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© The Rockefeller University Press, 0021-9525/2003/3/909 $5.00
The Journal of Cell Biology, Volume 160, Number 6, 909-918

Skeletal muscle repair by adult human mesenchymal stem cells from synovial membrane

¹ Laboratory for Skeletal Development and Joint Disorders, Department of Rheumatology, University Hospitals, Katholieke Universiteit Leuven, 3000 Leuven, Belgium
² Laboratory of Histology, Biomedical Research Institute-DWI, Limburgs Universitair Centrum, 3590 Diepenbeek, Belgium
³ Center of Human Genetics, University Hospitals, Katholieke Universiteit Leuven, 3000 Leuven, Belgium
⁴ Department of Physiology and Pharmacology, Université Catholique de Louvain, 1200 Brussels, Belgium

Address correspondence to Frank P. Luyten, Laboratory for Skeletal Development and Joint Disorders, Dept. of Rheumatology, Katholieke Universiteit Leuven, Herestraat 49, 3000 Leuven, Belgium. Tel.: 32-16-346341. Fax: 32-16-346200. E-mail: frank.luyten{at}uz.kuleuven.ac.be

We have demonstrated previously that adult human synovial membrane-derived mesenchymal stem cells (hSM-MSCs) have myogenic potential in vitro (De Bari, C., F. Dell'Accio, P. Tylzanowski, and F.P. Luyten. 2001. Arthritis Rheum. 44:1928–1942). In the present study, we have characterized their myogenic differentiation in a nude mouse model of skeletal muscle regeneration and provide proof of principle of their potential use for muscle repair in the mdx mouse model of Duchenne muscular dystrophy. When implanted into regenerating nude mouse muscle, hSM-MSCs contributed to myofibers and to long term persisting functional satellite cells. No nuclear fusion hybrids were observed between donor human cells and host mouse muscle cells. Myogenic differentiation proceeded through a molecular cascade resembling embryonic muscle development. Differentiation was sensitive to environmental cues, since hSM-MSCs injected into the bloodstream engrafted in several tissues, but acquired the muscle phenotype only within skeletal muscle. When administered into dystrophic muscles of immunosuppressed mdx mice, hSM-MSCs restored sarcolemmal expression of dystrophin, reduced central nucleation, and rescued the expression of mouse mechano growth factor.

Key Words: Duchenne muscular dystrophy; dystrophin; cell transplantation; muscle development; insulin-like growth factor I

^* Abbreviations used in this paper: AdCMV-LacZ, adenovirus containing the LacZ gene under the CMV promoter; ß-gal, ß-galactosidase; ß2M, ß2-microglobulin; BM, bone marrow; CE, cell equivalents; CEN18, centromere 18; CMV, cytomegalovirus; CN, centronucleated; CTX, cardiotoxin; DMD, Duchenne muscular dystrophy; ET, electrotransfer; hSM-MSC, human synovial membrane-derived mesenchymal stem cell; IF, immunofluorescence; ISH, in situ hybridization; MGF, mechano growth factor; MRF, myogenic regulatory factor; MSC, mesenchymal stem cell; MyHC-IIx/d, myosin heavy chain type IIx/d; PCNA, proliferating cell nuclear antigen; Q, quantitative; pCMV-dystrophin, plasmid DNA containing human dystrophin under the CMV promoter; SM, synovial membrane; SQ, semiquantitative; TA, tibialis anterior; TEM, transmission electron microscopy.

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