Background
Senescence increases the risks of inflammatory bowel diseases and colon cancer. Intestinal stem cells (ISCs) in crypts differentiate into epithelial cells and thereby maintain intestinal homeostasis. However, the influence of aging on the functions of ISCs is largely unknown. The mutation rate is highest in the small and large intestines. Numerous types of naturally occurring DNA damage are removed by the DNA damage response (DDR). This response induces DNA repair and apoptosis; therefore, its dysregulation leads to accumulation of damaged DNA and consequently cellular dysfunctions, including tumorigenesis. This study investigated whether aging affects the DDR in mouse ISCs.
Methods
Young (2–3-month-old) and old (> 19-month-old) Lgr5-EGFP-IRES-creERT2 mice were irradiated. The DDR in Lgr5-positive ISCs was compared between these mice by immunohistochemical analyses.
Results
Induction of DDR marker proteins (phosphorylated ATR and 53BP1), inflammatory factors (phosphorylated NF-κB and interleukin-6), and a mitochondrial biogenesis-associated gene (peroxisome proliferator-activated receptor-γ coactivator 1α) was lower in old ISCs than in young ISCs in vivo.
Conclusion
The competence of the DDR in ISCs declines with age in vivo.
Electronic supplementary material
The online version of this article (10.1186/s41232-019-0096-y) contains supplementary material, which is available to authorized users.
Restoration of tissue homeostasis by controlling stem cell aging is a promising therapeutic approach for geriatric disorders. The molecular mechanisms underlying age-related dysfunctions of specific types of adult tissue stem cells (TSCs) have been studied, and various microRNAs were recently reported to be involved. However, the central roles of microRNAs in stem cell aging remain unclear. Interest in this area was sparked by murine heterochronic parabiosis experiments, which demonstrated that systemic factors can restore the functions of TSCs. Age-related changes in secretion profiles, termed the senescence-associated secretory phenotype, have attracted attention, and several pro- and anti-aging factors have been identified. On the other hand, many microRNAs are linked with the age-dependent dysregulations of various physiological processes, including “stem cell aging.” This review summarizes microRNAs that appear to play common roles in stem cell aging.
Molecular mechanisms of aging specific to each stem cell (SC) are being elucidated. However, the common molecular basis for senescence in various SCs remains largely unexplored. Here, we have shown that the dysregulation of DNA damage response (DDR) modulated by lymphoid enhancer-binding factor 1 (Lef1) and DDR-microRNAs (DDR-miRs) is the common molecular basis for aging in SCs. We identified Lef1as the most repressed transcription factor with aging in common between mesenchymal stem/stromal cells (MSCs) and hematopoietic stem/progenitor cells. Like the expression profiles of aged MSCs, Lef1 knockdown reduced broad microRNAs and loss of induction of DDR-miRs in young MSCs. DDR capacity was also diminished in aged SCs in vivo. Moreover, Lef1 deficiency in intestinal stem cells induced precocious dysregulation of DDR and inflammation and senescence in the remote brain. This study demonstrates that the Lef1/DDR-miR axis is the common molecular basis underlying SC aging.
Molecular mechanisms of aging specific to each stem cell (SC) are being elucidated. However, the common molecular basis for senescence in various SCs remains largely unexplored. Here, we have shown that the dysregulation of DNA damage response (DDR) modulated by lymphoid enhancer-binding factor 1 (Lef1) and DDR-microRNAs (DDR-miRs) is the common molecular basis for aging in SCs. We identified Lef1as the most repressed transcription factor with aging in common between mesenchymal stem/stromal cells (MSCs) and hematopoietic stem/progenitor cells. Like the expression profiles of aged MSCs, Lef1 knockdown reduced broad microRNAs and loss of induction of DDR-miRs in young MSCs. DDR capacity was also diminished in aged SCs in vivo. Moreover, Lef1 deficiency in intestinal stem cells induced precocious dysregulation of DDR and inflammation and senescence in the remote brain. This study demonstrates that the Lef1/DDR-miR axis is the common molecular basis underlying SC aging.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.