Mechanisms Involved in the Aging of Hematopoietic Stem Cells

Stem cell populations decline in activity with age, and the hematopoietic stem cells resident in bone marrow, responsible for generating blood and immune cells, are no exception. Their decline is one of the contributing factors leading to immunosenescence and inflammaging, the aging of the immune system. With age, the immune system becomes less effective in its tasks of destroying pathogens and errant cells, but also becomes chronically overactive at the same time. The result is inflammation, disruption of tissue regeneration, growing risk of cancer, increasing numbers of senescent cells, and vulnerability to infection.

Restoration of the hematopoietic stem cell population is one of the three necessary arms of immune rejuvenation. This will require advances in control over cell behavior, but is not too far beyond the present state of the art. The first generation of cell therapies resulted in cell transplants that near all die rather than engraft and participate in tissue maintenance. Today's stem cell therapies for the most part produce benefits due to temporary shifts in cell signaling brought about by the transplanted cells prior to their death. Reliable approaches by which large fractions of transplanted hematopoietic stem cells survive and take up residence will be needed. Transplanted cells will still suffer the consequences of a damaged surrounding tissue environment, but repairing that is a broader topic: it will need the other facets of the SENS damage repair approach to aging.

The other two arms of immune rejuvenation are regrowth of the thymus and clearance of malfunctioning immune cells. The thymus atrophies with age, but is required for the maturation of T cells of the adaptive immune system. These cells are initially created by hematopoietic stem cells in the bone marrow, migrate to the thymus, and there transformed into T cells of various types. As the thymus fades away this supply of T cells diminishes, ensuring that ever fewer naive T cells are available to tackle new threats. Lacking reinforcements, a growing fraction of the T cell population becomes senescent, exhausted, or uselessly specialized to persistent viruses such as cytomegalovirus. Other T cells malfunction and attack tissues, generating the varied and poorly mapped forms of autoimmunity that occur in late life.

Given a way to rapidly replace the entire immune cell population - restoration of the thymus and hematopoietic stem cell population may well be sufficient - it would make sense to destroy all of an older individual's immune cells. This would wipe the slate clean, removing all forms of damage and misconfiguration in immune cell populations. Vaccinations would have to be undertaken again, but that is a small price to pay for the opportunity to turn back immune system aging.

Updates on Old and Weary Haematopoiesis

Haematopoiesis is the process of the generation of all differentiated blood cells in the organism, including red blood cells, platelets, innate immune cells, and lymphocytes; all found to fade in functionality in aged individuals. Haematopoiesis is carried out by a rare population of haematopoietic stem cells (HSCs), which in adults, reside mainly in the bone marrow. There, they either remain dormant, i.e., in a quiescent state, or undergo proliferation and differentiation, depending on their cell-intrinsic transcriptional programs and the external cues from the surroundings.

Adult HSCs seem to be a heterogeneous subset of mainly multipotent and unipotent progenitors affiliated to specific lineages, and the ratio of their skewing shifts when homeostasis is perturbed. HSC maintenance relies on the support from the microenvironment or niche, necessary to preserve the self-renewing potential of HSCs. Extensive research on HSC niches composition shows that they are closely related to the vasculature in the bone marrow, with mainly endothelial, perivascular, and mesenchymal stromal cells secreting factors that support HSC maintenance. In this scenario, the effects of ageing on haematopoiesis may be the result of age-related alterations in all blood cell subsets, including HSCs and progenitors, as well as in the HSC niche.

In mice, the number of phenotypically defined HSCs can increase up to tenfold with ageing. In contrast, their functionality in terms of self-renewal and repopulating ability is remarkably reduced. Clonal HSC composition in old mice shows increased variability of clones derived from a single stem cell with smaller size per clone, when compared to young mice. Competitive transplantation of these HSCs proved that young HSCs perform better, with three-fold higher yield of mature granulocytes and lymphocytes. Furthermore, age-related defective HSCs seem to be able to differentiate into the myeloid lineage, but are incapable of the balanced generation of lymphocytes following transplantation. Thus, HSC defects are reflected in insufficiencies in their progeny of differentiated cells and contribute to poorer systemic performance of the haematopoietic system, i.e., immunosenescence.

At the molecular level, DNA damage and telomere shortening seem to be major mechanisms underlying the age-related decrease in the functionality and durability of HSCs. DNA damage accumulation is intimately related to increased reactive oxygen species (ROS) levels. In fact, HSCs reside in hypoxic bone marrow niches, which maintain their long-term self-renewal by mechanisms such as limiting their ROS production. Stressors, such as infections or chronic blood loss, shift HSCs from the quiescent to cycling state, which consequently leads to increased ROS levels and DNA damage.

Inflammageing is the characteristic process of chronic inflammation that has been described in aged individuals, with an increase of inflammatory cytokine levels that correlate with morbidity and age-related diseases. The HSC compartment is tightly connected to inflammatory processes, as a producer of innate immune cells. Furthermore, HSCs express pattern recognition receptors required for the identification of dangers, and a variety of cytokines and their receptors. Activation of these signalling pathways elicits HSC differentiation and myeloid skewing, aimed at mediating rapid myeloid cell recovery. However, when not finely regulated, they may cause HSC exhaustion.

HSC survival and function relies on the support from the microenvironment or niche in the bone marrow. Stem cell niches are complex and unique structures, yet they share many features that include cellular interactions, secreted factors, extracellular matrix, physical factors, metabolic conditions, and importantly, processes of scarring and inflammation. The changes in the bone marrow niche of aged mice include differences in gene expression and molecular structure in perivascular cells, arteries, and capillaries. In aged mice, enhancement of the Notch signalling pathway in endothelial cells can partially address some of these changes. Niche-forming vessel improvements are followed by increased HSC numbers, but no changes in their functionality. This suggests that niche-based rejuvenating strategies may have only partial efficiency to recover HSCs to a youthful state.

In conclusion, HSC ageing is characterised by reduced self-renewal, myeloid and platelet HSC skewing, and expanded clonal haematopoiesis that is considered a preleukaemic state. The underlying molecular mechanisms seem to be related to increased oxidative stress due to ROS accumulation and DNA damage, which are influenced by both cell- and cell non-autonomous mechanisms such as prolonged exposure to infections, inflammageing, immunosenescence, and age-related changes in the HSC niche. Thus, HSC ageing seems to be multifactorial and we are only beginning to connect all the dots.


Bicyclic peptide cytoxic drug conjurgates should be less toxic in clearing out existing hematopoietic stem cells than either chemotherapy or antibody drug conjurgates due to their rapid clearance from the body via the kidneys.

Posted by: Jim at September 6th, 2018 11:06 PM

"Antibodies and their very long systemic exposure are one of the key modalities in oncology development, both as a vehicle to deliver cytotoxics (antibody drug conjugates or ADCs) and in immuno-oncology. However, after billions of dollars of investment over the past 20 years, we still only have two approved ADCs (Adcetris and Kadcyla) due to the challenge of reaching an acceptable therapeutic index given prolonged exposure of normal tissue to toxin. Substantially less investment has gone into targeted delivery of radionuclides. Yet there has been some success using peptides as the delivery vector (peptide receptor radionuclide therapy)."

Posted by: Jim at September 7th, 2018 12:14 AM
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