(103b) Regulation of Growth Factor Signaling and Regeneration by Modifications of Heparan Sulfate Proteoglycans in the Extracellular Matrix

Axolotls (and other Urodele amphibians) are unique among adult vertebrates in their ability to regenerate complex body structures after traumatic injury. We used an in vivo gain-of-function assay in the axolotl to demonstrate both qualitative and quantitate differences in extracellular matrix (ECM)-associated heparan sulfate proteoglycans (HSPG) regulate growth factor signaling that in turn regulates formation of limb skeletal structures. Most importantly, this activity is present in mammalian HSPG present in mouse skin in vivo as well as in commercially available, purified preparations of HSPG. This activity can both inhibit regeneration or induce de novo limb structure, thus regulation of HSPG is a mechanism for the regulation of regeneration, and establishes a crucial functional link between regeneration in salamanders and mammals. In light of recent findings that not all preparations of HSPG have activity in our regeneration assay, we have begun to screen for pro-regenerative HSPG activity between difference HSPG sources. Understanding the signals and responses of cells, whether they are pro- or anti-regenerative will be critical to achieving the goal of regenerative engineering to reform complex structure and restore function in humans.