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Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery
K L Rudolph1, S Chang, M Millard
1Department of Adult Oncology, Medicine and Genetics, Dana-Farber Cancer Institute, 44 Binney Street (M413), and Harvard Medical School, Boston, MA 02115, USA.
Abstract:
Accelerated telomere loss has been proposed to be a factor leading to end-stage organ failure in chronic diseases of high cellular turnover such as liver cirrhosis. To test this hypothesis directly, telomerase-deficient mice, null for the essential telomerase RNA (mTR) gene, were subjected to genetic, surgical, and chemical ablation of the liver. Telomere dysfunction was associated with defects in liver regeneration and accelerated the development of liver cirrhosis in response to chronic liver injury. Adenoviral delivery of mTR into the livers of mTR(-/-) mice with short dysfunctional telomeres restored telomerase activity and telomere function, alleviated cirrhotic pathology, and improved liver function. These studies indicate that telomere dysfunction contributes to chronic diseases of continual cellular loss-replacement and encourage the evaluation of "telomerase therapy" for such diseases.
Insights
Telomere shortening accelerates liver cirrhosis and organ failure in mice. Restoring telomerase activity reversed these effects, suggesting telomere therapy for chronic liver disease.
Area of Science:
- Hepatology
- Molecular Biology
- Gerontology
Background:
- Accelerated telomere loss is implicated in end-stage organ failure for chronic diseases with high cellular turnover, like liver cirrhosis.
- The role of telomere attrition in liver disease progression remains incompletely understood.
Purpose of the Study:
- To investigate the direct impact of telomere dysfunction on liver regeneration and cirrhosis development.
- To assess the therapeutic potential of restoring telomerase activity in a murine model of liver injury.
Main Methods:
- Utilized telomerase-deficient mice (mTR-/-) subjected to liver ablation (genetic, surgical, chemical).
- Assessed liver regeneration, cirrhosis development, and telomere dysfunction.
- Administered adenoviral mTR to restore telomerase activity in affected mice.
Main Results:
- Telomere dysfunction impaired liver regeneration and accelerated cirrhosis following chronic liver injury.
- Restoration of telomerase activity via adenoviral mTR improved telomere function and alleviated cirrhotic pathology.
- Liver function was significantly improved in mice receiving telomerase therapy.
Conclusions:
- Telomere dysfunction is a contributing factor to chronic liver diseases characterized by continuous cell loss and replacement.
- Telomere maintenance is crucial for liver regeneration and preventing disease progression.
- These findings support the potential of telomerase therapy for treating chronic liver diseases.