Tokyo, Japan – Researchers at Tokyo Metropolitan University have quantified how different batches of mesenchymal stem cells respond to the mechanical rigidity of their environment. They focused on how certain proteins were “localized” in cell nuclei and found important trends in how this changed with stiffness. Their results explain inconsistencies between previous results and can serve as a guide to how scientists control the health of stem cells for research and medical treatments.

Mesenchymal stem cells (MSCs) are important “precursor cells” that can turn into muscle, cartilage, bone or fat cells. In 2006, pioneering work by Engler and co-workers showed that they can control which cell-typical mesenchymal stem cells they are converted into (or “differentiated”) by simply placing them on surfaces with a different mechanical stiffness or modulus of elasticity. Since then, scientists have been trying to identify exactly how this is happening. The problem is that the phenomenon turns out to be robust and reproducible very sensitive to the exact environment in which they are placed, even which batch they come from. Much is at stake: reliable control of the MSC states would mean more research and even potential biomedical applications.

This search inspired a team led by Associate Professor Hiromi Miyoshi of Tokyo Metropolitan University to investigate how different batches of MSCs respond to different environments. They focused on two proteins present in MSCs, the YAP protein, which helps cells respond to mechanical environments, and RUNX2, a key player in converting MSCs into osteoblasts that eventually become bones. They examined how different batches of MSC have different distributions of YAP and RUNX2 in their cells. For their “stiff” environments, they chose a specially developed gelatin substrate that has significantly better reproducibility than popular collagen alternatives.

From the start, they found that their batches were very different. In groundbreaking experiments examining how they turned into bone-forming or fat-forming cells, they found that the batches produced very different amounts of calcium and fat deposits. But when it came to their mechanically responsive behavior, it turned out that they weren’t as wildly different as originally thought. First, the team found that the amount of YAP in the nuclei (or “localization”) changes consistently between batches and plateaus for the same stiffness. For RUNX2, although the localization varied differently, they still plateaued at a certain stiffness value (other than YAP). Even then, the trend in RUNX2 localization was linear to the plateau.

With this type of information, anyone could make a gel with a certain stiffness and actively control the levels of YAP / RUNX2 in the nucleus of mesenchymal stem cells. In this way, they could adjust when and how their cells differ. The team hopes that this new level of control over cell fate will help accelerate research into MSCs and potentially lead to therapeutic applications.

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This work was supported by a JSPS KAKENHI Grant-in-Aid for Scientific Research (JP19J13048) and AMED under grant number 18gm5810012h9904.

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