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Regulation of Regeneration by Heparan Sulfate Proteoglycans in the Extracellular Matrix

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Abstract

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 the 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.

Lay Summary

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. Recent studies provide evidence that this blueprint is encoded in part by an information-rich extracellular matrix (ECM) within the loose connective tissues that controls the behavior of regeneration-competent cells. The ability of the ECM to do this is associated with sugar-rich macromolecules 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 the connective tissue cells and the ECM that they synthesize.

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Acknowledgements

I thank Dr. Susan V. Bryant and Dr. Ken Muneoka for insights into the importance of designing gain-of-function experiments for regeneration, Dr. Anne Phan for her extraordinary efforts in the discovery of the role of HSPGs in regeneration, and Dr. Cato Laurencin for his insights into the convergence of regeneration biology and engineering leading to the emergence of regenerative engineering for inducing human regeneration.

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  1. Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA, 92697, USA

    David M. Gardiner

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Correspondence to David M. Gardiner.

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David M. Gardiner declares no conflict of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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Gardiner, D.M. Regulation of Regeneration by Heparan Sulfate Proteoglycans in the Extracellular Matrix. Regen. Eng. Transl. Med. 3, 192–198 (2017). https://doi.org/10.1007/s40883-017-0037-8

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