Immunity and Ontogenic Decline of Regenerative Capacity in Xenopus

Indiana University, Bloomington IN

Investigators

Abstract

Larval frogs (tadpoles) regenerate lost limbs completely at early stages of development but lose this ability as they approach metamorphosis. This decline in regenerative capacity in larvae occurs during development of several components of the adaptive immune system in these animals. Experiments designed in this study will test the hypothesis that changes in the developing frog's immune system, including the appearance of cells characteristic of an inflammatory response, modify the local limb environment to interfere with or preclude cellular events required for regeneration when the limb is lost. Previous analyses of tadpole limb regeneration by this laboratory have shown the expression of many inflammation-related genes and the appearance of various immunomodulatory proteins in the limb during the first days of regeneration. Other investigators working with skin regeneration in several mouse models have shown the regeneration seen at fetal stages of development persists in adults that are immunodeficient and have fetal-like immune systems. This study will examine and quantify inflammation at the cellular and molecular levels during the early period of limb regeneration at larval stages when regeneration occurs successfully and at later stages when regeneration is poor. Procedures that affect inflammation positively and negatively will also be tested for their effects on regenerative capacity, using both molecular and morphological assays. The results are expected to reveal a strong correlation between loss of regenerative potential during development and strong or prolonged local inflammatory reactions to the regenerative stimulus. Such results will impact the emerging field of regenerative biology by highlighting the importance of peripheral immunity and immunomodulation in the local development of stem cells and tissue regeneration. The immune-regulating properties of various stem cells in mammalian models and their importance in tissue regeneration are increasingly recognized. Similar findings in a well-characterized amphibian model of regeneration will lead to greater understanding of the regenerative ability of these animals and the decline of this capacity in mammals. The broader impacts of the work, which are important not only for scientific advances but also for the education of graduate students in regenerative biology, include integrating considerations of the organism's immunity with cellular and molecular aspects of limb development, an integration required for a full appreciation of the factors controlling regeneration of organs in animals where the adaptive immune system is already functioning.