Manipulation of the nucleoscaffold potentiates cellular reprogramming kinetics.

Area of Science:

• Cell Biology
• Biophysics
• Genetics

Background:

• Somatic cell fate is determined by transcription factors and chromatin, maintained by silencing alternative fates via the nuclear scaffold.
• Lamin A/C is a core component of the nuclear scaffold, crucial for nuclear structure and function.

Purpose of the Study:

• To investigate the role of the nuclear scaffold, particularly Lamin A/C, in maintaining cell fate in human fibroblasts.
• To compare the effects of Lamin A/C knockdown and progerin mutation on nuclear properties and cellular reprogramming.

Main Methods:

• Assessed nuclear morphology and mechanical properties using microfluidic cellular squeezing.
• Analyzed chromatin accessibility and gene expression changes following Lamin A/C manipulation.
• Evaluated cellular reprogramming kinetics and senescence induction.

Main Results:

• Lamin A/C deficiency/mutation disrupted nuclear morphology and mechanics.
• Loss of Lamin A/C opened silenced heterochromatin and increased DNA accessibility.
• Lamin A/C loss accelerated reprogramming; progerin mutation induced senescence and inhibited reprogramming genes.

Conclusions:

• The nuclear scaffold, via Lamin A/C, physically safeguards cell fate.
• Lamin A/C's mechanical and structural roles are critical for maintaining cellular identity and preventing senescence.