Associate Professor of Biological Sciences
PhD, 1998 California Institute of Technology
|Office:||340F Christopher S. Bond Life Sciences Center|
Signaling and activity of skeletal muscle satellite cells
Research descriptionSkeletal 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.
Chowdhury, A.S.; Paul, A.; Bunyak, F.; Cornelison, D.D.W.; Palaniappan, K., "Semi-automated tracking of muscle satellite cells in brightfield microscopy video," Image Processing (ICIP), 2012 19th IEEE International Conference on , vol., no., pp.2825,2828, Sept. 30 2012-Oct. 3 2012 doi: 10.1109/ICIP.2012.6467487
Farina, N. H., Hausburg, M., Betta, N. D., Pulliam, C., Srivastava, D., Cornelison, D. D. W., & Olwin, B. B. (2012). A role for RNA post-transcriptional regulation in satellite cell activation. Skeletal Muscle 2:21
Stark, D. A., Karvas, R. M., Siege, A. L., & Cornelison, D. D. W. (2011). Eph/ephrin interactions modulate muscle satellite cell motility and patterning. Development, 138(24), 5279-5289.
Alfaro, L. A. S., Dick, S. A., Siegel, A. L., Anonuevo, A. S., McNagny, K. M., Megeney, L. A., Cornelison D. D. W., Rossi, F. M. V. (2011). CD34 promotes satellite cell motility and entry into proliferation to facilitate efficient skeletal muscle regeneration. Stem Cells, 29(12), 2030-2041.
Berg, Z., Beffa, L. R., Cook, D. P., & Cornelison, D. D. W. (2011). Muscle satellite cells from GRMD dystrophic dogs are not phenotypically distinguishable from wild type satellite cells in ex vivo culture. Neuromuscular Disorders, 21(4), 282-290.
Siegel, A. L., Kuhlmann, P. K., & Cornelison, D. D. W. (2011). Muscle satellite cell proliferation and association: New insights from myofiber time-lapse imaging. Skeletal Muscle, 1:7
Pisconti, A., Cornelison, D. D. W., Olguín, H. C., Antwine, T. L., & Olwin, B. B. (2010). Syndecan-3 and notch cooperate in regulating adult myogenesis. Journal of Cell Biology, 190(3), 427-441