Epigenetic Erosion in Adult Stem Cells: Drivers and Passengers of Aging

Abstract

In complex organisms, stem cells are key for tissue maintenance and regeneration. Adult stem cells replenish continuously dividing tissues of the epithelial and connective types, whereas in non-growing muscle and nervous tissues, they are mainly activated upon injury or stress. In addition to replacing deteriorated cells, adult stem cells have to prevent their exhaustion by self-renewal. There is mounting evidence that both differentiation and self-renewal are impaired upon aging, leading to tissue degeneration and functional decline. Understanding the molecular pathways that become deregulate in old stem cells is crucial to counteract aging-associated tissue impairment. In this review, we focus on the epigenetic mechanisms governing the transition between quiescent and active states, as well as the decision between self-renewal and differentiation in three different stem cell types, i.e., spermatogonial stem cells, hematopoietic stem cells, and muscle stem cells. We discuss the epigenetic events that channel stem cell fate decisions, how this epigenetic regulation is altered with age, and how this can lead to tissue dysfunction and disease. Finally, we provide short prospects of strategies to preserve stem cell function and thus promote healthy aging.

Keywords: adult stem cells; aging; differentiation; epigenetic regulation; hematopoietic stem cells; muscle stem cells; self-renewal; spermatogonial stem cells; tissue maintenance.

Figure 1

Intrinsic and extrinsic factors cause epigenetic erosion in adult stem cells. The diagram depicts major factors that contribute to stem cell aging and also affect the fidelity of epigenetic regulation (indicated in the middle by repressive histone methylation (red hexagons) or activating histone methylation (green hexagons); histone acetylation (blue diamonds) and DNA methylation (yellow circles). For further details please see text.

Figure 2

Transmission of epimutations during stem cell development. (a) Stages of stem cell development without epimutations. (b) Acquisition of an epimutation (indicated by a flash) at an early stage is transmitted to all subsequent progenitor and differentiated cells. (c) Occurrence of an epimutation at a late stage affects only a small population of differentiated cells. (d) Epimutations can accumulate during stem cell development. Abbreviations: quiescent stem cell (qSC); activated stem cell (aSC); committed stem cell (cSC); progenitor cell (PC); differentiated cell (DC); self-renewal (sr); differentiation division (dd).

Figure 3

Scheme of the myogenic program. In response to muscle damage, quiescent MuSCs in the periphery of the myofibers become activated and enter the cell cycle. The daughter cells either self-renew into MuSCs, or they differentiate into myoblasts. These progenitor cells proliferate further until they eventually terminally differentiate and fuse with each other to form a myotube.