A team of scientists has discovered that some hematopoietic stem cells (HSCs) lose their ability to differentiate into useful somatic cells and that removing those bad HSCs is beneficial.
Blood creation diminishes with age
Hematopoiesis refers to the production of blood cells, both white and red. HSCs, which create these blood cells, are known to change with aging, developing mutations and losing the ability to perform their basic function [1]. Unsurprisingly, replacing the HSCs of older animals with those of younger animals imcreases lifespan [2] and putting older HSCs into younger animals decreases it [3].
HSCs age in several ways: genetic mutation is a crucial part [4], but epigenetic aging leading to altered gene expression [5] and mitochondrial changes [6] are also key factors. Some HSCs, however, remain quiescent, retaining their intrinsic abilities [7]. This work, therefore, focuses on determining which cells in aged animals retain useful abilities and which do not.
Younger stem cells perform better
In their first experiment, the researchers began with a population of young mice that had been lethally irradiated, killing all of their natural HSCs, then transplanting both young and old HSCs into the same mice. As expected, the older HSCs did not repopulate the bone marrow nearly as much as the younger HSCs did.
The researchers then transplanted either young or old HSCs into lethally irradiated, middle-aged (13-month-old) mice. These HSCs had a great many differences in the kinds of blood cells into which they differentiated: toung HSCs were more likely to differentiate into B cells, while old HSCs were more likely to differentiate into T cells and myeloid immune cells. However, the mice given younger HSCs had far more white blood cells and more robust immune systems in total.
As expected, the older HSCs led to epigenetically older blood, and mice given younger HSCs significantly outperformed mice given older HSCs on every metric that the researchers tested, including strength, balance, endurance, and fear conditioning.
Looking for the good ones
The researchers then performed RNA sequencing of both young and old HSCs. The gene expression of younger HSCs was largely similar between them, but old HSCs had significant distinguishing features, to the point that the quiescent cells were able to be clustered into three distinct groups. Surprisingly, many of the genes that are upregulated with aging were not upregulated in the third group (q3). Instead, the gene expression of this group was a lot more, although not entirely, like the gene expression of the young HSCs.
However, the researchers needed a good way to quickly determine which cells were in q3, looking for a marker that is readily identifiable with antibodies. They found that the surface marker CD150 increases with age-related gene expression markers but does not increase in the q3 cells.
This information was used to create distinct populations of aged cells, some with low CD150 and others with high CD150. Using their lethally irradiated young mice, the researchers determined that the cells had far different capabilities. The cells that were high in CD150 could proliferate but could not differentiate into functional cells. Genes related to stem cells activation were functional; the CD150-high cells simply could not create the basic blood cells that the mice needed.
On the other hand, the cells that were low in CD150 were able to do this, creating far more multipotent cells that led to the downstream creation of red and white blood cells. The researchers gave irradiated, 13-month-old mice cells that were derived from older donors but were separated to haave less CD150. These mice trended towards having better blood cell measurements than similar mice given unseparated HSCs. Mice that were only given cells high in CD150 performed much worse than either group, and there, the differences were statistically significant.
Similarly, the mice given CD150-low cells performed much better than the mice given CD150-high cells, with the mice given unseparated cells being in the middle. Epigenetically, the blood cells of the mice given CD150-low cells were found to be significantly younger. Most importantly, the mice given the CD150-low cells lived noticeably longer.
The researchers did not directly test the removal of CD150-high cells from naturally aged, unirradiated mice. However, their work shows that this may be a viable prospect. This, therefore, would be the next logical step to conduct, and if that is found to be viable and safe, the step after could be to test such an approach in people.
Literature
[1] Jaiswal, S., & Ebert, B. L. (2019). Clonal hematopoiesis in human aging and disease. Science, 366(6465), eaan4673.
[2] Guderyon, M. J., Chen, C., Bhattacharjee, A., Ge, G., Fernandez, R. A., Gelfond, J. A., … & Li, S. (2020). Mobilization‐based transplantation of young‐donor hematopoietic stem cells extends lifespan in mice. Aging Cell, 19(3), e13110.
[3] Leins, H., Mulaw, M., Eiwen, K., Sakk, V., Liang, Y., Denkinger, M., … & Schirmbeck, R. (2018). Aged murine hematopoietic stem cells drive aging-associated immune remodeling. Blood, The Journal of the American Society of Hematology, 132(6), 565-576.
[4] Moehrle, B. M., & Geiger, H. (2016). Aging of hematopoietic stem cells: DNA damage and mutations?. Experimental Hematology, 44(10), 895-901.
[5] Sun, D., Luo, M., Jeong, M., Rodriguez, B., Xia, Z., Hannah, R., … & Goodell, M. A. (2014). Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell stem cell, 14(5), 673-688.
[6] Mansell, E., Sigurdsson, V., Deltcheva, E., Brown, J., James, C., Miharada, K., … & Enver, T. (2021). Mitochondrial potentiation ameliorates age-related heterogeneity in hematopoietic stem cell function. Cell Stem Cell, 28(2), 241-256.
[7] Foudi, A., Hochedlinger, K., Van Buren, D., Schindler, J. W., Jaenisch, R., Carey, V., & Hock, H. (2009). Analysis of histone 2B-GFP retention reveals slowly cycling hematopoietic stem cells. Nature biotechnology, 27(1), 84-90.
