[Show abstract][Hide abstract] ABSTRACT:
Aging in a statistical sense is the increasing probability of death with increasing time of an organism’s existence (1, 2).
Can we extrapolate this to self-regenerating tissues and most particularly to the stem cells that drive the replenishment
of lost and damaged cells throughout life? To be succinct, how close is the linkage between the vitality of the stem cell
population and organismal longevity? These questions are currently without clear answers and the nature of the linkage, if
any, is likely to be complicated, but is nonetheless conceptually compelling. However, in the most straightforward and blunt
analysis, limiting numbers of hematopoietic stem cells, for example, resulting in aplastic anemia is an infrequent cause of
death (3). Moreover, the hallmark property that distinguishes stem cells from most other somatic cells, their ability to self-replicate,
in theory should provide a life-long supply. It was shown many years ago that hematopoietic stem cells could be transplanted
into myeloablated recipients and continue to produce large numbers of differentiated blood cells over a time period that greatly
exceeded the lifespan of the donor mouse (4). Serial transplants, in which an original bone marrow graft is passaged through
a series of recipients, put even greater demands on stem cell proliferation and differentiation and thus demonstrate the tremendous
regenerative potential of these cells. However, the number of transplant iterations that may be carried out is limited using
marrow from young mice (5, 6), and further reduced if donors are old (6, 7). In fact it is restricted to less than five, depending
on mouse strain, and although it has been argued that the limitation is not so much a result of diminished stem cell potential
as in the transplantation procedure itself (8), it is now clear that stem cells’ regenerative properties diminish during the
enforced stress of transplantation and during aging (9–15). Thus, there are growing indications that decrements in stem cell
numbers and perhaps more importantly, function, play a role in the aging process. For example, it is well known that age-related
decline in the immune system is associated with diminished ability to stave off infection and probably accounts for diminished
surveillance and killing of malignant cells (16–21). Whether or not the primary lesion for immune decline resides, at least
partially, at the stem cell level is without a definitive answer. For example, in the case of the involution of the thymus,
more complicated scenarios, including effects on the thymic epithelium, have been invoked (21).
[Show abstract][Hide abstract] ABSTRACT:
Successful bone marrow transplantation involves migration of hematopoietic stem cells through the blood, entering the extravascular hematopoietic cords, lodging in the proper niche, and expanding and differentiating to produce large numbers of mature cells -- all without depletion of the stem cell pool. An additional variable in these processes is the age of both the donor bone marrow and the recipient. Basic stem cell biology and transplant biology aim to uncover the molecular mechanisms controlling these processes.
Mouse genetics is a frequently used tool that allows dissection of individual pathways that influence properties of hematopoietic stem cells. Recently, the conception of a niche has been expanded to include evidence for a vascular and an endosteal niche. Additionally, hematopoietic stem cell interactions within the niche have been further defined, documenting the importance of cell cycle, cell adhesion, response to cytokine stimulation and age-dependent functional changes. A new model for hematopoietic stem cell aging was proposed that supports the hypothesis that stem cell aging is at least partially due to an accumulation of DNA damage leading to exhaustion.
This review focuses on the last year's progress using mouse genetics as a tool to study intrinsic mechanisms of hematopoietic stem cell biology.
Current Opinion in Hematology 08/2006; 13(4):209-15. DOI:10.1097/01.moh.0000231416.25956.35 · 4.05 Impact Factor