Specific cell states underlie complex tissue regeneration in spiny mice

Area of Science:

• Mammalian regeneration and comparative biology
• Cell cycle regulation and tissue repair

Background:

• Epimorphic regeneration in vertebrates relies on cell proliferation.
• Spiny mice (Acomys) exhibit remarkable regeneration, contrasting with fibrotic repair in laboratory mice (Mus).
• Understanding the specific cell types and dynamics driving mammalian regeneration remains limited.

Purpose of the Study:

• To investigate the proliferation dynamics and cell states involved in Acomys regeneration.
• To compare regenerative mechanisms in Acomys with fibrotic repair in Mus.
• To identify key cellular factors contributing to successful mammalian tissue regeneration.

Main Methods:

• Temporal pulse-chase experiments using thymidine analogs to track cell cycle progression.
• Immunostaining and single-cell RNA sequencing (scRNA-seq) to identify cell types and states.
• Cross-species comparison of stromal cell behavior and gene expression profiles in response to injury.

Main Results:

• Acomys stromal cells rapidly re-enter the cell cycle post-injury with spatiotemporal control, restricting proliferation distally.
• Mus stromal cells exhibit S-phase arrest without division after thymidine analog incorporation.
• Distinct cell types (CRABP1+, αSMA+) are associated with regeneration in Acomys versus scarring in Mus, with unique gene expression profiles identified.
• CRABP1+ fibroblasts are retained in adult Acomys but lost during development in Mus, yet their presence alone does not guarantee regeneration in Mus.

Conclusions:

• Mammalian regeneration depends on finely regulated cell proliferation dynamics and specific cell states.
• Injury-induced cell states promoting persistent cell cycle progression are critical for complex tissue regeneration.
• Species-specific differences in cell type presence and cell state acquisition underlie regenerative versus fibrotic healing.