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Author Spotlight: Implementing the Enhanced Recovery After Surgery Concept in Rehabilitation Following Anterior Cruciate Ligament Reconstruction
Published on: March 1, 2024
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Sex-Based Differences in Cell Types and Gene Expression within the Anterior Cruciate Ligament
Steven M Garcia1,2, Justin Lau1,2,3, Aboubacar Wague1,2
1San Francisco Veterans Affairs Health Care System, San Francisco, California.
The Journal of Bone and Joint Surgery. American Volume
|January 26, 2026
Summary
Female progenitor cells in anterior cruciate ligaments (ACL) show gene expression linked to collagen degradation, potentially explaining higher ACL tear risk in women. This highlights sex-based cellular differences in musculoskeletal injuries.
Area of Science:
- Musculoskeletal Medicine
- Cellular Biology
- Genomics
Background:
- Sex-based disparities in anterior cruciate ligament (ACL) injury rates and severity present a significant challenge in musculoskeletal medicine.
- The underlying causes for these disparities, particularly the higher ACL tear risk in females, remain unclear.
- This study investigates the hypothesis that cellular differences in human progenitor cells contribute to sex-based differences in ACL injury risk.
Purpose of the Study:
- To investigate sex-based differences in cellular composition and gene expression within human anterior cruciate ligament (ACL) samples.
- To identify specific cell populations and molecular pathways that may explain differential ACL injury rates between males and females.
- To explore potential therapeutic targets for reducing ACL injury risk and improving outcomes.
Main Methods:
- Anterior cruciate ligament (ACL) samples were obtained from male and female patients undergoing ACL reconstruction.
- Live cells were isolated using flow cytometry and subjected to single-cell RNA sequencing.
- Differential gene expression analysis was performed, defining significant differences as >25% increase in expression (log2 fold change > 0.32) and p < 0.05. Cell subpopulations were characterized via immunofluorescence.
Main Results:
- Significant sex-based differences were identified across all native cell types within the ACL.
- Fibroblast progenitor-like cells (TPPP3+) from female patients exhibited higher expression of genes associated with collagen dysregulation and degradation compared to male counterparts.
- These findings indicate a distinct molecular profile in female ACL progenitor cells.
Conclusions:
- A ligament progenitor cell population with sex-dependent gene expression profiles has been identified.
- These cellular differences suggest that sex-based variations in stem cell populations may underlie differential injury rates and outcomes in musculoskeletal injuries.
- Targeting the identified differential gene expression in TPPP3+ cells could offer novel therapeutic strategies for strengthening the ACL and mitigating rupture risk, especially in female athletes.
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