Immune tradeoffs during tissue regeneration in mammals

Discovering the mechanisms that induce tissue regeneration in animals remains one of the great, unanswered questions in biology. Why can salamanders re-grow amputated limbs but humans cannot? A particularly intriguing hypothesis, though poorly investigated, is the apparent loss of regenerative capacity during amniote evolution in favor of a strong adaptive immune response to protect against infection, the result of which is excessive wound fibrosis and a failure to regenerate damaged tissue. For homeotherms in particular, enhanced specificity of the immune response coupled with rapid wound closure and scarring has been viewed as a selectively advantageous solution to injury in the face of persistent microbial threat. Regeneration and wound healing studies examining this hypothesis have commonly focused across early ontogenetic stages in fetal and newborn animals when the immune system transitions from an underdeveloped state (where scar-free healing occurs), to a mature system after which regenerative ability precipitously declines in mammals and tissues heal with a scar. While evolution may have favored more specific immunity over regenerative ability in adult mammals, cases where adult regeneration persists provide a unique opportunity for investigating whether enhanced regenerative ability is accompanied by changes in immune function. Our recent discovery that wild African spiny mice (Acomys) are capable of regenerating skin, hair follicles, and cartilage, represents one of only a handful of documented cases of genuine tissue regeneration in wild, pathogen-exposed, immunocompetent adult mammals. Furthermore, compared to a sympatric genus (Myomyscus) that cannot regenerate tissue, it indicates that there is considerable interspecific variation in regenerative ability among some wild mammalian populations. Importantly, this comparison presents an opportunity to discover the mechanistic underpinning for enhanced regeneration in adult mammals, and presents a novel study system for examining hypotheses formulated to explain why some animals can regenerate and others cannot. Here, we propose to use comparative studies in these wild rodents to examine and quantify whether immune system tradeoffs impose constraints on tissue regeneration, a key hypothesis that has emerged from studies of model organisms, but that has yet to be tested in a system where individuals with fully developed immune systems can be compared. Specifically, we will address the hypothesis that trade-offs in immunity along (1) innate vs. adaptive and (2) pro vs. anti-inflammatory axes underlie variation in the ability and rate of regeneration between these wild species. Quantifying immune and inflammatory changes at the cellular and molecular level in response to injury is expected to reveal a bias towards innate immunity and anti-inflammatory modulators in regenerators (Acomys) and a shift towards adaptive immune and pro-inflammatory responses in non-regenerators (Myomyscus and Mus). This proposal is significant because our experiments will provide insight into how physiological responses to injury drive local changes in the cellular regenerative response. Furthermore, our results will produce strong evidence that either supports or rejects the hypothesis that tradeoffs along immune and inflammatory axes influence regenerative ability. Finally, our wild study system, for which we have documented both intra- and interspecific variation in regenerative ability, provides a new and unique opportunity for advancing our understanding of potential mechanisms that regulate regeneration in vertebrates. Regeneration biology is a fascinating topic that has great potential to engage young students and encourage them to seek further scientific training. The PIs will engage young Kenyan students in the process of science and discovery using regeneration biology in spiny mice as a tool. Specifically, the PIs will make a series of visits to a girls secondary school (Daraja Academy) near their field site using spiny mice to showcase basic concepts in regeneration biology. In a second phase of the program, students will visit the field site, and will have the opportunity to directly observe and participate in the spiny mice project. At the university level, the PIs will recruit students at all levels (postdoc, graduate students, undergraduates), including recruiting a Kenyan PhD student via an active collaboration with Dr. Kiama who serves as senior personnel on this proposal.