AxoMatrx · How do dynamic changes extracellular matrix guide regenerative events in Axolotl?
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2022-09-01 → 2024-08-31
- EU contribution
- €186,167
- Participants
- 2
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
How do dynamic changes extracellular matrix guide regenerative events in Axolotl?
The ability to regrow body parts has captivated the minds of people for generations. In Greek mythology, the Lernaean Hydra was a multi-headed sea serpent that possessed remarkable regenerative capabilities as for every head it lost, it regrew two. While aspirations of modern-day scientists do not include the regeneration of multiple heads, the regrowth of organs is still considered the “holy grail” of regenerative medicine. Not unlike mythological creatures, the salamander Ambystoma Mexicanum (axolotl) possesses vast regenerative potential including the re-formation of complete limbs throughout its lifetime. In contrast, mammalian limb regeneration is limited to very distal portions of amputated digits and mostly during neonatal times. Axolotl limb regeneration involves the formation of a stem cell regenerative niche, the blastema, which is mainly comprised of proliferative dedifferentiated connective tissue cells that initiates the regenerative response. The major goal of this proposal (AxoMatrx) is to identify the extracellular cues governing blastema formation and regeneration initiation, and to use these ECM components to facilitate mammalian regeneration. The work ongoing in AxoMatrx has implications for both basic research and clinical drug development. In the context of basic research, using the next generation sequencing (NGS) and modern genetic tools, it was definitively shown that the blastema is mostly comprised from dedifferentiating PRRX1+ fibroblast and peri-skeletal cells, putting to rest many years of debate into to the origin of the cells. The next logical question then was how or what cues govern this dedifferentiating process, a question largely unanswered to this day. In AxoMatrx we chose to tackle this question by looking at the dynamic changes in the extracellular matrix (ECM) thus answering parts of this question would be valuable to progressing the field. The more obvious implication would be that of clinical drug development as identifying cues which could be important for limb regeneration could potentially facilitate better healing outcomes for people suffering from amputations or other maladies affecting their limbs or parts of them. Overall, in this project to date we could show that unique ECM landscape could affect cell cycle status of limb cells and we are still ongoing in trying to identify which cues could facilitate this response.
Data: CORDIS, © European Union
Project objective
How do dynamic changes of the extracellular matrix guide regenerative events in Axolotl?To what extent the dedifferentiation of mature cells is an intrinsic property of the cells or a product of interaction with the microenvironment is an exigent question in the regeneration field. In this project I will assess what initiates the regenerative response with an emphasis on deciphering what components are important for formation of the blastemal stem cell niche. Specifically, I will address whether ECM actively regulates the limb regenerative response or is merely a bystander. Although the importance of MMPs and ECM components in limb regeneration has been reported several times, few attempted to understand the role of ECM as signaling hub rather than as a “passive wall”.To address this, I will use tools developed in the Tanaka lab and combine those with my ECM expertise. I will characterize active ECM components during several distinct stages of limb regeneration to create an ECM “atlas” depicting extracellular changes during healing. I will use the obtained dataset to identify proteins which are important for the regenerative response by depleting these factors during axolotl regeneration and by testing their ability to induce ectopic limb growth using the Accessory Limb Model. Lastly, I will attempt to translate the axolotl findings to the mammalian setting and facilitate regeneration in a non-regenerating context.Surprisingly to date, no systemic characterization of extracellular molecules has been reported in regenerative systems, nor was any axolotl regenerative cue yet successfully translated to mammals. Thus, this characterization and candidate identification have far-reaching implications for both development and regenerative biology.
Original text from CORDIS.
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Data: CORDIS, © European Union