Extended Exposure to Stiff Microenvironments Leads to Persistent Chromatin Remodeling in Human Mesenchymal Stem Cells

Area of Science:

• Biomaterials Science
• Cell Biology
• Regenerative Medicine

Background:

• Mesenchymal stem cells (MSCs) are vital for regenerative therapies, often requiring ex vivo expansion.
• Cellular microenvironments, particularly stiffness, can significantly impact MSC function and regenerative capacity.
• Mechanical cues may be stored via epigenomic mechanisms, creating a 'mechanical memory'.

Purpose of the Study:

• To investigate the role of epigenomic modifications in storing mechanical cues experienced by human mesenchymal stem cells (hMSCs).
• To quantify the effects of short-term and long-term mechanical dosing on epigenetic changes in hMSCs.
• To determine if mechanical memory in hMSCs is reversible or irreversible.

Main Methods:

• Utilized hydrogels with allyl sulfide cross-linkers and controlled radical polymerization for in situ hydrogel softening.
• Cultured hMSCs in dynamically softening hydrogels to simulate varying mechanical environments over time.
• Quantified epigenetic modifications, including histone acetylation and chromatin organization, and expression of epigenetic modulators.

Main Results:

• Histone acetylation and chromatin organization in hMSCs rapidly adapted to hydrogel softening.
• The reversibility of these epigenetic changes depended on the duration of exposure to the stiff microenvironment.
• Differential expression of epigenetic modulators was observed based on the cells' culture history.

Conclusions:

• Epigenetic remodeling in hMSCs can be persistent, suggesting a mechanism for mechanical memory.
• The duration of mechanical stimulation influences the stability and potential irreversibility of epigenetic changes.
• Understanding this mechanical memory is crucial for optimizing hMSC-based regenerative therapies.