Biology

A Gentler Approach to Transplanting Young Hematopoietic Stem Cells into Old Mice Modestly Extends Life Span



Stem cell populations become damaged and dysfunctional with age. Some of this is issues with the stem cells themselves, and some of this results from problem with the signaling environment and function of the stem cell niche. Which of these factors is more important likely varies by stem cell population. Among the best studied of stem cell types, the evidence suggests that muscle stem cells remain capable in old age, but become ever more quiescent, while hematopoietic stem cells become damaged and dysfunctional, unable to perform. Hematopoietic stem cells reside in the bone marrow and are responsible for generating blood and immune cells. Altered and reduced hematopoiesis is an important aspect of immune system decline with age, and thus providing functional replacement cells to older individuals may prove to be a useful form of rejuvenation therapy.

Unfortunately, the introduction of new hematopoietic stem cells at present requires removal of the existing population in order to make space in the stem cell niches of the bone marrow. The options for replacement are somewhat blunt and limited, deriving from the bone marrow transplant field. The standard approach is chemotherapy, which is quite unpleasant to experience, and further comes accompanied by a non-trivial risk of death or failure to adequately reconstitute the immune system following transplantation. That risk profile is considerably worse in older patients, and thus this sort of therapy is largely restricted to treatment of serious disease in the old, such as cancer.

A better, more gentle approach is needed if replacement of hematopoietic stem cells is to become a widespread preventative treatment for older individuals, a way to postpone immunosenescence. In the past, I have suggested the application of suicide gene therapies to the selective destruction of cell populations, as presently being pioneered by Oisin Biotechnologies to target senescent and cancerous cells. Here, researchers apply a different approach, using signals that convince stem cells from the bone marrow to leave their niches and migrate into the bloodstream. This is already widely used as a way to collect cells from donors, and the data here provides compelling evidence for it to leave the niches empty enough to allow a meaningful number transplanted stem cells to engraft and set to work. That this approach modestly extends life in mice, when used to transplant young hematopoietic stem cells into older animals, is a good demonstration of the gentle nature of the technique in comparison to chemotherapy.

Mobilization-based transplantation of young-donor hematopoietic stem cells extends lifespan in mice

Stem cells are critical to tissue regeneration and homeostasis during aging and disease. As a hallmark of aging, stem cell dysfunction is critical to improving the quality of life for people with advanced age. Stem cell-based therapy holds considerable promise for treating aging-related diseases, with hematopoietic stem cells (HSCs) being the most widely used for stem cell therapies. It is becoming increasingly clear that age-related changes in the niche space can induce alterations in hematopoiesis, including myeloid lineage skewing. However, extrinsic stimulation of HSCs with cytokines is highly dependent on intrinsic determinants. To date, the “gold standard” measure of HSC functionality remains an in vivo repopulating assay to determine their ability to re-establish lineage cell production in recipients during hematopoietic stem cell transplantation (HSCT). Unfortunately, conventional HSCT procedures require harsh cytotoxic conditioning – irradiation and/or chemotherapy – that alters HSC niches in the bone marrow, permanently damaging bone architecture. These limitations have confounded efforts to assess health-associated benefits of HSC replacement and rejuvenation.

The majority of HSCs reside in specialized niches within the bone marrow, although some HSCs leave these niches and migrate into the blood, ~1-5% of total HSCs each day. Mobilization of HSCs into the peripheral blood can be achieved through administration of G-CSF, an effect that is dramatically increased when G-CSF is administered in combination with other mobilizers, such as AMD3100. This HSC mobilization strategy constitutes the basic mechanism underlying collection of peripheral blood donor stem cells in the clinic. Critically, this increased mobilization also creates temporarily empty niches in the bone marrow, opening a window of opportunity for donor cell engraftment. Here, we use a novel mobilization-based HSCT procedure to investigate the health-associated benefits of replacing HSCs from aged recipients with young-donor HSCs. Additionally, we take advantage of the niche-preserving properties of this mobilization-based HSCT to investigate the influence of aged niche signaling upon a low percentage of young-donor HSCs.

Using this approach, we are the first to report an increase in median lifespan (12%) and a decrease in overall mortality hazard (hazard ratio: 0.42) in aged mice following transplantation of young-donor HSCs. The increase in longevity was accompanied by reductions of frailty measures and increases in food intake and body weight of aged recipients. Young-donor HSCs not only preserved youthful function within the aged bone marrow stroma, but also at least partially ameliorated dysfunctional hematopoietic phenotypes of aged recipients. This compelling evidence that mammalian health and lifespan can be extended through stem cell therapy adds a new category to the very limited list of successful anti-aging/life-extending interventions. Our findings have implications for further development of stem cell therapies for increasing health and lifespan.

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