Exploring the Regenerative Potential of The Spiny Mouse with Spatial Transcriptomics

Abstract

Scar formation, a natural part of wound healing, can lead to functional impairments such as reduced joint mobility or diminished skin sensitivity. More critically, scarring in vital organs like the heart after a myocardial infarction results in permanent tissue loss and decreased function. These challenges highlight the need for regenerative approaches that restore tissue functionality. This thesis investigates the exceptional regenerative capabilities of the spiny mouse (Acomys), which uniquely regenerates complex tissues after injuries, unlike non-regenerative mammals such as the house mouse (Mus musculus). Spiny mice, adapted to predator-rich environments, can shed and fully regenerate their skin, including dermal layers, hairs, and muscles. By studying these mechanisms, we aim to uncover pathways to improve human regenerative medicine. In studying ear regeneration, we explored gene expression and cellular dynamics during tissue regrowth in spiny mice compared to house mice and gerbils. Regeneration in Acomys proceeds asymmetrically, likely relying on signals associated with nerves and blood vessels. Spatial transcriptomics (tomo-seq) identified genes linked to immune cells (e.g., Cd209a, Clec4g) and fibroblasts that promote regeneration. These genes are also expressed in the back skin of spiny mice, suggesting a broader regenerative potential. In contrast, non-regenerative species lack similar expression patterns, highlighting the importance of immune responses and extracellular matrix (ECM) factors in driving regeneration. To investigate whether this regenerative ability also extends to other organs, we studied heart regeneration using a heart attack model. Spiny mice demonstrated remarkable resilience, with lower mortality and improved heart function despite scar formation. Unlike the house mouse, where scar tissue increases over time, the scar in spiny mice remains stable and does not grow larger. This stability is accompanied by higher vascularization and better heart performance compared to house mice. Analysis of the ECM revealed differences in scar stiffness and collagen composition, suggesting adaptive remodeling that preserves function in Acomys. When exploring molecular mechanisms of heart repair, spatial transcriptomics of injured heart tissues revealed species-specific ECM responses and identified potential regulatory genes such as Rbm7 and Tceal3. Spiny mice developed more mature, functional scar structures characterized by a collagen-rich "basket-weave" pattern, which is associated with favorable healing outcomes. In conclusion, the spiny mouse serves as a powerful model for understanding regeneration. By elucidating the roles of immune cells and ECM remodeling, this research advances our knowledge of tissue repair and regeneration mechanisms. Future studies on these factors could inform the development of regenerative therapies for skin injuries and heart diseases, addressing critical gaps in current treatments. This work establishes a foundation for leveraging the spiny mouse’s unique biology to improve regenerative medicine while emphasizing the need for further exploration of ECM and immune-related pathways.