Selective Elimination of Senescent Fibroblasts by Targeting the Cell Surface Protein ACKR3
Kento Takaya1, Toru Asou1, Kazuo Kishi1
1Department of Plastic and Reconstructive Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.
Abstract:
The accumulation of senescent cells in aging tissues is associated with age-related diseases and functional decline. Thus, senolysis, a therapy aimed at rejuvenation by removing senescent cells from the body, is being developed. However, this therapy requires the identification of membrane surface antigens that are specifically expressed on senescent cells for their selective elimination. We showed that atypical chemokine receptor 3 (ACKR3), a receptor of the CXC motif chemokine 12 (CXCL12) implicated in cancer, inflammation, and cardiovascular disorders, is selectively expressed on the surface of senescent human fibroblasts but not on proliferating cells. Importantly, the differential presence of ACKR3 enabled the isolation of senescent cells by flow cytometry using anti-ACKR3 antibodies. Furthermore, antibody-dependent cellular cytotoxicity assays revealed that cell surface ACKR3 preferentially sensitizes senescent but not dividing fibroblasts to cell injury by natural killer cells. Conclusively, the selective expression of ACKR3 on the surface of senescent cells allows the preferential elimination of senescent cells. These results might contribute to the future development of novel senolysis approaches.
Insights
Senolytic therapy aims to remove aging cells. Researchers found atypical chemokine receptor 3 (ACKR3) on senescent cells, enabling their selective elimination and potential rejuvenation.
Area of Science:
- Cellular senescence
- Immunology
- Molecular biology
Background:
- Cellular senescence contributes to aging and age-related diseases.
- Senolysis, a therapy to remove senescent cells, requires specific targets on these cells.
- Atypical chemokine receptor 3 (ACKR3) is involved in various physiological and pathological processes.
Purpose of the Study:
- To identify specific surface markers for senescent cells for targeted elimination.
- To investigate the role of atypical chemokine receptor 3 (ACKR3) in cellular senescence.
Main Methods:
- Flow cytometry using anti-ACKR3 antibodies to detect ACKR3 expression.
- Antibody-dependent cellular cytotoxicity (ADCC) assays to assess senescent cell elimination.
- Analysis of ACKR3 expression on senescent versus proliferating human fibroblasts.
Main Results:
- Atypical chemokine receptor 3 (ACKR3) is selectively expressed on the surface of senescent human fibroblasts, not proliferating cells.
- ACKR3 expression allowed for the isolation of senescent cells via flow cytometry.
- Senescent cells with surface ACKR3 were preferentially sensitized to natural killer cell-mediated lysis.
Conclusions:
- Selective expression of ACKR3 on senescent cells provides a target for their preferential elimination.
- ACKR3 can be utilized for developing novel senolytic therapies.
- This finding may advance strategies for combating age-related diseases through rejuvenation.
Related Concept Videos
01:09Introduction to Fibroblasts
02:15Replicative Cell Senescence