P-selectin levels distinguished two groups of aging blood stem cells with different functions
P-selectin levels distinguished two groups of aging blood stem cells with different functions
Hematopoietic stem cells in the bone marrow continually replenish the blood and immune system. In an article published on August 5, the authors analyzed individual human cells and tested two fractions of mouse cells through competitive transplantation. In the human data, high expression of SELP, the gene encoding the cell surface protein P-selectin, identified a distinct cell state. Mouse cells with high levels of this protein were less effective at restoring blood production.
A hematopoietic stem cell must maintain its own population over the long term while producing descendants from multiple lineages. With age, the bone marrow increasingly produces myeloid cells, which give rise to some components of the innate immune system, while stem cells become less able to sustain blood production over time. The authors looked for cells at an early stage of this shift, when part of the stem cell pool still retains more stable function.
In a published single-cell atlas of human bone marrow, SELP expression increased from young donors to middle-aged individuals. Their stem cells formed two groups. Cells with high SELP expression showed greater activity of genes involved in inflammation and myeloid development. They also displayed signs of oxidative stress and DNA damage. Cells with low SELP expression retained genes associated with antioxidant defense and lymphoid development, which produces the immune system's B- and T-cells.
The authors then sorted mouse cells by P-selectin level and tested the function of the two fractions through competitive transplantation. In each experiment, they mixed each fraction with the same number of competitor cells. Together, these cells populated the bone marrow of an irradiated recipient and restored its blood. After 16 weeks, the blood contained fewer descendants of cells with high P-selectin levels. These cells showed a stronger bias toward the myeloid lineage and were less likely to persist within the bone marrow stem cell population. The fraction with low protein levels restored blood production more effectively.
The two fractions also differed in gene regulation. Different regions of DNA were accessible in each fraction, allowing the cells to read different sets of instructions. In cells with high P-selectin levels, these regions were associated with inflammation and formation of the platelet lineage. In cells with low levels, they were associated with metabolic resilience and protection against oxidation. In a separate mouse experiment, an inflammatory stimulus rapidly increased the proportion of cells with high P-selectin levels and intensified oxidative stress in these cells.
The aging stem cell population therefore contains both cells that are less able to sustain blood production over the long term and cells with a better preserved reserve. In the mouse model, P-selectin level provided a measurable marker of this difference. It distinguished cells with vulnerable function from cells that retained their reserve more effectively.