Faculty Member - Division of Biological Sciences University of Missouri-Columbia

Wild type and syndecan-4 null muscle after injury and regeneration: the wild type muscle has reformed smooth, well-ordered myofibers, while the syndecan-4 null muscles, due to the defects in satellite cell function, have formed poorly patterned, nonfunctioning myofibers.

Research description

Skeletal muscle is formed during embryonic and postnatal development by commitment of mesodermal cells in the somite to a myogenic fate, terminal differentiation of those myoblasts into nonproliferating myocytes, and fusion of myocytes into multinuclear, contractile myofibers that form the basic unit of skeletal muscle. Because differentiation requires permanent withdrawal from the cell cycle, specialized adult stem cells known as satellite cells (because they are located at the periphery of myofibers) are required to provide replacement myoblasts after development. In healthy tissue these cells are ‘quiescent’- they are very small and compact, do not proliferate, have minimal metabolism, and express few gene products. When muscle is damaged due to disease (such as Duchenne’s Muscular Dystrophy), injury, or exercise, the resident satellite cells are ‘activated’ to leave their host fiber, grow in size, proliferate extensively, and eventually differentiate to replace the damaged muscle. Although satellite cells are thought to be essential for muscle maintenance, growth, and repair, we know surprisingly little about them: their embryonic origin and relationship to the cells that differentiated to form the existing muscle, the mechanism by which they sense local muscle damage, the signals regulating their proliferation and differentiation, and whether they are the source of new satellite cells after regeneration is complete are still open questions.

My lab works with primary satellite cells from the mouse, using whole-fiber culture and mass satellite cell preparations to ask questions about the signaling events that control satellite cell activity. In particular, syndecan-4, a heparan sulfate proteoglycan that spans the cell membrane and regulates response to growth factors, cytoskeletal events, and intracellular signaling appears to be very important for satellite cell function: in the syndecan-4 knockout mouse, satellite cells fail to activate, proliferate, or differentiate properly. While these animals appear relatively normal, if their muscle is injured it fails to regenerate. We have examined the molecular role of syndecan-4 in satellite cell signaling by comparing gene expression in normal and syndecan-4 null satellite cells over the early stages of injury and regeneration using Affymetrix gene chips. Surprisingly, the molecular mechanisms controlling satellite cell behavior appear to be very different from those used by myoblasts during development. We are investigating possible regeneration-specific signaling pathways to try to better understand the events governing satellite cell behavior, as well as potentially altering that behavior for therapeutic use.

We have also started a new line of experiments asking about the intrinsic migratory behavior of satellite cells on their host fiber, what soluble and adhesive factors regulate this activity, and whether it is a necessary component of successful muscle regeneration. Using a 3D timelapse videomicroscopy system, we can film satellite cells activating, proliferating, migrating, and interacting for up to several days continuously. We find that satellite cells are highly motile on a native substrate, respond differentially to specific extracellular signals, and may use pathfinding molecules more commonly associated with neuronal migration and outgrowth to transit to damaged areas of the myofiber.

Selected publications

Tanaka KK, Hall JK, Troy AA, Cornelison DDW, Majka SM, and Olwin BB Syndecan-4-expressing muscle progenitor cells in the SP engraft as satellite cells during muscle regeneration (2009). Cell Stem Cell 4: 217-225

Siegel AL, Atkinson K, Fisher K, Davis GE, and Cornelison DDW 3-D timelapse analysis of muscle satellite cell motility (2009). Stem Cells 27: 2527-2538

Capkovic KL, Stevenson S, Johnson MC, Thelen JJ and DDW Cornelison. Neural cell adhesion molecule (NCAM) marks adult myogenic cells committed to differentiation. Exp. Cell Res. 314(7):1553-65.

Cornelison DDW Context is everything: influences on satellite cell activity in vivo and in vitro (Invited review) (2008). J Cell Biochem. 105: 663-669.

Cornelison, D.D.W., Wilcox-Adelman, S. A., Goetinck, P. F., Rauvala, H., Rapraeger, A., and Olwin, B.B. 2004. Essential and nonredundant roles for syndecan-3 and syndecan-4 in skeletal muscle development and regeneration. Genes and Development 18, 2231-2236.

Cornelison, D.D.W., Filla, M.S., Stanley, H.M., Rapraeger, A.C., and Olwin, B.B. 2001. Syndecan-3 and syndecan-4 specifically mark skeletal muscle satellite cells and are implicated in satellite cell maintenance and muscle regeneration. Developmental Biology 239, 79-94.

Cornelison, D.D.W., Olwin, B.B., Rudnicki, M.A., and Wold, B.J. 2000. MyoD-/- satellite cells in single-fiber culture are differentiation defective and MRF4 deficient. Developmental Biology 224, 122-137.

Cornelison DDW and Wold BJ Single-cell analysis of regulatory gene expression in quiescent and activated mouse skeletal muscle satellite cells (1997) Dev Biol. 191: 270-83