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

• Published in: Advanced science Vol. 6; no. 3; pp. 1801483 - n/a
• Main Authors: Killaars, Anouk R., Grim, Joseph C., Walker, Cierra J., Hushka, Ella A., Brown, Tobin E., Anseth, Kristi S.
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 06.02.2019; John Wiley and Sons Inc
• Subjects: allyl sulfide hydrogels; chromatin remodeling; DNA methylation; Epigenetics; Gene expression; Hydrogels; Influence; mechanical memory; Membranes; mesenchymal stem cells; Morphology; photosoftening; Proteins; Software; Stem cells; chromatin remodeling; mechanical memory; allyl sulfide hydrogels; mesenchymal stem cells; photosoftening
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.201801483

Bone marrow derived human mesenchymal stem cells (hMSCs) are a promising cell source for regenerative therapies; however, ex vivo expansion is often required to achieve clinically useful cells numbers. Recent results reveal that when MSCs are cultured in stiff microenvironments, their regenerative capacity can be altered in a manner that is dependent on time (e.g., a mechanical dosing analogous to a chemical one). It is hypothesized that epigenomic modifications are involved in storing these mechanical cues, regulating gene expression, and ultimately leading to a mechanical memory. Using hydrogels containing an allyl sulfide cross‐linker and a radical‐mediated addition‐fragmentation chain transfer process, in situ softened hMSC‐laden hydrogels at different time points are achieved and the effects of short‐term and long‐term mechanical dosing on epigenetic modifications in hMSCs are quantified. Results show that histone acetylation and chromatin organization adapt rapidly after softening and can be reversible or irreversible depending on time of exposure to stiff microenvironments. Furthermore, epigenetic modulators are differentially expressed depending on the culture history. Collectively, these experiments suggest that epigenetic remodeling can be persistent and might be a memory keeper. Persistence in epigenetic remodeling is studied by using allyl sulfide hydrogels that can undergo a radical‐mediated addition‐fragmentation chain transfer process to in situ soften human mesenchymal stem cell‐laden hydrogels at different time points. Short‐term and long‐term mechanical dosing shows that histone acetylation and chromatin organization can be reversible or irreversible, suggesting epigenetics is a mechanical memory keeper.