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Mechanisms of Muscle Stem Cell Expansion with Cytokines

^a Bioengineering Department, University of Pittsburgh;
^b Growth and Development Laboratory, Children's Hospital of Pittsburgh, Department of Orthopaedic Surgery, Department of Molecular Genetics and Biochemistry, University of Pittsburgh;
^c Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

Key Words. Muscle-derived stem cell • Cytokines • Proliferation • Division time • Mitotic fraction

Johnny Huard, Ph.D, Children's Hospital of Pittsburgh Growth and Development Lab, 3705 Fifth Ave., 4151 Rangos Research Center, Pittsburgh, Pennsylvania 15213, USA. Telephone: 412-692-7830; Fax: 412-692-7095; e-mail: jhuard{at}pitt.edu

Stem cell expansion and proliferation are important for cell transplantation and stem cell-mediated applications. While we have demonstrated that muscle stem cells can be obtained from adult skeletal muscle tissue, these cells represent only a small percentage of the muscle-derived cells and require in vitro expansion for successful stem cell-mediated therapies. In this study, we have examined the potential of several cytokines to stimulate stem cell growth by combining a non-exponential mathematical model with a unique cell culture system. The growth kinetics of two populations of muscle stem cells were characterized in culture medium supplemented with epidermal growth factor (EGF), fibroblast growth factor-2 (FGF-2), insulin-like growth factor-1 (IGF-1), FLT-3 ligand, hepatocyte growth factor, or stem cell factor (SCF). The division time (DT) and fraction of mitotically active cells were investigated as key parameters to further understand the mechanism of the expansion of the stem cell populations. Our results show that expansion of the freshly isolated, muscle-derived stem cells (MDSC) occurred by recruiting cells into the cell cycle in the presence of EGF, IGF-1, and SCF. However, expansion of the cultured stem cell clone, MC13, is attributed to a reduction of the length of the cell cycle in the presence of FGF-2, EGF, IGF-1, and SCF. Both MDSC and MC13 growth were inhibited in the presence of FLT-3 ligand by increasing the length of the cell cycle. Our results suggest that EGF, IGF-1, FGF-2, and SCF are important cytokines for stimulating the proliferation of MDSC. In addition, this study illustrates that expansion of stem cells occurs through different mechanisms, which consequently demonstrates the importance of monitoring several parameters of cell growth, such as DT and dividing fraction, following stimulation with growth factors.

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