CDC42 Inhibition Promotes Intestinal Stem Cell Function in Aged Mice
The inhibition of CDC42 is starting to look like a most interesting intervention, based on the animal data produced over the past decade or so. A small molecule approach to CDC42 inhibition, using CASIN, has been assessed in a number of animal studies focused on the hematopoietic stem cell population responsible for generating blood cells and immune cells. Treatment of mice with CASIN results in improved hematopoietic stem cell function, improved immune function, and extended life span. The life span extension was achieved following a single course of treatment with CASIN in middle-aged mice, suggesting that a one-time intervention can produce a lasting improvement in the immune system over the remainder of later life. The state of the immune system itself is, of course, very influential on tissue function and the progression of aging and age-related disease.
Today's open access paper reports on a study focused on a different stem cell population, the intestinal stem cells that support the lining of the gut. Like all stem cell populations, intestinal stem cells decline with age. They become less active, more damaged, and their niches change in ways that promote this lost function. That CASIN treatment can help intestinal stem cell function, and produce improvement in the state of the intestinal epithelium as a result, suggests that the benefits to this therapy are not solely due to improved immune function. If seen to affect two stem cell populations, it may influence numerous other stem cell populations as well.
The regenerative capacity of intestine decreases upon aging. Organ homeostasis in the intestine is maintained by intestinal stem cells (ISCs). A decline in ISC function is a main reason for the impaired regeneration of intestinal epithelium upon aging. ISCs express the marker gene Lgr5 and are located next to differentiated Paneth cells at the base of the intestinal crypt. To function properly under homeostasis, ISCs differentiate into highly proliferative transient amplifying (TA) cells. Upon their migration from the crypt base to the villus, TA cells further differentiate into mature cell types including cells in the intestinal villus made of enterocytes, goblet cells, and enteroendocrine cells.
The small RhoGTPase Cdc42 cycles between an active, GTP-bound form (Cdc42-GTP) and an inactive, GDP-bound form. It is thought that biological activity of Cdc42 is regulated by its active form, i.e., the level of Cdc42-GTP. The relative ratio of active Cdc42 is elevated in various tissues of aged mice compared to that of young mice, whereas animals in which Cdc42 activity is increased by genetic means show diverse premature aging phenotypes. It is possible that there is a causative link between Cdc42 activity and aging, and increased Cdc42 activity has indeed been reported to be a causative stem cell intrinsic mechanism for the aging of hematopoietic stem cells (HSCs).
For ISCs, their regeneration capacity declines upon aging, and multiple mechanisms including changes in Wnt signaling could be involved in the process. We show here that an aging-associated increase in the Cdc42 activity in ISCs causes a decline in ISC function and impairs intestinal epithelial regeneration. Suppression of Cdc42 activity can ameliorate ISC regeneration in vitro, and pharmacologic targeting of Cdc42 critically enhances intestinal regeneration upon stress in vivo up on aging. Our studies imply that a tight regulation of the Cdc42 activity is critical for maintaining tissue homeostasis within the intestine during aging and that suppression of aging-related increased Cdc42 activity allows for enhanced tissue regeneration in vivo.