One of the reasons why the immune system declines with age is that hematopoietic stem cell populations that are resident in the bone marrow and responsible for creating immune cells become progressively more damaged and dysfunctional over time. It isn't just the stem cells, however. Stem cells reside within structures of supporting cells known as niches. The niche itself becomes damaged and dysfunction, contributing to the problems exhibited by stem cell populations.
One of the most direct approaches to stem cell aging is to introduce into the body a replacement population of undamaged, rejuvenated stem cells, such as those that can be generated via the creation of induced pluripotent stem cells from a patient tissue sample. Some preparation and finessing is needed for hematopoietic stem cell transplants to ensure the transplanted cells survive, but this is already accomplished as a form of treatment for severe disease. The preparation is stressful on the patient at the present time, but it should be possible to develop less stressful approaches if the potential for a much broader use of hematopoietic stem cell transplantation emerges.
Unfortunately, and as noted in today's open access paper, the age-damaged state of the stem cell niche ensures that one cannot just transplant youthful hematopoietic stem cells and expect it to reliably improve function. Young cells are impeded by the damaged niche, and coerced into adopting a state that is closer to that of old cells. This is a universal issue across stem cell populations, and a solution is much needed.
Aging is linked to various dysfunctions of the immune system, including the decline of its primary developmental source: the hematopoietic stem cell (HSC) niche. This decline leads to chronic inflammation, increased vulnerability to infections, cancer, autoimmune diseases, and reduced vaccine efficacy. As individuals age, the HSC niche undergoes significant changes, including greater adipocyte accumulation and alterations in the molecular microenvironment, which may influence the development and function of immune cells. Among these cells, the impact of the aging HSC niche on dendritic cell (DC) function is less understood.
Heterochronic autologous HSC transplantation is a promising intervention to prevent age-related disorders, contributing to the extension of healthspan and longevity, however, several murine experiments failed to produce the expected results, which led us to presume that the problem lies within the old HSC niche. Therefore, we created in vitro models of young and old HSC niches and examined how these microenvironments affect the differentiation and maturation and functionality of BM-derived DCs (BMDCs).
An analysis of the conditioned media from young and aged HSC niches revealed that the environment of aged niches exhibited an increased presence of adiponectin. This media was subsequently utilized in BMDC differentiation and maturation protocols, with their effects closely monitored. Our results indicate that the old HSC niche microenvironment promotes premature BMDC activation, characterized by elevated MHC class II expression and enhanced allostimulatory capacity of BMDCs at their immature stage.
Additionally, lipopolysaccharide stimulation of BMDCs, used to induce DC maturation, significantly increased CD86 expression on BMDCs from the aged niche. However, these cells did not show superior allostimulatory capacity compared to their counterparts from the young niche environment. By analyzing the BMDC cytokine profile, we observed that when cultured in aged niche-conditioned media, the BMDCs secreted significantly higher levels of IL-6, indicating a heightened proinflammatory activation state. Collectively, our findings suggest that aging-related changes within the HSC niche can considerably alter DC functionality by disrupting their normal development from BM precursors.
View the full article at FightAging
