Healing large bone fractures using limb regeneration factors

In the frame of her postdoctoral research project "Soft connective tissue cells in axolotl bone healing", Anastasia Polikarpova seeks to identify cells and molecules that can promote regeneration in delayed bone fracture healing. Bone fractures are an increasing medical problem in an ageing society. Though most fractures heal within months, so-called critical size defects (CSD) - characterised by loss of a larger volume of bone tissue - present a serious challenge, with no effective treatment available. To understand which factors are important for bone healing, Polikarpova will use knowledge obtained from the Mexican salamander, axolotl. Like mammals, axolotls cannot heal CSD; however, they do have the ability to fully regenerate an amputated limb, including lost bones. Cells of the soft connective tissue (skin, muscle, tendons) make a substantial contribution to bone formation in regenerated limb. The project will investigate if these cells are able to migrate to the bone fracture region and how these cells could be activated in the process of large bone fracture healing.

Axolotls, also known as Ambystoma mexicanum, are fascinating creatures with extraordinary regenerative abilities. Despite their remarkable ability to regrow entire limbs with fully formed bones, they struggle to regenerate large bone fractures. To understand this better, Dr. Polikarpova conducted a study using a model called a "critical size defect" (CSD), which typically does not heal on its own. In the project "Healing large bone fractures using limb regeneration factors" Dr. Polikarpova focused on studying the genes expressed in different types of cells involved in bone healing. By comparing connective tissue cells from the regenerating limb (blastema), small fractures, and the non-healing CSD, she hoped to find clues to improve CSD healing. Dr. Polikarpova found that genes related to growth and development were highly active in the regenerating blastema tissue. Interestingly, these factors were missing or less active in the CSD, which might explain why it does not heal well. She also found that cells in the CSD did not transform and multiply as effectively as those in the blastema. To try kickstart bone healing in the CSD, she tested adding known blastema-specific proteins directly into the fracture site. Unfortunately, this did not lead to significant healing. Dr. Polikarpova and her colleagues then delivered these proteins directly into the CSD, hoping for a better outcome. While this did increase some markers related to healing, it was not enough to fully repair the bone. The research team is now investigating other factors that might be crucial for bone healing. They found that certain pathways are important in the early stages of regeneration. These pathways are active in the regenerating limb but not as much in the CSD. By understanding these pathways better, they hope to find new ways to activate bone regeneration in difficult fractures. This study sheds light on the complex process of bone regeneration in axolotls. It also highlights similarities between axolotl bone healing and that of other animals such as mice. Dr. Polikarpova plans to share her findings in scientific journals and conferences, and the research team will make their data publicly available for further research in the field of regeneration. In summary, while axolotls have amazing regenerative abilities, healing large bone fractures remains a challenge. This research provides valuable insights into the genetic and cellular processes involved. By understanding these processes better, scientists aim to lay the foundation for better treatments to help heal difficult fractures, not just in axolotls, but potentially also in humans.