Regulation of Regeneration by Heparan Sulfate Proteoglycans in the Extracellular Matrix

David M. Gardiner

Just as the building of a house requires a blueprint, the rebuilding of lost or damaged body parts through regeneration requires a set of instructions for the assembly of the various tissues into the right places. Much progress has been made in understanding how to control the differentiation of different cell types to provide the building blocks for regeneration, such as bone, muscle, blood vessels and nerves/Schwann cells. These are the cells that follow the blueprint (the pattern-following cells) and end up in the right places relative to each other in order to restore the lost function. Much less is known about the cells that are specialized to generate and regenerate the blueprint (the pattern-forming cells) in order to instruct the pattern-following cells as to how and where to rebuild the structures. Recent studies provide evidence that the pattern-forming cells synthesize an information-rich extracellular matrix (ECM) that controls the behavior of pattern-following cells leading to the regeneration of limb structures. The ability of the ECM to do this is associated with glycosaminoglycans that have specific spatial and temporal modifications of sulfation patterns. This mechanism for controlling pattern formation appears to be conserved between salamanders and mammals, and thus the next challenge for inducing human regeneration is to identify and understand the biology of these pattern-forming cells and the ECM that they synthesize.