A mechanism regulating regeneration of the caudal fin in zebrafish has been disclosed by an international team of scientists led by Associate Professor
Atsushi Kawakami from Tokyo Institute of Technology.
Regeneration is an inherent property of life. However, the potential
to regenerate differs across species: while fish and amphibians can
re-grow appendages such as limbs, tails, and fins, mammals, including
humans, cannot restore injured organs to their original shape and
function. Therefore, elucidation of molecular mechanisms underlying the
amazing regenerative capacity of lower vertebrates can show approaches
to restore complex organs in humans, which is a clinical goal of the
‘While acute inflammation is necessary to initiate tissue repair, chronic inflammation blocks further regeneration.’
identify key molecules responsible for tissue repair, they compared gene
transcription in the larvae of the wild-type and mutant zebrafish
deficient in fin regeneration. They found that some inflammatory
mediators, especially cytokine interleukin 1 beta (Il1b), were
upregulated in the mutant and remained there for a long time after
amputation of the larval tail.
The mutant zebrafish also lacked myeloid
cells such as macrophages, necessary to prevent programmed cell death
(apoptosis) of the regenerative cells. The scientists therefore
suspected a link among the increase in Il1b, absence of macrophages, and
death of regenerative cells.
Il1b is considered to be mostly produced by myeloid cells.
Surprisingly, after fin amputation, Il1b was primarily observed in
epithelial cells surrounding the site of injury where it caused
inflammation and apoptosis of the regenerative cells and inhibited the
extension of the fin fold. However, if macrophages come to action, they
could suppress Il1b expression, attenuate inflammation, and promote
survival of the regenerative cells in the fin, thus behaving as critical
regulators of inflammation during tissue repair.
All these data point to the negative effect of Il1b on the
regenerative processes taking place after fin amputation. Yet, it is not
that simple. By creating an Il1b-deficient zebrafish, the researchers
found that transient, contrary to prolonged, presence of Il1b activated
the expression of regeneration-induced genes and was essential for cell
proliferation at the amputation site and regeneration of the injured
Thus, the study of Dr. Kawakami and his colleagues revealed an
unexpected association between regeneration and inflammation which acts
as a double-edge sword: while acute inflammation is necessary to
initiate tissue repair, chronic inflammation blocks further regeneration. As Il1b is evolutionary conserved in vertebrates, it
remains to be determined whether similar mechanisms can function in
mammals, including humans, as well as to identify anti-inflammatory
factors released by macrophages.