Mechanobiological rejuvenation of mesenchymal stem cell therapeutics

As the worldwide population continues to age, there is an increasing need for improved regenerative therapies. Mesenchymal stem cells (MSCs) are a promising therapeutic cell type for a wide range of age-related degenerative conditions. A major limiter of current MSC therapies is cellular senescence, a process in which cells stop growing and lose their regenerative properties. Senescence in MSCs can be caused by poor donor health or advanced age and through expansion in cell culture prior to therapeutic implantation. In this work, we examined the effects of mechanical conditioning on senescence in MSCs. Using a novel technology developed in our laboratory, we applied cyclic mechanical stretch and drug treatment to MSCs derived from aged patients. We demonstrated that conditioning with physiological mechanical loading rejuvenates a broad range of aged MSC functionality, including, proliferation, culture expansion, multipotency, metabolism, and DNA damage repair mechanisms. A detailed analysis of transcriptomic and epigenetic changes induced by mechanical loading revealed that these lasting functional enhancements are likely due to broad changes in chromatin organization, reversing some of the gene expression patterns that occur during MSC senescence. Computational modeling studies of the forces applied to the MSCs during mechanical conditioning demonstrated that the optimal mechanical conditioning regime may unravel chromatin and enable re-organization of the genetic landscape without inducing physical DNA damage. Taken together, this work demonstrates that mechanical conditioning can rejuvenate aged MSC function and improve their prospects in cell-based regenerative therapies.