Ageing and rejuvenation of tissue stem cells and their niches

Abstract

Most adult organs contain regenerative stem cells, often organized in specific niches. Stem cell function is critical for tissue homeostasis and repair upon injury, and it is dependent on interactions with the niche. During ageing, stem cells decline in their regenerative potential and ability to give rise to differentiated cells in the tissue, which is associated with a deterioration of tissue integrity and health. Ageing-associated changes in regenerative tissue regions include defects in maintenance of stem cell quiescence, differentiation ability and bias, clonal expansion and infiltration of immune cells in the niche. In this Review, we discuss cellular and molecular mechanisms underlying ageing in the regenerative regions of different tissues as well as potential rejuvenation strategies. We focus primarily on brain, muscle and blood tissues, but also provide examples from other tissues, such as skin and intestine. We describe the complex interactions between different cell types, non-cell-autonomous mechanisms between ageing niches and stem cells, and the influence of systemic factors. We also compare different interventions for the rejuvenation of old regenerative regions. Future outlooks in the field of stem cell ageing are discussed, including strategies to counter ageing and age-dependent disease.

Fig. 1 |. Organs with stem cells and stem cell niches.

a | Several organs in humans and other mammals contain stem cells and stem cell niches. The figure depicts organs that are highly regenerative, with very active stem cells; organs that have restricted regeneration, sometimes with stem cells restricted to specialized regions; and organs that are regenerative upon injury, with dormant stem cells that are mostly activated in response to injury. Some organs do not regenerate and have no stem cells (or the presence of stem cells is controversial). b | Organization of adult stem cell niches in the brain, blood and muscle. Examples of markers for adult neural stem cells (NSCs) include SOX2, Nestin, glial fibrillary acid protein (GFAP) and CD133. Examples of markers for adult haematopoietic stem cells (HSCs) in humans include the presence of CD34 and the absence of CD38. Example of markers for muscle stem cells (MuSCs) include PAX7, CD34 and CD56 (human). SVZ, subventricular zone.

Fig. 2 |. Changes in stem cells and their niches during ageing.

a | Ageing changes in the stem cell lineage. During ageing, subpopulations of stem cells can enter deep quiescence, and their ability to activate is reduced. Other subpopulations of stem cells can exhibit aberrant activation, reduced activation and clonal expansion (haematopoietic stem cells (HSCs)). There is also a bias in progenitor commitment and abnormal differentiation during ageing. b | Ageing changes in the niche. Ageing leads to immune cell infiltration, inflammation, secretion of cytokines (for example, interferon), expression of cell adhesion molecules (vascular cell adhesion molecule 1 (VCAM1)) by blood vessel cells, extracellular matrix secretion (collagen type XVII α1 chain (COL17A1)) and increased stiffening of the niche. MuSC, muscle stem cell; NSC, neural stem cell.

Fig. 3 |. Cell-autonomous and non-cell-autonomous mechanisms of stem cell ageing.

During ageing, stem cells undergo cell-autonomous changes, including modulations of signalling cascades, transcription factors (BMAL, STAT3 and FOXO) and chromatin regulators (DNA methyltransferase 3A (DNMT3A) and TET2). Many of these cell-autonomous changes are affected by non-cell-autonomous mechanisms originating from various sources. Stem cells experience non-cell-autonomous influences from proximal niche cells, involving growth factors such as transforming growth factor-β (TGFβ) and cytokines such as interleukin-6 (IL-6) secreted by niche cells, cytokines such as interferon secreted by infiltrated immune cells, and extracellular matrix proteins (collagen type XVII α1 chain (COL17A1)) secreted by niche cells. Stem cells are also modulated by long-range factors such as the nervous system or blood (with circulating growth factors such as insulin-like growth factor 1 (IGF1) and cytokines and chemokines (CXCL11, RANTES and cyclophilin A), which are themselves under the influence of the environment (diet and circadian rhythm). Yellow indicates factors and mechanisms linked to the diet (for example, nicotinamide adenine dinucleotide (NAD)). BMAL (shown in blue) is a transcription factor linked to circadian rhythm. Red indicates factors and mechanisms linked to inflammation.