Properties of Self Renewal Relevant to Molecular Ageing

A few characteristics of self-renewal bear mention. First, most proliferation in an adult mammal is not self-renewing. Self-renewal appears to be a specific and unusual property of stem cells and other rare cell types that are capable of limited numbers of self-renewing divisions after periods of dormancy. Strictly speaking, not all self-renewing cells are "stem cells": adult tissue-specific stem cells (e.g., hematopoietic stem cells) are "multipotent" in that they can give rise to differentiated progeny of several

Norman E. Sharpless

Department of Medicine and Genetics, The Lineberger Comprehensive Cancer Centre, The University of North Carolina Chapel Hill, North Carolina, United States. e-mail: [email protected]

K.L. Rudolph (ed.), Telomeres and Telomerase in Ageing, Disease, and Cancer. © 2008 Springer-Verlag Berlin Heidelberg different types. In contrast, there are a few kinds of self-renewing cells such as pancreatic P-cells and memory T-cells that have a restricted potential for differentiation, thus generating progeny similar to the parental cell. This type of self-renewing cell is sometimes termed a "unipotent progenitor." Admittedly, the distinction between tissue-specific stem cells and unipotent progenitors is somewhat arbitrary, with the latter representing a subset of the former. For convenience, the term stem cell will be used in reference to both types of adult self-renewing cells in this chapter unless otherwise indicated. In contrast, the term progenitor will designate cell types derived from stem cells that are relatively undifferentiated but that are nonetheless incapable of long-term self-renewal. Progenitors in this sense are also sometimes called transit amplifying cells.

Many stem cells are believed to produce differentiated cells through a series of increasingly more committed progenitor intermediates. This hierarchical structuring has been characterized in greatest detail in the hematopoietic system, where long-term hematopoietic stem cells (LT-HSC) produce multipotent progenitor subsets that retain full lineage potential yet have little or no capacity for self-renewal (Bryder et al. 2006). These multipotent progenitors in turn give rise to oligopotent progenitors (Akashi et al. 2000, Kondo et al., 1997), which in turn give rise to more lineage-restricted progenitors from which all of the mature blood cells eventually arise (Fig. 9.1). While Figure 9.1 depicts HSC and progeny, similar hierarchies are thought to exist in many other tissues (brain, gut, liver, lung, etc.) containing tissue-specific stem cells. In the hematopoietic system, these stem and progenitor cell subsets can be purified to near-homogeneity by differences in immunophenotype. For example, true murine LT-HSC express low levels of lineage markers (lin-) specific to the differentiated progeny, high levels of the Kit receptor (Kit+), high levels of a cell surface marker called Sca1 (Sca+), and low levels of another antigen, Cd34 (Cd34 lo). As the Lin-Kit+Sca+Cd34 lo LT-HSC divide asymmetrically, they produce another LT-HSC and a more differentiated daughter cell with reduced potential for self-renewal (a short-term HSC or ST-HSC) which harbors increased Cd34 expression (Osawa et al. 1996). Thus, LT-HSC and ST-HSC can be distinguished immunophenotypically by expression of Cd34. Similar multimarker panels can be used to identify the various blood intermediates shown in Figure 9.1.

This hierarchical differentiation scheme appears to have advantages. It allows for an enormous amplification in the numbers of differentiated cells from a single stem cell by combining subsequent steps in differentiation with rapid proliferation (Hodgson and Bradley 1984, Passegue et al. 2005). Also, the multistep differentiation scheme places limited proliferative demand on the self-renewing stem cells themselves so that these cells divide very infrequently (Bradford et al. 1997, Cheshier et al. 1999). In the hematopoietic system, greater than 90% of HSC are in the G0/Gj phase of the cell cycle in the unstressed organism (Yamazaki et al. 2006), while downstream progenitors cycle much more rapidly (Passegue et al. 2005). The minimal proliferative pressure on stem cells has the benefit of not subjecting them to the potentially mutagenic hazards of DNA replication and cell division, and may thus contribute to the integrity and longevity required of these cells. Also, as stem cells appear to be a substrate for oncogenic mutations that lead to cancer, this quiescence may be important to tumor suppression in this compartment. As G0 is a relatively metabolically

Stem Cell

Self renewal

LT-HSC

Multipotent Progenitors (MPP)

Oligo-potent Progenitors

Lineage-restricted Progenitors

Mature effector cells

Common myeloid progenitor

Common lymphoid progenitor

Erythrocytes Platelets Granulocytes Macrophages T-cells B-cells

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'Proliferative! Index

Fig. 9.1 Hematopoietic developmental hierarchy. Self-renewing HSC reside at the top of the hierarchy, giving rise to a number of multipotent progenitors. Multipotent progenitors give rise to oligopotent progenitors, including the common lymphoid progenitor (CLP), which gives rise to mature B lymphocytes, T lymphocytes, and natural killer (NK) cells. The common myeloid progenitor (CMP) gives rise to granulocyte/macrophage progenitors (GMP) that differentiate into monocytes/macrophages and granulocytes, and megakaryocyte/erythrocyte progenitors (MEP) that differentiate into megakaryocytes/platelets, and erythrocytes. Development from the oligopotent progenitors through to mature blood cells proceeds through a number of intermediate progenitors (not shown). The developmental passage of HSC through multipotent progenitors, oligopotent progenitors, and lineage-specific progenitors is generally associated with increases in proliferative index, although this trend is not absolute and has not been resolved for all stages of development (See Color Plate)

inactive phase of the cell cycle, it has been suggested that stem cells may be subjected to lower levels of DNA damage-inducing metabolic by-products and reactive oxygen species than more metabolically active differentiated cell types (Rossi et al. 2005).

Moreover, while once believed to be far more restricted, tissue-specific stem cells are now known to be involved in controlling homeostasis in many tissues, including those with lower turnover rates such as the brain (Weissman 2000). While biologists may disagree over the physiological significance of such cells in the adult, their existence in rodents is beyond dispute, and their existence in human tissue is strongly suggested. Given this fact, it is reasonable to postulate that at least some characteristics of ageing once thought to be solely "degenerative" might in fact reflect a diminution of regenerative capacity by the resident stem cells of the affected tissue. It is not obvious which features of ageing reflect solely tissue degeneration versus stem cell functional decline (or some combination), and elucidating the relative contributions of these two mechanisms of ageing on a tissue-by-tissue basis will be a principal focus of future research in mammalian ageing. Moreover, as stem cells reside in specialized niches, where they receive and respond to external cues to proliferate, differentiate, or self-renew (Moore and Lemischka 2006, Schofield 1978), it seems likely that the stem cell microenvironment exerts significant influence on stem cell ageing (see Waterstrat et al. this volume).

Lastly, it is important to note that the capacity for self-renewal appears to come with some danger for the entire organism (Campisi 2003, Krishnamurthy et al. 2004, Reya et al. 2001). Genetic lesions that evade repair in stem cells can be propagated to their self-renewing progeny, and in such a way can accumulate with age. In particular, mutations that provide a growth advantage in a self-renewing compartment provide positive selection for the mutant cell, with malignant transformation being the endpoint of the accumulation of multiple cancer-promoting mutations. In contrast, mutations in proliferating cells that are fated to differentiate or die are thought to have little or no oncogenic potential unless the mutagenic process establishes the capacity for self-renewal on otherwise non-self-renewing cells. As stem cells are exposed to an array of endogenous and exogenous mutagens, oncogenic events in stem cell compartments should occur throughout the mammalian life span. To counter this, stem cells appear to have evolved mechanisms aimed at maintaining genomic integrity beyond that of other proliferating cells, for example, expression of ABC/MDR transporter genes (Rossi et al. 2005, Zhou et al. 2001) to efflux xenobiotic toxins from the cell. When mutations occur despite these error prevention mechanisms, evolutionarily perfected tumor-suppressor mechanisms (e.g., senescence) exist that sense malignant growth and censor would-be malignant stem cell clones. However, the function of these checkpoints in the stem cell compartment needs to be further explored (see Gutierrez and Ju, this volume). This relationship between self-renewing cells and cancer prevention predicts that such tumor suppressor mechanisms may also inadvertently contribute to ageing by contributing to stem cell attrition.

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