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Adult Mouse Digit Amputation and Regeneration: A Simple Model to Investigate Mammalian Blastema Formation and Intramembranous Ossification
Published on: July 12, 2019
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Transcriptomic landscape around wound bed defines regenerative versus non-regenerative outcomes in mouse digit
Archana Prabahar1,2, Connie S Chamberlain3, Ray Vanderby3
1Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, Ohio, United States of America.
Plos Computational Biology
|April 9, 2025
Summary
Understanding digit regeneration in mice reveals distinct molecular differences. Non-regenerative digits show intense early gene activity and unique macrophage responses, unlike regenerative ones, offering insights into regenerative medicine.
Area of Science:
- Regenerative Medicine
- Molecular Biology
- Mammalian Limb Regeneration
Background:
- The mouse distal terminal phalanx (P3) exhibits a puzzling regeneration threshold: <33% amputation regenerates, while >67% does not.
- Understanding the molecular basis of this regenerative disparity is critical for advancing regenerative medicine.
Purpose of the Study:
- To investigate the wound bed microenvironment's role in regenerative versus non-regenerative digit amputation outcomes.
- To identify molecular mechanisms differentiating successful regeneration from failure.
Main Methods:
- Utilized a P3-specific amputation model in mice.
- Employed time-series RNA sequencing (RNA-seq) and macrophage assays.
- Analyzed transcriptional responses and cytokine interactions.
Main Results:
- Non-regenerative digits displayed a more intense early transcriptional response in the wound bed.
- Distinct early macrophage phenotypes were observed between regenerative and non-regenerative outcomes.
- Regenerative digits showed unique co-expression modules linked to Bone Morphogenetic Protein 2 (Bmp2) and HOX gene family transcription factors (e.g., HOXA11, HOXD11).
Conclusions:
- Early transcriptional and macrophage responses significantly differ between regenerative and non-regenerative digit amputations.
- HOX gene family transcription factors may act as master regulators of regenerative gene signatures.
- A deep learning model successfully predicted amputation parameters from RNA-seq data, suggesting regenerative potential is encoded transcriptomically.
