Macrophages are required for organ regeneration in zebrafish

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“Macrophages are required for organ regeneration in zebrafish”

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How the immune system responds to injury in many organs and tissues allows for their repair and regeneration. However, for some species such as humans, damage to organs such as the brain, spinal cord or heart is irreversible. Imagine if we were able to renew these. For organ transplant candidates and recipients, the nerve-wracking “call” waiting, or lifelong need for immunosuppressive drugs, is no longer necessary.

New research from the Storrs Institute for Medical Research used highly regenerative zebrafish to investigate the timing and genetic programs of macrophages, a type of white blood cell, in the repair and regeneration of the zebrafish’s sensory organ. Understanding how the immune system responds to injury, first by inducing inflammation followed directly by an anti-inflammatory response, provides invaluable knowledge for designing targeted immunotherapies that may be applicable in combating human conditions such as hearing loss, deafness, heart or spinal cord damage.

Recently Posted in Nature Communications On September 20, 2022, postdoctoral researcher Nicholas Denans, PhD, in the lab of Stowers Investigator Tatjana Piotrowski, PhD, discovered a new anti-inflammatory model of macrophages. Rather than the well-established view that states of anti-inflammatory activation of macrophages are associated with only one type of signaling pathway, Dinan found that the same group can, and should, go through each of the three anti-inflammatory states of organ regeneration.

“Organ regeneration provides an exciting opportunity to study the immune system and inquire as to why some species are able to regenerate organs such as the heart or lost limbs while others, such as humans, cannot,” Piotrowski said.

The hair cells of zebrafish sensory organs are an ideal system for investigating the pathways and cell types involved in regeneration as they are easily destroyed by antibiotics and begin to regenerate within five hours. This enabled researchers to determine the exact timing and genetic programs of each state of anti-inflammatory macrophage activation.

“Our hypothesis is that human macrophages do not receive an appropriate chemical activation ‘cocktail’ to direct pro-regenerative processes,” said Denans. “Identifying the molecular recipe for macrophage activation in zebrafish may one day enable us to design regenerative immune therapies in humans.”

Necessary for organ regeneration, macrophages, which literally translates in Latin as “big eaters,” ingest foreign particles such as dead cells and bacteria and use enzymes to digest them. In addition to their appetite for cooking, these cells signal the pro- and anti-inflammatory pathways to secrete chemicals, or cytokines to either recruit additional types of white blood cells or trigger anti-inflammatory pathways to repair cells and tissues.

Investigating macrophages at high spatial resolution and at multiple converging time points during zebrafish sensory hair cell death and regeneration has been critical. For the first time, the study demonstrates that a single group of this type of cell translocates sequentially and independently 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 genetic programs involved in macrophage-mediated repair and regeneration,” said Denans. In other words, different types of injuries may lead to different types of inflammatory responses. We want to understand whether this “language” is universal or if there is a variety of dialects.

While the study represents the first time that macrophage cases have been sequenced with extraordinary accuracy, preliminary comparisons with previously reported pathways in various organs and species suggest that this mechanism is likely to be conserved.

“When you look in more detail, macrophages are not only required to initiate regeneration, but also interact with the brain by communicating with neurons to re-establish and maintain synapses that are necessary for proper organ function after regeneration,” Piotrowski said.

The team hopes that additional studies based on this new finding will provide the basis for designing customized immunotherapies to reduce disease, and possibly enable greater regeneration capabilities in regenerative-limited animals such as humans.

“This is just one step in a series of steps to entertain the idea of ​​developing regenerative immunotherapies in humans,” said Denans.

Reference: Denans N, Tran NTT, Swall ME, Diaz DC, Blanck J, Piotrowski T. An anti-inflammatory activation sequence controls macrophage transcriptional dynamics during tissue injury in zebrafish. nat common. 2022; 13 (1): 5356. doi: 10.1038 / s41467-022-33015-3

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