Animal Regeneration and its Loss: the Mouse as a Model of Limited Regeneration

Citation

Tan, Fayth Hui (2023) Animal Regeneration and its Loss: the Mouse as a Model of Limited Regeneration. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/wedb-2f55. https://resolver.caltech.edu/CaltechTHESIS:05292023-182121722

Abstract

In this dissertation, we explore animal regeneration through a comparative evolutionary-developmental framework. In Chapter 1, we review animal regeneration and its loss through examining broad developmental and physiological factors that correlate with regenerative ability. We also highlight the mouse as a model of regeneration loss, examining the limited regeneration of the digit tip and the heart. For each context, we discuss how these regenerative processes occur, the physiological and molecular factors involved, and previous attempts to induce or improve the regenerative response.

In Chapter 2, we explore the possibility of inducing regeneration in non-regenerating systems. Along with experiments in the jellyfish Aurelia coerulea, (formerly A. aurita sp. 1 strain) and the fruit fly Drosophila melanogaster, we find that supplementation with the amino acid L-leucine and sucrose induce appendage regeneration across these highly evolutionarily-diverged organisms. We discuss how this intervention highlights the conserved role of energetic parameters in regeneration, and how surpassing nutrient-based limitations may unlock regenerative responses in diverse contexts.

In Chapter 3, we characterize the derivatives of cardiac neural crest cells (CNCCs) in the hearts of neonatal mice at P1 and >P7. We confirm previous work on the diverse cardiac derivatives resulting from CNCCs, and provide additional evidence for CNCC-derived cardiomyocytes, a contribution still contested in current literature. We also demonstrate how CNCC derivatives form a distinct age-related developmental trajectory in the heart, and discuss how these changes may affect cardiac physiology and relate to the loss of neonatal heart regeneration.

Finally, in Chapter 4, we propose future directions based on the work carried out in Chapter 3. While CNCCs have explicitly been studied in the context of heart regeneration in zebrafish, their role in neonatal mouse heart regeneration has not been explored. First, we suggest further investigation into the differences between CNCC-derived and non-CNCC derived CMs, to see if their proliferative ability and molecular profile show different temporal dynamics over the course of embryonic and early postnatal stages. Then, to examine all CNCC-derived cell types in regenerating P1 and non-regenerating P8 hearts, we propose a single-nuclei RNA-sequencing experiment to better resolve questions about how the myocardial lineage interacts with nonmyocytes, and to capture the full extent of potential cardiomyocyte decline postnatally. Lastly, to understand how CNCC derivatives influence endogenous heart regeneration, we design a dual Cre and (r)tTA driver system in transgenic mice to perform a conditional ablation experiment of CNCCs in a cryoinjury model of neonatal heart regeneration.

Thesis Files