Forming regenerative stem cells
We have shown that limb regeneration involves the induction of stem cells from different tissue layers such as skin, dermis, muscle, nerve sheaths in order to regenerate the complex cohort of tissues of a functional limb. We have also tracked the neural stem cells involved in regenerating the spinal cord and brain. Cells in the tissue react to amputation by responding to a series of molecular factors deriving from the blood and the wounded epidermis to start the process of cell migration and cell proliferation. We have identified the blood-borne factors PDGF and BMP2/7, that stimulate cell crawling to the amputation site and cell proliferation. Another factor we identified, MARCKS-Like Protein coming from the injured skin defines a new signalling pathway involved in starting the process of cell division of many cells types after amputation.
Successful regeneration of a complex body part such as the limb involves not only tissue growth but coordination of the different tissues, as well as the whole structure forming the correct parts of the limb. Amputation of the axolotl limb at the wrist induces only regeneration of the hand whereas amputation in the upper arm initiates regeneration of the entire arm. We study the unanswered question of how the limb regenerates the correct parts. We showed that a subpopulation of the skin called dermal cells organize the regeneration of all the other tissues. These cells also “know” whether they are upper limb or hand cells. We are working on the molecular code that allows such a cell to know whether it comes from the upper arm, the hand, the pinky or the thumb, and the instructions that tell these cells what part of the limb to regenerate
Regeneration of nervous system and mammalian organoids
We also use the larval axolotl to understand how a functional nervous system is regenerated from its stem cells. We have identified signals that induce spinal cord regeneration, and we are now working on brain and eye regeneration. The axolotl is an outstanding model of a simple vertebrate brain. Beyond the axolotl, we have identified conditions to form three- dimensional spinal cord organoids from mouse embryonic stem cells and retinal organoids from human stem cells. These organoids undergo a remarkable process of self-organization—they form the correct neuronal cells types in the right place without a spatial orientation cue.