Injury stimulates stem cells to resist radiation-induced apoptosis
Preprint posted on 30 June 2019 https://www.biorxiv.org/content/10.1101/688168v1
Mechanical injury poses a major threat to the integrity of tissues over the course of an organism’s lifetime. Mechanisms to repair tissue damage include scar formation, and in the case of some animals, stem-cell driven regeneration. In the highly regenerative planarian flatworm, mechanical injury induces the death of differentiated cells, while kick starting proliferation in stem cell populations. Being highly proliferative, stem cells are uniquely sensitive to radiation-induced DNA damage.
Shiroor et al. characterized the behavior of the planarian stem cell population, called neoblasts, upon mechanical injury. Surprisingly, they found that wounding an animal shortly after radiation protects stem cells from death. Specifically, cell death around neoblasts at a wound site allows them to survive lethal doses of radiation and contribute to regenerative growth.
In order to easily visualize stem cell behavior after injury, the group reduced their numbers by exposing flatworms to a low dose of radiation, a treatment that selectively kills stem cells. Surprisingly, they found that when worms were injured within 24 hours of irradiation, stem cells survived and accumulated at wound sites, regardless of the size or location of the wound.
The authors hypothesized that the high numbers of stem cells at wound sites of radiated animals might be due to stem cell proliferation. However, when they looked for markers of dividing cells, the found that stem cells from radiated and damaged worms were not dividing more than stem cells from radiated worms. The then considered the possibility that tissue injury protects the stem cells from the effects of radiation. To test this hypothesis, the group visualized stem cells at multiple time points after radiation, and found that the numbers of stem cells did not sharply decrease in animals that were radiated and damaged. Amazingly, the stem cells of damaged worms survived radiation doses known to kill 100% of stem cells in undamaged worms!
To more accurately measure death in stem cell populations, the group dissociated planaria into a cell suspension, used DNA content to sort out stem cells, and an antibody to mark cells that were undergoing apoptosis. They found that without injury, radiation decreased the total number of stem cells, and increased the number that stained positively for the marker of apoptosis. However, when animals were radiated and injured, the total number of stem cells increased, and the number of stem cells that stained positively for the marker of apoptosis decreased, relative to the uninjured and radiated worms.
How does tissue injury protect stem cells from radiation-induced death? The group hypothesized that signals from dying cells surrounding the wound site might promote survival in the neighboring stem cells. They exposed worms to agents that induced cell death, radiated the worms, and visualized stem cells. Amazingly, worms in which apoptosis had been induced, in the absence of injury, also had high numbers of surviving stem cells following radiation. This suggests that apoptosis alone is enough to rescue stem cells from death by radiation.
The environmental signals that initiate stem cell proliferation following injury remain mysterious. This work highlights the contributions of dying cells to kick starting regenerative stem cell behaviors, serving to better our understanding of the complex reaction to tissue injury.
Questions for Authors
What specific signals from dying cells might be able to be received by neoblasts?
Are you able to see neoblast death (by TUNEL staining or another method) far away from a wound site following radiation? Do you predict the signals from dying cells to be long-distance?
Posted on: 9 July 2019Read preprint