Investigating skeletal resorption as a tissue-specific mechanism promoting skeletal tissue integration in the axolotl (Ambystoma mexicanum).

• Applicant: Rita Aires, Ph.D.
• Subject Area: Developmental Biology ; Animal Physiology and Biochemistry ; Cell Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 523178173

Regeneration, i.e., the ability to regrow missing body parts or organs, varies greatly throughout the animal kingdom. In mammals, including humans, regenerative potential is very restricted. In contrast, salamanders can regenerate a wide variety of body structures, such as the eye lens, heart, brain, and the limbs. The axolotl (Ambystoma mexicanum) is the most used salamander model for the study of regeneration. Indeed, its impressive talent for restoring body parts is best appreciated during limb regeneration, which occurs regardless of the position where amputation occurs. The limb is a complex structure composed by many types of tissues, which include skin, connective tissue, blood vessels, nerves, muscles, and skeletal tissue (cartilage and bone). Given their roles in load-bearing and soft tissue support, the structural integrity of cartilage and bone is extremely important for proper limb function. Indeed, in human patients, an impaired or defective bone healing after injury can lead to chronic conditions that have important socio-economic costs. In contrast, axolotls can not only re-form and re-pattern cartilage and bone during limb regeneration, but also integrate them successfully into the mature tissue. Therefore, a key question in the field is how this skeletal integration occurs. Recently, our lab found that, in early stages of axolotl limb regeneration, active resorption of the mature skeleton is important for the correct integration of mature and newly-regenerated tissues. Furthermore, this amputation-induced resorption process seems to be triggered exclusively when the amputation occurs in the calcified region of the limb’s skeletal element or in its immediate vicinity, but not when cartilage tissue is affected. This indicates that skeletal resorption is an important regenerative response that is specifically activated when mineralized regions of the skeleton are injured and that this process promotes the integration of newly formed cartilaginous regions with calcified mature skeleton. However, how skeletal resorption is triggered, how resorption promotes skeletal integration, and if resorption also promotes skeletal integration after injury of other mineralized structures in the body is currently unknown. This project will focus on answering these questions by investigating 1) the factors responsible for triggering skeletal resorption in resorption-inducing amputation planes; 2) the mechanisms by which skeletal resorption controls the integration of mature and newly-regenerated tissue during regeneration; and 3) its importance during regeneration and/or healing of other mineralized structures. For this, I will use state-of-the-art spatial transcriptomic techniques, advanced microscopy and transgenic axolotl lines. As such, this study will uncover mechanisms determining a successful integration of the regenerated skeletal tissue in the axolotl, thus opening new avenues of research into the topic of skeletal regeneration.

• DFG Programme: Research Grants