Stabilization of heterochromatin by CLOCK promotes stem cell rejuvenation and cartilage regeneration

Area of Science:

• Cell Biology
• Chronobiology
• Aging Research

Background:

• Growing evidence links circadian clock function to aging.
• The role of circadian clock proteins in stem cell aging remains unclear.
• Investigating CLOCK's function in human mesenchymal stem cell (hMSC) aging is crucial.

Purpose of the Study:

• To investigate the role of CLOCK in hMSC aging.
• To determine if CLOCK can be targeted to alleviate aging-associated syndromes.
• To explore CLOCK's noncanonical functions in maintaining genomic stability.

Main Methods:

• Assessed CLOCK expression during hMSC aging.
• Overexpressed and knocked down CLOCK in hMSCs.
• Utilized gene therapy with lentiviral vectors in mouse models.
• Performed mechanistic studies involving protein complex formation and genomic analysis.

Main Results:

• CLOCK expression decreased with hMSC aging.
• CLOCK deficiency accelerated hMSC senescence.
• CLOCK overexpression, even in a transcriptionally inactive form, rejuvenated aged hMSCs.
• CLOCK stabilized heterochromatin and repetitive genomic sequences by complexing with nuclear lamina and KAP1.
• CLOCK gene therapy enhanced cartilage regeneration and reduced age-related joint degeneration in mice.

Conclusions:

• CLOCK plays a critical, transcription-independent role in counteracting hMSC aging.
• CLOCK stabilizes heterochromatin and genomic integrity, crucial for mitigating aging.
• CLOCK represents a potential therapeutic target for age-related diseases and tissue regeneration.