A Regulator of Age-Related Stem Cell Exhaustion in Flies
Stem cells support surrounding tissue by providing a supply of new cells to replace those lost to the Hayflick limit on somatic cell replication. This activity declines with age, and the reduced supply of replacement cells is a major contributing cause of loss of tissue function. For at least some types of stem cell, loss of activity is a response to the aged environment rather than a matter of cell damage or reduced stem cell population size. Here, researchers explore the mechanisms by which stem cell activity declines with age in flies, and find one point of potential intervention that might be influenced to increase stem cell activity in old flies.
During aging, miscellaneous changes occur in tissue stem cells. Tissue stem cells often exhibit two opposite phenotypes: proliferation and exhaustion. Proliferation can lead to dysplasia and tumorigenesis. Stem cell exhaustion is often defined as a decline in stem cell numbers and renewal capacity. Although stem cell quiescence and exhaustion share the same property of suppressed proliferation, they are distinct in a sense that quiescent cells, but not exhausted cells, can proliferate upon receiving stresses. Thus, stem cell exhaustion can be defined as a stress-induced cellular status exhibiting decrease of either the cell number or proliferative capacity, which makes stem cells refractory to stimulation and unable to renew upon receiving additional stresses.
Aging-induced stem cell exhaustion occurs in many types of tissue stem cells in mice, including hematopoietic stem cells, intestinal stem cells (ISCs), skeletal muscle stem cells, and hair follicle stem cells. Stem cell exhaustion can occur due to two mechanisms: (1) replicative stress in response to proliferation and (2) mechanisms independent of cell proliferation. The resulting phenotype, proliferation or exhaustion, likely depends on the tug of war competition between conflicting signals. In Drosophila, ISCs demonstrate a proliferative phenotype during aging. Many studies focused on what is driving aging-induced ISC proliferation and elucidated the mechanisms such as JNK signaling, commensal dysbiosis, epithelial barrier disruption, mitochondrial regulation, and an ABC transporter-mediated folate accumulation. Although PIWI was suggested to suppress Jak-Stat-mediated exhaustion of ISCs, signaling that skews ISCs toward exhaustion during aging is not known. There might be some undiscovered signals that lead cells toward exhaustion.
There are many silent changes in chromatin structures and gene expression that are not necessarily reflected in manifested phenotypes during aging. Here through analyses of chromatin accessibility and gene expression in intestinal progenitor cells during aging, we discovered changes of chromatin accessibility and gene expression that have a propensity to exhaust intestinal stem cells (ISCs). During aging, Trithorax-like (Trl) target genes, ced-6 and ci, close their chromatin structures and decrease their expression in intestinal progenitor cells. Inhibition of Trl, ced-6, or ci exhausts ISCs. This study provides new insight into changes of chromatin accessibility and gene expression that have a potential to exhaust ISCs during aging.