Salamander Brain Regeneration Unlocks Mysteries of Evolution and Regeneration

Author: BGI Genomics
Published: 2022/09/26 - Updated: 2023/01/04 - Peer-Reviewed: Yes
Contents: Summary - Main - Related Publications

Synopsis: Examining genes and cell types that allow axolotls to regenerate their brains may be key to improving treatment for severe injuries and unlocking regeneration potential in humans. Unlike other salamanders undergoing metamorphosis, axolotls (pronounced ACK-suh-LAH-tuhl) never outgrow their larval, juvenile stage, a neoteny phenomenon. It is also known for regenerating lost limbs and other tissues such as the brain, spinal cord, tail, skin, limbs, liver, skeletal muscle, heart, upper and lower jaw, and ocular tissues such as retina, cornea, and lens. In nature, there are many self-regenerating species, and the regeneration mechanisms are pretty diverse. With multi-omics methods, scientists around the world may work together more systematically.

Axolotl (Ambystoma mexicanum)

The axolotl, Ambystoma mexicanum, is a paedomorphic salamander closely related to the tiger salamander. Axolotls are unusual among amphibians in that they reach adulthood without undergoing metamorphosis. Instead of taking to the land, adults remain aquatic and gilled. The feature of the axolotl that attracts the most attention is its healing ability: the axolotl does not heal by scarring and is capable of the regeneration of entire lost appendages in months, and, in some instances, more vital structures, such as the tail, limb, central nervous system, and tissues of the eye and heart. They can even restore less vital parts of their brains. They can also readily accept transplants from other individuals, including eyes and parts of the brain - restoring these alien organs to full functionality. In some cases, axolotls have been known to repair a damaged limb and regenerate an additional one, ending up with an extra appendage that makes them attractive to pet owners as a novelty.

Main Digest

Single-cell Stereo-seq reveals induced progenitor cells involved in axolotl brain regeneration.

The axolotl Ambystoma mexicanum is a popular pet due to its unique and cute appearance. Unlike other salamanders undergoing metamorphosis, axolotls (pronounced ACK-suh-LAH-tuhl) never outgrow their larval, juvenile stage, a phenomenon called neoteny. It is also known for its ability to regenerate lost limbs and other tissues such as the brain, spinal cord, tail, skin, limbs, liver, skeletal muscle, heart, upper and lower jaw, and ocular tissues such as retina, cornea, and lens. Upon brain injury, mammals, including humans, are almost incapable of regenerating the lost tissue. In contrast, some animals such as fish and axolotls may replenish injured brain regions with new neurons.

Brain regeneration requires coordination of complex responses in a time and region-specific manner. To better understand this process, BGI and its research partners have applied Stereo-seq technology to reconstruct the axolotl brain architecture during developing and regenerating processes at single-cell resolution in a study published on the cover of Science.

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Cell regeneration images at seven timepoints following an injury; control image is on the left - Image Credit: BGI Genomics.
Cell regeneration images at seven timepoints following an injury; control image is on the left - Image Credit: BGI Genomics.
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Examining the genes and cell types that allow axolotls to regenerate their brains may be the key to improving treatments for severe injuries and unlocking human regeneration potential. The research team collected axolotl samples from six development stages and seven regeneration phases with corresponding spatiotemporal Stereo-seq data. The six developmental stages include:

Through the systematic study of cell types in various developmental stages, researchers found that during the early development stage, neural stem cells located in the VZ region are difficult to distinguish between subtypes, and with specialized neural stem cell subtypes with regional spatial characteristics from adolescence, thus suggesting that various subtypes may have different functions during regeneration.

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Axolotl brain developmental and regeneration processes - Image Credit: BGI Genomics.
Axolotl brain developmental and regeneration processes - Image Credit: BGI Genomics.
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In the third part of the study, the researchers generated a group of spatial transcriptomic data of telencephalon sections that covered seven injury-induced regenerative stages.

After 15 days, a new subtype of neural stem cells, reaEGC (reactive ependymoglial cells), appeared at the wound area.

Partial tissue connection appeared at the wound, and after 20 to 30 days, new tissue had been regenerated, but the cell type composition was significantly different from the non-injured tissue.

The cell types and distribution in the damaged area did not return to the state of the non-injured tissue until 60 days post-injury.

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Tissue types the axolotl can regenerate, as shown in red (Debuque and Godwin, 2016).
Tissue types the axolotl can regenerate, as shown in red (Debuque and Godwin, 2016).
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The key neural stem cell subtype (reaEGC) involved in this process was derived from the activation and transformation of quiescent neural stem cell subtypes (wntEGC and sfrpEGC) near the wound after being stimulated by injury.

What are the similarities and differences between neuron formation during development and regeneration?

Researchers discovered a similar pattern between development and regeneration, which is from neural stem cells to progenitor cells, subsequently into immature neurons, and finally to mature neurons.

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Neuron generation trajectories - Image Credit: BGI Genomics.
Neuron generation trajectories - Image Credit: BGI Genomics.
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By comparing the molecular characteristics of the two processes, the researchers found that the neuron formation process is highly similar during regeneration and development, indicating that injury induces neural stem cells to transform themselves into a rejuvenated state of development to initiate the regeneration process.

"Our team analyzed the important cell types in the process of axolotl brain regeneration and tracked the changes in its spatial cell lineage," said Dr. Xiaoyu Wei, the first author of this paper and BGI-Research senior researcher. "The spatiotemporal dynamics of key cell types revealed by Stereo-seq provide us a powerful tool to pave new research directions in life sciences."

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Spatial and temporal distribution of axolotl brain development - Image Credit: BGI Genomics.
Spatial and temporal distribution of axolotl brain development - Image Credit: BGI Genomics.
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Corresponding author Xun Xu, Director of Life Sciences at BGI-Research, noted that:

"In nature, there are many self-regenerating species, and the mechanisms of regeneration are pretty diverse. With multi-omics methods, scientists worldwide may work together more systematically."

Note: This study has passed ethical reviews and follows the corresponding regulations and ethical guidelines.

BGI Genomics

BGI Genomics, headquartered in Shenzhen, China, is the world's leading provider of genomic sequencing and proteomic services. Our services cover over 100 countries and regions, involving more than 2,300 medical institutions.

Genes That Repair Spinal Cord in Fish Also Present in Humans: Many of the genes that repair an injured spinal cord in a fish called the lamprey are also active in the repair of the peripheral nervous system in mammals.

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This peer reviewed publication pertaining to our Anthropology and Disability section was selected for circulation by the editors of Disabled World due to its likely interest to our disability community readers. Though the content may have been edited for style, clarity, or length, the article "Salamander Brain Regeneration Unlocks Mysteries of Evolution and Regeneration" was originally written by BGI Genomics, and submitted for publishing on 2022/09/26 (Edit Update: 2023/01/04). Should you require further information or clarification, BGI Genomics can be contacted at the bgi.com/global website. Disabled World makes no warranties or representations in connection therewith.

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