Nuclei sense complex tissue shape and direct intestinal stem cell fate

Area of Science:

• Biophysics
• Cell Biology
• Tissue Engineering

Background:

• Tissue architecture and function are critically influenced by mechanical cues.
• Previous research on isolated cells inadequately predicts tissue-level mechanical responses.
• The role of cell nuclei in sensing forces within 3D tissues and directing differentiation is largely unknown.

Purpose of the Study:

• To investigate how cell nuclei sense mechanical forces within 3D tissues.
• To elucidate the role of nuclear mechanics in directing stem cell differentiation.
• To identify the nuclear scaffolding protein lamin-A as a key mechanosensor.

Main Methods:

• Utilized live reporters and material-based organoid models to study nuclear mechanosensing.
• Engineered spatiotemporally controlled tissue curvature using photo-degradable hydrogels.
• Analyzed lamin-A levels and nuclear wrinkling in response to mechanical forces in organoids and tissue explants.

Main Results:

• Lamin-A levels and nuclear wrinkling increase with elevated forces on differentiated Paneth cell nuclei.
• Enhanced nuclear mechanotransduction promotes cell differentiation, even under stem cell-promoting conditions.
• Spatially patterned lamin-A levels were directed across mouse and human organoids by engineered tissue curvature.

Conclusions:

• The cell nucleus functions as an active mechanosensor of tissue shape.
• Nuclear mechanics play a crucial role in directing stem cell fate and differentiation.
• A conserved nuclear mechanosensing pathway in epithelial tissues was uncovered, linking tissue mechanics to cell fate.