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© The Rockefeller University Press, 0021-9525/1998//1257 $5.00
The Journal of Cell Biology, Volume 142, Number 5, , 1998 1257-1267

Articles

Development of Approaches to Improve Cell Survival in Myoblast Transfer Therapy



Zhuqing Qu*, Levent Balkir{ddagger},§, Judith C.T. van Deutekom*, Paul D. Robbins§, Ryan Pruchnic*, and Johnny Huard*

* Department of Orthopedic Surgery, Musculoskeletal Research Center, University of Pittsburgh and Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15261; {ddagger} Department of Human Genetics, and § Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15261

Myoblast transplantation has been extensively studied as a gene complementation approach for genetic diseases such as Duchenne Muscular Dystrophy. This approach has been found capable of delivering dystrophin, the product missing in Duchenne Muscular Dystrophy muscle, and leading to an increase of strength in the dystrophic muscle. This approach, however, has been hindered by numerous limitations, including immunological problems, and low spread and poor survival of the injected myoblasts. We have investigated whether antiinflammatory treatment and use of different populations of skeletal muscle–derived cells may circumvent the poor survival of the injected myoblasts after implantation. We have observed that different populations of muscle-derived cells can be isolated from skeletal muscle based on their desmin immunoreactivity and differentiation capacity. Moreover, these cells acted differently when injected into muscle: 95% of the injected cells in some populations died within 48 h, while others richer in desmin-positive cells survived entirely. Since pure myoblasts obtained from isolated myofibers and myoblast cell lines also displayed a poor survival rate of the injected cells, we have concluded that the differential survival of the populations of muscle-derived cells is not only attributable to their content in desmin-positive cells. We have observed that the origin of the myogenic cells may influence their survival in the injected muscle. Finally, we have observed that myoblasts genetically engineered to express an inhibitor of the inflammatory cytokine, IL-1, can improve the survival rate of the injected myoblasts. Our results suggest that selection of specific muscle-derived cell populations or the control of inflammation can be used as an approach to improve cell survival after both myoblast transplantation and the myoblast-mediated ex vivo gene transfer approach.

Key Words: myoblast transplantation • inflammation • gene transfer • adenovirus • muscle derived stem cells

Abbreviations used in this paper: AV, adenovirus; DAP, dystrophin-associated protein; DMD, Duchenne Muscular Dystrophy; HSV-1, Herpes Simplex virus type 1; IL-1Ra, interleukin-1 receptor antagonist protein; MyHC, myosin heavy chain; ONPG, o-nitrophenyl-β-D-galactopyranoside; PP, preplate.

Address all correspondence to Johnny Huard, Ph.D., Assistant Professor, Department of Orthopedic Surgery and Molecular Genetics & Biochemistry, Children's Hospital of Pittsburgh and University of Pittsburgh, Pittsburgh, Pennsylvania, 15261. Tel.: 412-692-7807. Fax: 412-692-7095. E-mail: jhuard+@pitt.edu


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