Oxygen Signaling And Inflammation As Key Influences On Mouse Digit Regeneration
Each year, more than 185,000 people in the U.S. lose a limb to injury or pathological conditions. Currently, the only replacement for amputated limbs is the fitting of a prosthetic device. While artificial limbs greatly enhance the lives of amputees, these devices have their limitations. Prosthetics tend to have reduced (or no) function and limited sensation. These devices require charging and maintenance, are expensive, and have a shorter life than a natural limb. Additionally, artificial limbs are not able to completely replace the biological roles of natural bone such as calcium-ion exchange and hematopoiesis. To overcome the limitations of prosthetics, the ideal replacement for an amputated limb would be the regrowth of a patient's own biological limb. Mammals have the ability to regenerate the distal portion of the third phalangeal element (P3). This regeneration response progresses through several distinct phases which are defined in this thesis. The initial phases - inflammation, histolysis, and epidermal closure - are not unique to the P3 amputation response, but are seen following injury to almost every tissue. For mammals, the most common response to injury is a repair process that starts with inflammation, histolysis and wound closure, but produces aberrant collagen deposition and loss of original structure. A mammalian P3 amputation is exceptional in that the initial stages following injury lead to a regeneration event. We aim to understand the initial stages of P3 regeneration and to determine if these stages play a role in creating (or inhibiting) a regeneration-permissive environment. We also examine what factors comprise a regeneration-permissive environment, specifically, how tissue oxygen tensions influence regeneration. We find that regeneration is dependent upon both temporal oxygen fluctuations and the initial influx of inflammatory cells. Future goals, based on this work, are to determine how we can manipulate both oxygen tensions and inflammation to augment the regeneration capabilities of the body.