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Published on: August 9, 2017
Characterization of p16-positive stromal cells in age-related cardiac disorders
Taiki Morimura1,2, Teh-Wei Wang1,2, Satoshi Kawakami1
1Division of Cancer Cell Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Insights
Senescence-associated fibroblasts (p16+ fibroblasts) drive cardiac fibrosis in aging hearts. Eliminating these cells reverses age-related fibrosis, offering new therapeutic targets for heart failure.
Area of Science:
- Cardiovascular Biology
- Aging Research
- Cellular Senescence
Background:
- Aging hearts exhibit structural changes like fibrosis and hypertrophy, leading to functional decline and heart failure.
- Cardiac stromal cells, including fibroblasts, are implicated in age-related cardiac alterations, with specific subsets potentially exerting greater influence.
Purpose of the Study:
- To investigate the role of p16-positive (p16+) senescence-associated cells in age-related cardiac fibrosis.
- To identify specific molecular pathways and cell types involved in cardiac aging.
Main Methods:
- Single-cell RNA sequencing was performed on aged p16-Tom mice to label and analyze p16+ cells.
- Transcriptomic analysis identified enriched signaling pathways in p16+ fibroblasts.
- Selective elimination of p16+ fibroblasts was conducted in aged p16-Col1a2-LRTD mice to assess functional impact.
Main Results:
- TGF-β signaling and BMP4 were significantly upregulated in p16+ fibroblasts compared to p16- fibroblasts.
- Upregulated pathways in p16+ fibroblasts potentially promoted collagen gene expression (Col4a1, Col5a3).
- Selective elimination of p16+ fibroblasts effectively ameliorated cardiac fibrosis in aged mice.
Conclusions:
- p16+ fibroblasts are critical drivers of age-associated cardiac fibrosis.
- Transcriptomic signatures of p16+ fibroblasts can help identify human fibroblast subsets contributing to age-related cardiac diseases like dilated cardiomyopathy.
Abstract:
The heart undergoes structural alterations, including fibrosis and cardiomyocyte hypertrophy with age. These alterations are accompanied by functional decline, resulting in heart failure. Although cardiac stromal cells such as fibroblasts and macrophages are known to play a role in age-related cardiac changes, specific subsets of these cells may have a more pronounced effect on the development of these alterations. In this study, we analyzed p16, a marker of senescence,-positive (p16+) cells in cardiac fibrosis by single-cell RNA sequencing of aged p16-Tom mice, in which p16+ cells can be labelled in the presence of tamoxifen. We found that TGF-β signalling were significantly enriched in the transcriptome of p16+ fibroblasts compared with p16- fibroblasts. Besides, BMP4 was upregulated in p16+ fibroblasts. This activation potentially promoted the expression of collagen genes such as Col4a1 and Col5a3. Selective elimination of p16+ fibroblasts ameliorated cardiac fibrosis in aged p16-Col1a2-LRTD mice, with levels comparable to those observed in young mice. These findings suggest that p16+ fibroblasts play a critical role in age-associated cardiac fibrosis. We further demonstrate the potential use of transcriptomic signatures of p16+ fibroblasts to identify human fibroblast subsets causing age-related cardiac diseases such as dilated cardiomyopathy.
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