Hematopoietic cell populations of various types differentiated from hematopoietic stem cells reside in the bone marrow and are responsible for creating blood and immune cells. Hematopoietic stem cells become dysfunctional with advancing age, as is true of all stem cell populations. The proximate causes of this dysfunction are likely different for every type of stem cell, however. Of the stem cell populations that are well-researched, some remain fully functional in principle but become increasingly quiescent. Others suffer an accumulation of molecular damage that renders them dysfunctional.
In all cases, it is likely that aging of the stem cell niche is an important cause of stem cell dysfunction. The niche is a collection of specialized cells that support stem cells in their function. In search of a greater understanding of the age-related decline of hematopoiesis, research groups have devoted attention to mapping the bone marrow niche and its component cells. The goal is to identify specific age-related changes that might prove to be good points for intervention. This leads to intriguing work such as that outlined in today's research materials, in which the scientists involved identified specific signaling in mesenchymal cells of the hematopoietic niche that appears relevant to the aging of hematopoietic stem cells.
As with any complex system, hematopoietic stem cells lose functionality as they age - and, in the process, contribute to the risk of serious diseases, including blood cancers. We know that the risk of developing aging-associated diseases is different among different individuals. Surprisingly, however, little is known about whether hematopoietic stem cells age differently between individuals. This is in part because these hematopoietic stem cells are so rare, researchers typically pool all of these stem cells together, studying them in aggregate.
Researchers recently studied hematopoietic stem cells at the single cell level in nine individual, genetically identical middle-aged mice - offering the first close look at how subtle changes in the bone marrow microenvironment ages hematopoietic stem cells across individual mice. Researchers found that despite the mice being all the same age, the hematopoietic stem cells in the bone marrow of these individual mice aged differently. But that's not all. The team could predict the function of the hematopoietic stem cells based on the activity of two growth factors that are also present in humans.
The two growth factors - Kitl and Igf1 - are produced by mesenchymal stromal cells (MSC) that surround the stem cells in the bone marrow microenvironment. By profiling the RNA transcriptome in these MSCs across individual mice, researchers found that the decline of these growth factors correlated with age-associated molecular programs in hematopoietic stem cells.
Here, we generated individual single cell transcriptomic profiles of hematopoietic and non-hematopoietic cell types in five young adult and nine middle-aged C57BL/6J female mice, providing a web-accessible transcriptomic resource for the field. Among all assessed cell types, hematopoietic stem cells (HSCs) exhibited the greatest phenotypic variation in expansion among individual middle-aged mice. We computationally pooled samples to define modules representing the molecular signatures of middle-aged HSCs and interrogated which extrinsic regulatory cell types and factors would predict variance in these signatures between individual middle-aged mice.
Decline in signaling mediated by ADIPOQ, KITL and IGF1 from mesenchymal stromal cells (MSCs) was predicted to have the greatest transcriptional impact on middle-aged HSCs, as opposed to signaling mediated by endothelial cells or mature hematopoietic cell types. In individual middle-aged mice, lower expression of Kitl and Igf1 in MSCs highly correlated with reduced lymphoid lineage commitment of HSCs and increased signatures of differentiation-inactive HSCs. These signatures were independent of expression of aging-associated pro-inflammatory cytokines. In sum, we find that Kitl and Igf1 expression are co-regulated and variable between individual mice at middle age and expression of these factors is predictive of HSC activation and lymphoid commitment independently of inflammation.
View the full article at FightAging
