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Cells keep a memory of their tissue origin during axolotl limb regeneration
Martin Kragl1,3,5,6, Dunja Knapp1,3,5, Eugen Nacu1,3, Shahryar Khattak1,3, Malcolm Maden4, Hans Henning Epperlein2 & Elly M. Tanaka1,3
1 Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108,
2 Institute of Anatomy, Medical Faculty, University of Technology Dresden, Fetscherstrasse 74,
3 Center for Regenerative Therapies, University of Technology Dresden, Tatzberg 47/49, 01307 Dresden, Germany
4 The Regeneration Project, McKnight Brian Institute, University of Florida, Rm 326 Bartram Hall, Gainesville, Florida 32611, USA
5 These authors contributed equally to this work.
6 Present address: Institute of Metabolic Physiology, Heinrich-Heine-Universit?t Düsseldorf, Universit?tsstrasse 1, 40225 Düsseldorf, Germany.
During limb regeneration adult tissue is converted into a zone of undifferentiated progenitors called the blastema that reforms the diverse tissues of the limb. Previous experiments have led to wide acceptance that limb tissues dedifferentiate to form pluripotent cells. Here we have reexamined this question using an integrated GFP transgene to track the major limb tissues during limb regeneration in the salamander Ambystoma mexicanum (the axolotl). Surprisingly, we find that each tissue produces progenitor cells with restricted potential. Therefore, the blastema is a heterogeneous collection of restricted progenitor cells. On the basis of these findings, we further demonstrate that positional identity is a cell-type-specific property of blastema cells, in which cartilage-derived blastema cells harbour positional identity but Schwann-derived cells do not. Our results show that the complex phenomenon of limb regeneration can be achieved without complete dedifferentiation to a pluripotent state, a conclusion with important implications for regenerative medicine.
