Genetic analysis and functional characterization of factors affecting BM-derived myogenesis

Xynos, Alexandros (2007). Genetic analysis and functional characterization of factors affecting BM-derived myogenesis. PhD thesis The Open University.



Numerous common and severe human muscle disorders could benefit from stem cell therapy that would allow replacement of degenerating muscle. A recent upsurge of reports, claiming that readily accessible haematopoietic stem cells (HSCs) participate in muscle regeneration, raises hopes for their clinical application. However, the biology of this process and the proof of the ability of HSCs to be reprogrammed remain elusive. Using murine bone marrow (BM) cells, carrying different reporter cassettes controlled by elements of the muscle-specific Myf5, MLC3F and MCK promoters, we demonstrated that haematopoietic cells in co-culture with myoblasts express muscle-specific genes. In spite of this, these cells show limited regeneration of muscle in Pax7-/- mice and never give rise to myoblast clones. Correspondingly, the gene expression profiling of haematopoietic CD45+/Sca1+ cells revealed partial but extended myogenic reprogramming, despite the absence of key myogenic transcription factors such as Pax7 and MyoD. Indeed, BM transplantation and co-culture experiments, using BM cells from Pax7-/- or MyoD-/- mice, suggested that neither Pax7 nor MyoD are essential for the participation of haematopoietic cells in muscle regeneration, indicating that the Pax7 pathway is not active in these cells. In-vitro experiments with muscle cells from Pax7-/- /Myf5nlacZ/+ and Pax7-/-/MLC3F-nlacZ-E mice confirmed the tight association of Pax7 with the muscle-stem-cell characteristics. Additionally, the Pax7 ectopic expression in BM cells infused to them the ability to generate myogenic clones "and increased their in-vivo myogenic potential. Overall, our results demonstrate that BM-derived CD45+/Sca1+ cells, while undergoing myogenic specification and differentiation, cannot be considered muscle stem cells, and this latter distinction from the satellite cells is most probably due to the inactivity of the Pax7 pathway.

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