Biology subjects

Shiroor, D. A.

Publications and source records attributed to Shiroor, D. A..

3 recordsLinked to original sources

bioRxiv2022

Inhibition of the ATM kinase rescues planarian regeneration after lethal radiation

As stem cells divide, they acquire mutations that can be passed on to daughter cells. To limit the possibility of propagating mutations, cells activate the DNA damage response (DDR) network, which dictates whether cells repair DNA or undergo apoptosis. At the helm of the DDR are three PI3-like kinases including Ataxia Telangiectasia Mutated (ATM). We report here that knockdown of ATM in planarian flatworms enables stem cells, which normally undergo apoptosis after radiation exposure, to survive lethal doses of radiation. In this context, stem cells circumvent apoptosis, replicate their DNA, and recover function using homologous recombination-mediated DNA repair. Despite radiation exposure, atm knockdown animals survive long-term and regenerate new tissues. These effects occur independently of ATMs canonical downstream effector p53. Together, our results demonstrate that ATMs primary function is to drive apoptosis, and suggest that inhibition of ATM could therefore potentially favor cell survival after radiation without adverse effects.

cell biology↗

bioRxiv2020

Planarian stem cells sense the identity of missing tissues to launch targeted regeneration

In order to regenerate tissues successfully, stem cells must first detect injuries and then produce missing cell types through largely unknown mechanisms. Planarian flatworms have an extensive stem cell population responsible for regenerating any organ after amputation. Here, we compare stem cell responses to different injuries by amputation of a single organ, the pharynx, or removal of tissues from other organs by decapitation. We find that planarian stem cells adopt distinct behaviors depending on what tissue is missing: loss of non-pharyngeal tissues increases numbers of non-pharyngeal progenitors, while removal of the pharynx specifically triggers proliferation and expansion of pharynx progenitors. By pharmacologically inhibiting either proliferation or activation of the MAP kinase ERK, we identify a narrow window of time during which proliferation, followed by ERK signaling, produces pharynx progenitors necessary for regeneration. Further, unlike pharynx regeneration, eye regeneration does not depend on proliferation or ERK activation. These results indicate that stem cells tailor their proliferation and expansion to match the regenerative needs of the animal.

developmental biology↗

bioRxiv2019

Injury stimulates stem cells to resist radiation-induced apoptosis

Stem cells are continuously exposed to multiple stresses including radiation and tissue injury. Because stem cells are central drivers of tissue repair and regeneration, it is essential to understand how their behavior is influenced by these stressors. Planarians have an abundant population of stem cells that are rapidly eliminated after radiation exposure via apoptosis. Low doses of radiation eliminate the majority of these stem cells, allowing a few to remain [1]. Here, we combine radiation with injury to define how surviving stem cells respond to tissue damage. We find that injuries induce stem cells to persist, but only if injured within a defined window of time surrounding radiation, and only immediately adjacent to the wound. Stem cells persist for several days without any proliferation. Instead, they are retained near the wound due to suppression of apoptosis, which we quantify in stem cells by combining FACS with Annexin V staining. Tissue injury is known to induce apoptosis in differentiated cells [2], and we hypothesize that these dying cells confer apoptosis resistance onto nearby stem cells. Indeed, pharmacological induction of cell death with cycloheximide is sufficient to prolong survival of radiated stem cells even in the absence of injury. Together, our results suggest a model in which dying cells provide a transient protective signal to nearby stem cells, altering their susceptibility to radiation-induced apoptosis.

developmental biology↗