Loss of Motility in Stem Cells may be Important in Tissue Aging

Stem cell aging is a complex business with many potential contributing causes that vary in importance between tissues and stem cell populations. Not all of those populations are even well studied enough to know how the mechanisms of stem cell aging compare in importance. The better known collections of mechanisms are (a) intrinsic damage to the stem cells, such as stochastic mutation to nuclear DNA, that reduces their function or ability to maintain their numbers, (b) a changing balance of signals in the cellular environment, perhaps due to cellular dysfunction in the stem cell niche, or due to chronic inflammation, that causes a reduction in stem cell activity.

The open access paper I'll point out today examines a mechanism that falls into the first of those categories, but one not often examined in this context of stem cell aging. The researchers propose that stem cell motility is systematically impacted with age, meaning that the stem cells are less able to move to where they are needed. This is most likely functionally equivalent to the loss of activity that arises in other ways, but the intermediary mechanisms connecting the root causes of aging to this specific loss are quite different in nature. It bears further investigation; the researchers here only look at a single population and tissue type. Is this a more general mechanism?

Intestinal crypts recover rapidly from focal damage with coordinated motion of stem cells that is impaired by aging

The rapid regeneration of the intestinal epithelium is enabled by fast-cycling Lgr5+ intestinal stem cells (ISCs) crowded into the base of the intestinal crypt. ISCs are not only limited in number and location, but also arranged in a specific pattern. Aging is one of critical factors which gradually decreases the functionality of stem cells, including diminishing the self-renewal ability of stem cells, which impairs the balance between stem and differentiated cells. Aging also weakens cellular functions, such as mitigating reactive oxygen species and DNA damage. However, how aging affects specific behaviors such as the patterning of intestinal crypt still not known.

To investigate the robustness of the patterning and its maintenance in vivo, we ablated individual cells in the crypt with high-pulse-energy femtosecond laser ablation and imaged the real-time dynamics of recovery with multiphoton microscopy. Such accurate manipulation is not achieved by current methods of radiation, chemical treatment, or genetic ablation of specified lineages. Surprisingly, after ablation of a small number of cells, migration of neighboring cells was sufficient to reestablish cellular contacts and the alternating pattern in the crypt base within hours, before any cells divided.

In addition, we observed coordinated motion of the cells at the edge of the crypt base that expelled debris out towards the lumen. The repair movements were impaired by both inhibition of cellular movement and aging, highlighting the importance of this dynamic response for the integrity of the niche. Crypt cell motion was reduced with inhibition of the ROCK pathway and attenuated with old age, and both resulted in incomplete pattern recovery. This suggests that in addition to proliferation and self-renewal, motility of stem cells is critical for maintaining homeostasis. Reduction of this newly-identified behavior of stem cells could contribute to disease and age-related changes.

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