Mechanisms of bone dynamics during fingertip regeneration in axolotl, mouse and human.

• Applicant: Dr. Tatiana Sandoval-Guzmán, Ph.D.
• Subject Area: Developmental Biology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 432439166

In contrast to humans, the regeneration of extremities occurs relatively fast and faithfully in animals such as salamanders. Even so, some rodents and primates (including humans), are able to regenerate the very distal end of the finger phalanx while more proximal amputations fail to regenerate. If we have retained the ability to regenerate the fingertip, why does a more proximal amputation result in wound healing and scaring? The ultimate goal of regenerative research is to understand why humans have limited regeneration and how we can improve it. With recent advances in genomic technology, scientists have progressed to uncover cellular and molecular elements in regeneration by studying animal models such as the Mexican salamander (axolotl). Still, remains unclear how after amputation the mature tissue at the stump can at the same time produce progenitor cells to restore multiple tissues, and integrate them with pre-existing tissue as one functional unit. Failure in this functional integration is detrimental to any naturally regenerating tissue or cell-based therapy.This proposal aims to find unifying mechanisms, or alternatives, that drive successful regeneration in the fingertip of three different species: axolotl, mouse and human. In particular, we will use the regeneration of the fingertip to understand bone regeneration, the vast remodeling of the bone at the stump, and its interaction with the new forming bone.Fingertip regeneration is a unique example of active renewal of multiple tissues in mammals. Therefore, understanding how the fingertip regenerates has important implications in unravelling the mechanisms of tissue healing and regeneration. Our further contribution is to cross over three different species in order to expand and speed the possibilities of experimentation and treatment validation. The axolotl has a remarkable ability to regenerate; the mouse model is an intermediate platform of translation to mammals; and human samples are the ultimate link to translation to human therapies. In axolotl and mouse, we will use the well-established amputation paradigm, transgenesis and live imaging to understand the cellular components of bone regeneration. With sequencing techniques, we will explore molecular components that drive the remodeling of the old bone and recruitment of bone forming cells. In human, we will obtain wound exudates and X-rays from patients with fingertip amputations in collaboration with our clinician partners. We will analyze with mass spectrometry the proteins secreted during the process of regenerating fingertips. While current efforts have been focused on the cells that can form new tissue, this project will describe the required environment to host progenitor cells and facilitate a functional interaction. In the long run, the results of our project will not only help develop novel regenerative therapies for the treatment of digit injuries but also be applied in other areas of human tissue repair.

• DFG Programme: Research Grants