Stowers scientists use zebrafish to understand the connection between the immune system and regeneration
New research used the highly regenerative zebrafish to investigate the timing and genetic programs of macrophages in the repair and regeneration of a zebrafish sensory organ.
20 September 2022
KANSAS CITY, MO — How the immune system responds to injury in many
organs and tissues allows and enables their repair and regeneration. Yet
for some species like humans, damage to organs such as the brain,
spinal cord, or heart is irreversible. Imagine if we were able to
regenerate these. For organ transplant candidates and recipients, the
nerve-wracking wait for “the call,” or the lifelong need for
immunosuppressing medications would no longer be necessary.
New research
from the Stowers Institute for Medical Research used the highly
regenerative zebrafish to investigate the timing and genetic programs of
macrophages, a type of white blood cell, in the repair and regeneration
of a zebrafish sensory organ. Understanding how the immune system
responds to injury, first by inducing inflammation immediately followed
by an anti-inflammatory response, provides invaluable knowledge for
designing targeted immunotherapies that may be applicable in combatting
human conditions like hearing loss or deafness, heart or spinal cord
damage.
Recently published in Nature Communications on September 20, Postdoctoral Researcher Nicolas Denans, PhD, in the lab of Stowers Investigator Tatjana Piotrowski, PhD,
discovered a new macrophage anti-inflammatory paradigm. Rather than the
established view that anti-inflammatory activation states for
macrophages are linked to just one type of signaling pathway, Denans
found that the same population can, and must, transition through each of
three anti-inflammatory states for organ regeneration.
“Organ regeneration offers an exciting opportunity for studying the
immune system and to inquire why some species can regenerate organs like
the heart or missing limbs while others like humans cannot,” said
Piotrowski.
Zebrafish sensory organ hair cells are an ideal system to investigate
the pathways and cell types involved in regeneration since they are
easily destroyed with antibiotics and begin regenerating within five
hours. This enabled the researchers to identify the exact timing and
genetic programs for each anti-inflammatory macrophage activation state.
“Our hypothesis is that human macrophages do not receive the proper
chemical activation “cocktail” to instruct pro-regenerative processes,”
said Denans. “Identifying the molecular recipe of macrophage activation
in zebrafish may one day enable us to design regenerative
immunotherapies in humans.”
Essential for organ regeneration, macrophages, which in Latin
literally translates as “big eaters,” engulf foreign particles like dead
cells and bacteria and use enzymes to digest them. In addition to their
culinary appetite, these cells signal both pro- and anti-inflammatory
pathways to secrete chemicals, or cytokines to either recruit additional
types of white blood cells or trigger anti-inflammatory pathways for
cellular and tissue repair.
Investigating macrophages at high spatial resolution and at multiple
closely spaced time points during zebrafish sensory hair cell death and
regeneration was critical. For the first time, the study demonstrates
that a single population of this cell type sequentially and
independently transitions through three different anti-inflammatory
states, each with its own unique molecular and genetic signature.
“The new evidence is a valuable resource for comparative studies on
the genetic programs involved in macrophage-mediated repair and
regeneration,” said Denans. “In other words, different types of injuries
may induce different kinds of inflammatory responses. We want to
decipher whether this “language” is universal or if there are a variety
of dialects.”
While the study marks the first time that the sequential macrophage
states have been resolved with extraordinary precision, preliminary
comparisons with previously reported pathways in different organs and
species suggest that this mechanism is likely conserved.