Researchers here report on a way to reverse some of the age-related dysfunction observed in the hematopoietic stem cell population resident in bone marrow. These cells are responsible for generating red blood cells and immune cells. Some fraction of the age-related decline in immune function derives from issues in the hematopoietic cell populations originating with hematopoietic stem cells. It seems that hematopoietic stem cells have a distinct iron metabolism, and iron accumulation produces dysregulation in these cells. Reducing the presence of iron in hematopoietic stem cells reverses some of these changes. In the bigger picture, iron is connected to aging, and global reductions in iron levels achieved via a variety of methods have been demonstrated to modestly slow life in short-lived laboratory species such as flies and worms. Just how much of that effect derives from improved hematopoietic and immune function is an open question.
Mechanisms governing the maintenance of blood-producing hematopoietic stem and multipotent progenitor cells (HSPCs) are incompletely understood, particularly those regulating cell fate, ensuring long-term maintenance, and preventing aging-associated stem cell dysfunction. We uncovered a role for transitory free cytoplasmic iron as a rheostat for adult stem cell fate control. We found that HSPCs harbor comparatively small amounts of free iron and show the activation of a conserved molecular response to limited iron - particularly during mitosis.
To study the functional and molecular consequences of iron restriction, we developed models allowing for transient iron bioavailability limitation and combined single-molecule RNA quantification, metabolomics, and single-cell transcriptomic analyses with functional studies. Our data reveal that the activation of the limited iron response triggers coordinated metabolic and epigenetic events, establishing stemness-conferring gene regulation. Notably, we find that aging-associated cytoplasmic iron loading reversibly attenuates iron-dependent cell fate control, explicating intervention strategies for dysfunctional aged stem cells.
Link: https://doi.org/10.1...tem.2024.01.011
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