By shifting mouse elderly hematopoietic stem cells (aged HSCs) to the environment of young mice (bone marrow niche), it was shown that the pattern of stem cell gene expression was rejuvenated to that of young hematopoietic stem cells. On the other hand, the function of elderly HSCs failed to recover in the young bone marrow niche. The epigenome (DNA methylation) of aged HSCs didnt 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.

A research group headed by Professor Atsushi Iwama in the Division of Stem Cell and Molecular Medicine, The Institute of Medical Science, The University of Tokyo (IMSUT) declared these world-first Outcomes and was published in the Journal of Experimental Medicine (online) on November 24th.

The results will contribute to the development of treatments for age-related blood diseases.

Professor Atsushi Iwama, Lead Scientist, IMSUT

The research group investigated whether rejuvenating aged HSCs in a young bone marrow market environment would rejuvenate.

Tens of thousands of elderly hematopoietic stem/progenitor cells gathered from 20-month-old mice were transplanted into 8-week-old young mice without pretreatment like 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 conducted.

They discovered that engrafted elderly HSCs were less capable of producing hematopoietic cells compared to younger HSCs. They also showed that differentiation of aged HSCs into multipotent progenitor cells was persistently impaired even in the young bone marrow market, and that the direction of differentiation was biased. It was found that the transfer of aged HSCs into the young bone marrow market does not enhance their stem cell function.

A more detailed analysis may reveal mechanisms that irreversibly affect aged HSC function Aging studies focusing on HSCs have been chased in mice with a bone marrow transfer model. However, the effect of aging on HSCs remains to be clarified.

Professor Iwama says as follows. This analysis has a substantial impact because it clarified the effect of aging on HSCs. Our results are expected to contribute to further elucidation of the mechanism of aging in HSCs and comprehension of the pathogenic mechanism of age-related blood disorders.

Source:

Journal reference:

Kuribayashi, W.,et al.(2020) Limited rejuvenation of aged hematopoietic stem cells in young bone marrow niche.Journal of Experimental Medicine.doi.org/10.1084/jem.20192283.

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