Extracellular control of muscle regeneration

Abstract

In urodele amphibian limb regeneration, the muscle provides a reservoir for uncommitted stem‐like blastema cells that will participate in the replacement of the lost structure. However, it is currently not clear what signals activate muscle‐associated satellite cells and/or dedifferentiation of multinucleate myofibers. Cultures of newt muscle fibers allow us to follow these physiological changes at the cellular level using time‐lapse video microscopy.Our studies on extracellular matrix (ECM) distribution during blastema formation demonstrate upregulation of hyaluronic acid (HA), fibronectin (FN), and Tenascin C, suggesting dynamic changes in the ECM composition. Contemporaneous with ECM reorganization, histological analyses of regenerating blastemas reveal increased satellite cell numbers and migration along with myofiber fragmentation. In order to gain a better understanding of the signaling properties of the ECM in regeneration, we are investigating various ECMs and their effects on cell physiology and morphology. Our data indicate that HA induces fragmentation of myotubes and limits adhesion whereas FN or laminin‐containing matrigel stimulates formation of myotubes.The establishment of a physiologically relevant environment and its manipulation in vitro will provide new insights into the control of the differentiated state of the cell by its ECM.Supported by DARPA, NIH, Searle Funds