Stem Cell Niches For Immune Cells Decline With Aging

Every tissue in the body has its corresponding population of stem cells or other progenitor cells that renew and repair it. These cells reside in a stem cell niche, a specialized set of cells that form an environment to regulate and control stem cell behavior. As the research community learns more, it is becoming apparent that changes and damage in the stem cell niche contributes more to the decline of stem cell function with age than any damage to the stem cells themselves.

Research along these lines tends to proceed cell type by cell type, however, and it's not always useful to generalize what is learned in muscle - perhaps the best studied tissue when it comes to stem cell biology - to all other tissue types in the body. But for the importance of stem cell niches, the same sort of behavior shows up in a number of different tissues: old stem cells transferred to a young niche act as though young, and young stem cells transferred to an old niche act as though old.

This dynamic is why the regenerative medicine community is going to have to figure out how to address the mechanisms of aging insofar as they affect stem cells: for a cell therapy to be effective in an old person, the aging of niches has to be reversed or at the very least worked around in some way.

Here is a recent open access paper that shows a stronger contribution to age-related decline from the niche than from the stem cells in another type of tissue:

Aging induced decline in T-lymphopoiesis is primarily dependent on status of progenitor niches in the bone marrow and thymus

The notion of aging-induced defects in the stem-cell niche rather than in the stem cells themselves, leading to system wide failure has been recently recognized in many systems, such as aging in oocytes/ovary, sperm/testis, and muscles. However, this scenario has not been widely accepted in T-lymphoid system aging.

Age-related decline in the generation of T cells is associated with two primary lymphoid organs, the bone marrow (BM) and thymus. Both organs contain lympho-hematopoietic progenitor/stem cells (LPCs) and non-hematopoietic stromal/niche cells.

Murine model showed this decline is not due to reduced quantities of LPCs, nor autonomous defects in LPCs, but rather defects in their niche cells. However, this viewpoint is challenged by the fact that aged BM progenitors have a myeloid skew - [the undesirable tendency to differentiate into myeloid cells rather than lymphoid cells].

By grafting young wild-type (WT) BM progenitors into aged IL-7R-/- hosts, which possess WT-equivalent niches although LPCs are defect, we demonstrated that these young BM progenitors also exhibited a myeloid skew. We, further, demonstrated that aged BM progenitors, recruited by a grafted fetal thymus in the in vivo microenvironment, were able to compete with their young counterparts, although the in vitro manipulated old BM cells were not able to do so in conventional BM transplantation.

Both LPCs and their niche cells inevitably get old with increasing organismal age, but aging in niche cells occurred much earlier than in LPCs by an observation in thymic T-lymphopoiesis. Therefore, the aging induced decline in competence to generate T cells is primarily dependent on status of the progenitor niche cells in the BM and thymus.

In the near term, working around this sort of issue for the purpose of stem cell therapies provided to old patients will probably involve finding and manipulating a limited number of signal pathways or epigenetic changes. This will to some degree override the effect of an old niches on resident or transplanted stem cells.

In the long term, however, the root causes of stem cell niche dysfunction must be addressed. At this time, we have no reason to believe that they are any different from the general causes of aging - accumulated damage of the various sorts outlined in the Strategies for Engineered Negligible Senescence. The system of tissue maintenance based on stem cells has evolved to decline in the face of increasing dysfunction, most likely as a way to reduce the risk of cancer. A range of controlling mechanisms linked to cell activity and tissue regeneration appear to manage a trade-off between risk of cancer (more activity) and aging by tissue decline (less activity).


My interpretation of a related paper - "Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state"

- is that cellular senescence is not due to any micro-damage to cellular structure, but occurs due to epigenetic drift, and may be fully reversible.
This excerpt is a nice summary of the authors' conclusion:

"Taken together, our results show that it is possible, using an adequate reprogramming strategy, to efficiently reprogram senescent cells and cells derived from very old individuals into iPSCs and that cellular senescence and aging are not barriers to reprogramming toward pluripotency. Crucially, we also demonstrated for the first time that, when redifferentiated back into fibroblasts, our cells have rejuvenated extended life spans and characteristics of young proliferative embryonic fibroblasts; thus, these cells have been completely rid of their former aged cellular phenotype. Our demonstration of the reversibility of major aspects of the cellular aging physiology provides a totally unexpected insight into the perceived importance of epigenetic modifications in aging and provides a new paradigm for cell rejuvenation."

Does the speed of epigenetic modification correlate with aging rates?

Posted by: Lou Pagnucco at October 8th, 2012 10:31 PM

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