Will mammals ever be able to regenerate tissues?
Regeneration differs across species. Fish and amphibians re-grow appendages such as limbs, tails, and fins. But mammals, including humans, cannot restore injured organs. Finding out what molecular mechanisms underlie the regeneration of lower vertebrates may help us restore complex organs in humans, a clinical goal of the future.
An international team of scientists led by Associate Professor Atsushi Kawakami, Tokyo Institute of Technology, has disclosed a mechanism regulating regeneration of the caudal fin in zebrafish. In order to identify key molecules responsible for tissue repair, researchers compared gene transcription (when a particular segment of DNA is copied into RNA) in the larvae of wild-type (normal) and mutant zebrafish deficient in fin regeneration.
They found some inflammatory agents — like the cytokine interleukin 1 beta (Il1b) — were increased in mutant fish and remained for a long time after amputation of the tail of the larvae. The mutant zebrafish also lacked the myeloid cells, such as macrophages, needed to prevent apoptosis — programmed cell death — of regenerating cells. This made researchers suspect a link between the increase in Il1b and death of regenerative cells.
The Il1b protein is primarily produced by myeloid cells, a type of blood cell that eats foreign or harmful cells. Surprisingly, after fin amputation, Il1b was mostly observed in thin (epithelial) cells surrounding the injury. The protein caused inflammation and cell death of regenerating cells. This process inhibited the extension of the fin. However, if macrophages had come into action, they could suppress Il1b, ending the inflammation while promoting survival of regenerative cells in the fin. A balance of macrophage cells would help regulate site inflammation in tissue repair.
There appears to be a clearly negative effect from Il1b protein on regeneration processes.
However, by creating an Il1b-deficient zebrafish, researchers found that a transient, as opposed to prolonged, exposure to the Il1b protein also activated regeneration-induced genes and was essential for cell proliferation at the amputation site and regeneration of the injured fin.
Dr. Kawakami's study reveals an unexpected association between regeneration and inflammation.
While acute inflammation is needed to initiate tissue repair, continuous inflammation blocks regeneration.
The Il1b protein is evolutionary conserved in vertebrates. This means it has remained essentially unchanged throughout evolution. It is a gene that it is unique and essential, changes to it are likely to be lethal. So, it remains to be determined whether similar mechanisms can be made to function in mammals, including humans.
The research is published in the February 23, 2017 issue of eLife.
Cellular responses to injury are recognized to be crucial for complete tissue regeneration, but their underlying processes remain incompletely elucidated. We have previously reported that myeloid-defective zebrafish mutants display apoptosis of regenerative cells during fin fold regeneration. Here, we found that the apoptosis phenotype is induced by the prolonged expression of interleukin 1 beta (il1b). Myeloid cells have been considered to be the principal source of Il1b, but we show that epithelial cells express il1b in response to tissue injury and initiate the inflammatory response, and that its resolution by macrophages is necessary for the survival of regenerative cells. We further show that Il1b also plays an essential role in normal fin fold regeneration by regulating the expression of regeneration-induced genes. Our study reveals that proper levels of Il1b signaling and tissue inflammation, which are tuned¬ by macrophages, play a crucial role in tissue regeneration.
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Mar 15, 2017 Fetal Timeline Maternal Timeline News News Archive
Increase of the protein Il1b (GREEN) stops regenerative cells and causes apotosis - cell death (RED).
This is the amputated larval tail of a mutant fish. This mutant lacks macrophage blood cells to eat harmful or foreign particles that would otherwise protect the fish.
Image Credit: Tokyo Institute of techonology