Extended Exposure to Stiff Microenvironments Leads to Persistent Chromatin Remodeling in Human Mesenchymal Stem Cells
Open Access
- 10 December 2018
- journal article
- research article
- Published by Wiley in Advanced Science
- Vol. 6 (3), 1801483
- https://doi.org/10.1002/advs.201801483
Abstract
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.Keywords
Funding Information
- National Institutes of Health (R01 RHL132353‐01, R21 AR067469)
- National Institutes of Health (T32 HL007822‐20)
- National Science Foundation (IGERT 1144807)
- National Institutes of Health (F31 HL142223‐01)
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