Identification of Heparan-Sulfate Rich Cells in the Loose Connective Tissues of the Axolotl (Ambystoma mexicanum) with the Potential to Mediate Growth Factor Signaling during Regeneration
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Limb regeneration is the outcome of a complex sequence of events that are mediated by interactions between cells derived from the tissues of the amputated stump. Early in regeneration, these interactions are mediated by growth factor/morphogen signaling associated with nerves and the wound epithelium. One shared property of these proregenerative signaling molecules is that their activity is dependent on interactions with sulfated glycosaminoglycans (GAGs), heparan sulfate proteoglycan (HSPG) in particular, in the extracellular matrix (ECM). We hypothesized that there are cells in the axolotl that synthesize specific HSPGs that control growth factor signaling in time and space. In this study we have identified a subpopulation of cells within the ECM of axolotl skin that express high levels of sulfated GAGs on their cell surface. These cells are dispersed in a grid-like pattern throughout the dermis as well as the loose connective tissues that surround the tissues of the limb. These cells alter their morphology during regeneration, and are candidates for being a subpopulation of connective tissue cells that function as the cells required for pattern-formation during regeneration. Given their high level of HSPG expression, their stellate morphology, and their distribution throughout the loose connective tissues, we refer to these as the positional information GRID (Groups that are Regenerative, Interspersed and Dendritic) cells. In addition, we have identified cells that stain for high levels of expression of sulfated GAGs in mouse limb connective tissue that could have an equivalent function to GRID cells in the axolotl. The identification of GRID cells may have important implications for work in the area of Regenerative Engineering.
KeywordsAxolotl Mouse Regeneration Heparan sulfate Morphogens Positional information
We wish to thank the members of the Bryant/Gardiner Lab for help with and encouragement of the research. Mouse limb skin tissue samples were kindly provided by Dr. David Rowe. Research was supported by an NIH Director’s Pioneer Award, and the National Science Foundation through its support of the Ambystoma Genetic Stock Center at the University of Kentucky, Lexington. Dr. Laurencin was the recipient of the Presidential Faculty Fellow Award from the National Science Foundation.
SB and DG conceptualized the presence of a positional information GRID; DG, AP, and TO designed the experiments; AP and TO conducted the experiments; DG, AP and TO wrote the draft of the manuscript; and all authors contributed to the final version of the manuscript.
Compliance with Ethical Standards
None of the authors have competing interests.
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