Epigenetic modifications to DNA, gene expression, and cell function all change for the worse in stem cells in old tissues. Researchers here show that putting old hematopoietic stem cells into a young tissue environment acts to reverse many of these changes to the transcriptome, the manufacture of RNA that is the first stage of gene expression, but has far less benefit when it comes to epigenetic changes and loss of cell function. Epigenetic modifications regulate gene expression, and gene expression determines cell behavior, so it is interesting to see such a divergence in outcomes between these properties of cells. Both replication of the results and a close inspection of the methodologies used are called for.
The functions and characteristics of hematopoietic stem cells (HSCs) change with age. The ability to produce blood cells is reduced and differentiation is biased, increasing the risk of developing myeloid tumors. By transferring mouse aged HSCs to the bone marrow niche of young mice, it was demonstrated that the pattern of stem cell gene expression was rejuvenated to that of young hematopoietic stem cells. On the other hand, the function of aged HSCs did not recover in the young bone marrow niche. The epigenome (DNA methylation) of aged HSCs did not change significantly even in the young bone marrow niche, and DNA methylation profiles were found to be a better index than the gene expression pattern of aged HSCs.
The research group investigated whether placing aged HSCs in a young bone marrow niche environment would rejuvenate the cells. Tens of thousands of aged hematopoietic stem cells and progenitor cells collected from 20-month-old mice were transplanted into 8-week-old young mice without pretreatment such as irradiation. After two months of follow-up, they collected bone marrow cells and performed flow cytometric analysis. The research team also transplanted 10-week-old young mouse HSCs for comparison. In addition, engrafted aged HSCs were fractionated and RNA sequence analysis and DNA methylation analysis were performed.
The researchers found that engrafted aged HSCs were less capable of producing hematopoietic cells than younger HSCs. They also showed that differentiation of aged HSCs into multipotent progenitor cells was persistently impaired even in the young bone marrow niche and that the direction of differentiation was biased. Thus it was found that the transfer of aged HSCs to the young bone marrow niche does not improve their stem cell function.