In Search of the Causes of Intestinal Stem Cell Exhaustion
Stem cell populations become exhausted with advancing age, unwilling to respond to the usual signaling and generate new daughter somatic cells to support tissue function. This is accompanied by changes in the expression of genes in these cell populations, a complex web of relationships that is far from fully explored. Gene expression is determined by the structure of chromatin, the packaged DNA in the cell nucleus. Epigenetic modifications to that structure occur constantly, changing its shape. This epigenetic regulation unfolds portions of the chromatin to allow the machinery of transcription access to specific gene sequences, and folds away other portions to hide them. Here, researchers engage with this complexity in search of genes that regulate intestinal stem cell exhaustion in flies, a starting point for later explorations in mammals.
Although stem cell quiescence and exhaustion in aged tissues 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. 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. 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. During aging, changes in chromatin structures and gene expression occur simultaneously in tissue stem cells. Changes in chromatin structures may underlie changes of some gene expression. 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.