Telomere Dysfunction Induces Environmental Alterations Limiting Stem Cell Function and Engraftment

In addition to cell intrinsic checkpoints, environmental alterations can limit the function of adult stem cells during ageing. In mouse models the function of stem cells declines in various compartments, including HSCs and muscle stem cells. The decline in adult stem cell function during mouse ageing has been associated with downregulation of notch signaling in muscle satellite cells (Conboy et al. 2003) and a switch in CeBP/alpha signaling in ageing liver (Iakova et al. 2003). A recent landmark study has shown that the connection of blood flow from young and old mice (parabiosis) improves stem cell function in various tissues of ageing mice, correlating with a reversion of some of the age-associated changes in signaling pathways in aged stem cells (Conboy et al. 2005). This study suggested that there are changes in the macroenvironment (systemic milieu) that negatively influence stem cell function. It is possible that an accumulation of "negative factors" occurs during ageing, impairing adult stem cell function. Alternatively, there might be an age-dependent decline in "positive factors" that are necessary for normal stem cell function. In these experiments, parabiosis could have led to an improvement in stem cell function by diluting "negative factors" and/or by increasing the concentration of "positive factors" in the aged organism (Rando 2006).

In addition to alterations in the macroenvironment, there is also evidence for age-associated alterations in the microenvironment (the stem cell niche) that limit stem cell function during ageing (Fig. 8.2). Ageing associated alterations in stem cell niche function appear to affect maintenance and function of melano-cyte stem cells (Nishimura et al. 2005), intestinal stem cells (Kim et al. 2005), spermatogonia (Ryu et al. 2006), muscle stem cells (Shefer et al. 2006), neural stem cells (Alvarez-Buylla and Lim 2004) as well as hematopoietic stem cells (Miller and Van Zant 2006; see Waterstrat et al., this volume). To understand the influence of ageing on the stem cell microenvironment it will be important to define the cell types that compose the stem cell niche in different organs. In the hemat-opoietic system, bone marrow stromal cells can contribute to the formation of stem cell niches. In addition, it has been proposed that there might be different niches composed of either osteoblasts or endothelial cells (Wilson and Trumpp 2006). A major function of the stem cell niche is to control the balance between HSC self-renewal and differentiation as well as the balance between stem cell quiescence and proliferation (Wilson and Trumpp 2006). As a major cell extrinsic factor, cytokines influence stem cell function and the cross talk between stem cells and their surrounding niches (Adams and Scadden 2006). Thus the macroenvironment (see above) could also influence the microenvironment (niche function).

An emerging field in stem cell research is to delineate molecular factors that are the cause of age-associated alterations in the stem cell environment. Studies on Tercmice have provided the first experimental evidence that telomere dysfunction can induce alterations in the environment that limit hematopoietic stem cell function (Ju et al. 2007b). One of the hallmark phenotypes of ageing Tercmice is a decrease in B-lymphopoiesis in bone marrow accompanied by an increase in myeloid proliferation. Cross-transplantation experiments of HSCs from Terc+'+ into Tercand vice versa revealed that these alterations in HSC function were mainly due to the environment and not caused by HSC intrinsic defects.

In addition to the effects on the function of HSCs, environmental alterations in telomere dysfunctional mice impaired engraftment of transplanted HSCs into stem cell niches. These results could have implications for new approaches in regenerative medicine aiming to use cell transplantation therapies to improve organ functions (Hornsby 2004, Shay and Wright 2000b). The studies on Tercmice indicate that alterations of the environment could limit such approaches by limiting the engraftment and function of transplanted cells.

Fig. 8.2 Telomere shortening reduces positive factors, accumulates negative factors, and induces an age-associated secretory phenotype in the macroenvironment; in the microenvironment it compromises the stromal cell compartment and alters cytokine profiles, thus influencing stem cell function in terms of balance between self-renewal and differentiation of HSC. This suggests that changes in the stem cell niche can also be involved in carcinogenesis

Fig. 8.2 Telomere shortening reduces positive factors, accumulates negative factors, and induces an age-associated secretory phenotype in the macroenvironment; in the microenvironment it compromises the stromal cell compartment and alters cytokine profiles, thus influencing stem cell function in terms of balance between self-renewal and differentiation of HSC. This suggests that changes in the stem cell niche can also be involved in carcinogenesis

Telomere dysfunction & the macroenvironment. It has first been recognized in cell culture experiments that telomere induced senescence induces a secretory phenotype resulting in elevated secretion of pro-inflammatory cytokines and growth factors (Krtolica et al. 2001). In accordance with these data, blood sera of late generation Terc show an age-dependent increase in the level of various cytokines and growth factors (Ju et al. 2007b). One of the upregulated factors was G-CSF, which showed an age-dependent increase in Terc mice, but not in age-matched Terc mice. Bone marrow transplantation experiments revealed that the elevation of G-CSF levels in Terc mice was independent of telomere dysfunction in HSCs but dependent on telomere dysfunction in the host environment. Treatment with recombinant human G-CSF mimicked some of the phenotypes of ageing Terc -/" mice including the impairment in B-cell development in bone marrow as well as the reduced engraftment of transplanted HSCs. In contrast, application of neutralizing antibodies lowered endogenous G-CSF levels in the plasma of aged Terc mice and improved the homing of HSCs into the deep bone marrow stroma of Terc mice (Ju et al. 2007b). Together, these studies demonstrate that telomere dysfunction induces alteration in the macroenvironment that can limit HSC function and engraftment.

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