Scientists Epigenetically Rejuvenate Aging Bone Marrow Stem Cells

Most people don’t think about their bones until maybe they break one. But breaking a bone, especially when you are older, could signify that your bones are weak. As we age, our bones become thinner, and our risk for diseases like osteoporosis is higher. This is because the stem cells responsible for keeping bone tissue dense and strong become impaired as we age.

Research over the past few years has shown that aging is a process that involves epigenetic factors, like changes in DNA methylation, post-translational modifications of histones, and chromatin accessible state.  Over the years, our cells are exposed to various environmental factors which accumulate over time, altering these mechanisms and the way our genes are expressed. This change in the epigenome ultimately compromises cell function, leading to the decline we observe as one ages.

To determine the epigenetic factors affecting bone development in aging, a group of scientists from Max Planck Institute for Biology of Ageing and CECAD at the University of Cologne conducted a study to investigate the epigenome of bone marrow mesenchymal stem cells (MSCs). In particular, they looked at how chromatin remodeling, the arrangement of DNA around histone proteins, determines the fate of MSCs. Their results are available online in Nature Aging.

Over our lifetime, bone marrow mesenchymal stem cells (MSCs) continuously synthesize bone tissue, cartridge, and fat cells. However, the older we get, the less capable these stem cells are at reproducing correctly. During replication, MSCs undergo epigenetic and transcriptional changes, which can be driven by chromatin accessibility. When the chromatin is loosely packed, transcription factors and other binding proteins can access the DNA and control gene expression. Access is cut off, though, when the chromatin is wrapped tightly around the DNA.

In this study, the researchers wanted to find out why MSCs manufacture less material to develop and maintain bones in aging, causing excess fat to build up in the bone marrow. Their focus was on the interplay between metabolism and the epigenome since metabolites are known to affect the activity of chromatin-modifying enzymes.

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In comparing the epigenome of these stem cells in young mice to older ones, they noticed a significant difference, specifically in the genes required for bone production. They reported that there was a shift in the subcellular localization of the metabolite acetyl-CoA upon aging, which reduced histone acetylation levels and chromatin accessibility.

Because epigenetic modifications are potentially reversible, they investigated whether the stem cells could be revitalized by reestablishing histone acetylation levels. To achieve this, sodium acetate was added directly to aged bone marrow stem cells. Sodium acetate is an external source of acetyl-CoA, and it can be converted into a material that allows enzymes to attach to histones, improving chromatin plasticity and thus bone-producing capacity.

“This treatment impressively caused the epigenome to rejuvenate, improving stem cell activity and leading to higher production of bone cells,” said Andromachi Pouikli, first author of the study.

As a further step, the researchers tested human MSCs to see if epigenome changes contributed to bone fractures or osteoporosis in older people. Using stem cells obtained from the bone marrow of patients after hip surgery, they analyzed the same pathways and histone acetylation levels as in the mice study. Again, the results were similar, even when compared with young, healthy individuals.

The team reported that “short-term treatment of MSCs with acetate resulted in increased histone acetylation and chromatin accessibility, leading to enhanced stem cell differentiation potential, suggests that intervening in the chromatin landscape represents a promising approach to rejuvenate aged MSCs.”

While sodium acetate is also available as a food additive, scientists warn that it should not be used to treat osteoporosis. “Our observed effect is very specific to certain cells, explains Peter Tessarz, who headed the study.”However, there are already first experiences with stem cell therapies for osteoporosis. Such a treatment with acetate could also work in such a case. However, we still need to investigate in more detail the effects on the whole organism in order to exclude possible risks and side effects.”

Source: Andromachi Pouikli, et al. (2021). Chromatin remodeling due to degradation of citrate carrier impairs osteogenesis of aged mesenchymal stem cells. Nature Aging.

Reference: Fountain of youth for ageing stem cells in bone marrow. Max-Planck-Gesellschaft. September 13, 2021.

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