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TISSUE-SPECIFIC STEM CELLS

Bone Marrow Transplantation Attenuates the Myopathic Phenotype of a Muscular Mouse Model of Spinal Muscular Atrophy

^aMolecular Neurogenetics Laboratory, Institut National de la Santé et de la Recherche Médicale, Inserm, U798, Evry, F-91057 France; University of Evry, Evry, F-91057 France;
^bInserm, U429, Paris, France;
^cDepartment de Pharmacologie Clinique, Hôpital de la Pitié-Salpêtrière, Paris, France

Key Words. Spinal muscular atrophy • Survival of motor neuron • Bone marrow • Transplantation • Skeletal muscle Hepatocyte growth factor

Correspondence: Judith Melki, M.D., Ph.D., Molecular Neurogenetics Laboratory, INSERM U798, 2 rue Gaston Crémieux CP5724, 91057 Evry, France. Telephone: 331-6087-4552; Fax: 331-6087-4550; e-mail: j.melki{at}genopole.inserm.fr

Received March 23, 2006; accepted for publication July 24, 2006.
First published online in STEM CELLS EXPRESS   August 3, 2006.



Bone marrow (BM) transplantation was performed on a muscular mouse model of spinal muscular atrophy that had been created by mutating the survival of motor neuron gene (Smn) in myofibers only. This model is characterized by a severe myopathy and progressive loss of muscle fibers leading to paralysis. Transplantation of wild-type BM cells following irradiation at a low dose (6 Gy) improved motor capacity (+85%). This correlated with a normalization of myofiber number associated with a higher number of regenerating myofibers (1.6-fold increase) and an activation of CD34 and Pax7 satellite cells. However, BM cells had a very limited capacity to replace or fuse to mutant myofibers (2%). These data suggest that BM transplantation was able to attenuate the myopathic phenotype through an improvement of skeletal muscle regeneration of recipient mutant mice, a process likely mediated by a biological activity of BM-derived cells. This hypothesis was further supported by the capacity of muscle protein extracts from transplanted mutant mice to promote myoblast proliferation in vitro (1.6-fold increase). In addition, a tremendous upregulation of hepatocyte growth factor (HGF), which activates quiescent satellite cells, was found in skeletal muscle of transplanted mutants compared with nontransplanted mutants. Eventually, thanks to the Cre-loxP system, we show that BM-derived muscle cells were strong candidates harboring this biological activity. Taken together, our data suggest that a biological activity is likely involved in muscle regeneration improvement mediated by BM transplantation. HGF may represent an attractive paracrine mechanism to support this activity.

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