Resurrected tissue: Mechanism that enables regeneration after extensive damage solves a 50-year-old mystery

Amazing stuff!

"... A new study from the Weizmann Institute of Science, ... reveals that the very enzymes responsible for cellular destruction—caspases—may also render certain cells resistant to death, enabling damaged tissue not only to regenerate but even to become more resilient. ..."

"... A delicate balance between tissue repair and excess growth is essential to any regenerative process. In the final part of their study, the researchers revealed how uncontrolled growth is prevented during tissue repair after injury. “DARE cells promote the growth of nearby NARE cells, apparently by secreting growth signals,” ... “In turn, NARE cells secrete signals that inhibit the growth of DARE cells. In fact, we’ve discovered a negative-feedback loop between the two cell populations that prevents overgrowth.” ...

“Many cancers originate in epithelial cells that have lost normal growth control, and many traditional cancer treatments aim to cause them to self-destruct through apoptosis. Our findings pave the way for understanding why such treatments sometimes fail and how they could be improved. The results also point toward new ways in which we might be able to accelerate beneficial regeneration of healthy tissue after injury.” ..."

From the abstract:

"Caspases are best known for promoting apoptosis, yet their role in tissue regeneration by compensatory proliferation remains unclear.
Using Drosophila wing discs and a delayed reporter for the initiator caspase-9 ortholog Dronc activity, we identify two apoptosis-resistant epithelial cell populations that mediate regeneration after ionizing radiation:
Dronc-activating (DARE) and
non-activating (NARE) cells.

Dronc activity in DARE cells, independent of Dark and effector caspases, drives regeneration both cell-autonomously and non-cell-autonomously.
The TNFR in DARE cells, Wengen, likely activated by ROS, strongly promotes DARE proliferation, while TNF/Eiger and TNFR Grindelwald moderately suppress it. Downstream, p38 MAPK is the main signaling essential for DARE and NARE cell proliferation.
Myo1D ensures DARE survival by preventing lethal effector caspase activation, whereas Myo7A/Crinkled supports moderate caspase activity.
Dying cells trigger DARE induction, and both DARE and NARE transmit apoptosis resistance to progeny, with DARE progeny showing enhanced resistance. Maintaining balanced DARE-NARE proliferation is crucial for proper regeneration, growth, and differentiation, insights that may be relevant to radiation-resistant cells in cancer therapy."

Resurrected tissue: Mechanism that enables regeneration after extensive damage solves a 50-year-old mystery

Resurrected Tissue (original news release) "Weizmann Institute researchers have solved a 50-year-old mystery, uncovering the molecular mechanism that enables tissue regeneration after extensive damage. The findings may pave the way for treatments that help prevent cancer from returning"

Apoptosis-resistant cells drive compensatory proliferation via cell-autonomous and non-autonomous functions of the initiator caspase Dronc (open access)

DARE cells (their bodies marked in green) and NARE cells (their bodies are unmarked) in the epithelial tissue from which the fly’s wing develops. In red are the nuclei of cells as they divide. The researchers discovered that NARE cells receive signals from neighboring DARE cells instructing them to proliferate