adult stem cells and posses an anti-apoptotic activity. In view of the above results we have hypothesized a role for mdr1 in the muscle regeneration machinery, possibly in the protection of the muscle stem cells pool from exhaustion. The dystrophin deficient mdx mouse is characterized by relatively mild overall symptoms. The efficient muscle regeneration capacity of mdx mouse is supported by a non-exhaustive muscle stem cell reservoir and perseverance muscle regeneration. To test a role for mdr1 in stem cells homeostasis we have crossed the mdr1-deficient mouse with the mdx mouse. The out come triple knockout mice (deficient for mdr1a, mdr1b and dystrophin) have born and developed normally and are fertile, however they present enhanced muscle degeneration, reduced percentage of muscle SP cells, reduced muscle content of desmin-positive cells and a striking reduced muscle regeneration capacity compared to mdx mouse. We concluded that in the mdx mouse mdr1 plays a central role in the preservation of the muscle stem cells and therefore in the muscle regeneration mechanism. We suggest a central role for mdr1 in a stress-induced tissue regeneration genetic program.
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