Neuron Generation Trajectories

Unraveling the Mysteries of Brain Regeneration – Groundbreaking Study Offers New Insights

Neural generation trajectories. Credit: BGI Genomics

First-ever axolotl stereo-seq gives new insights into brain regeneration.

Due to its distinctive and adorable look, the Ambystoma mexicanum axolotl is a popular pet. Unlike other metamorphosed salamanders, axolotls (pronounced ACK-suh-LAH-tuhl) never grow past their juvenile larval stage, a trait known as neoteny. It is also recognized for its ability to regenerate missing limbs and other tissues including the brain, spinal cord, tail, skin, limbs, liver, skeletal muscles, heart, upper and lower jaw and eye tissues such as the retina, cornea and lens.

Mammals, including humans, are almost incapable of rebuilding damaged tissue after brain injury. Some species, such as fish and axolotls, on the other hand, can replenish injured brain regions with new neurons.

Types of Tissue the Axolotl Can Regenerate

Types of tissue the axolotl can regenerate as shown in red. Credit: Debuque and Godwin, 2016

Brain regeneration requires the coordination of complex responses in a time- and region-specific manner. In an article published on the cover of Science, BGI and its research partners used Stereo-seq technology to recreate axolotl brain architecture throughout developmental and regenerative processes at single-cell resolution. Examining the genes and cell types that allow axolotls to renew their brains could lead to better treatments for serious injuries and unlock the potential for human regeneration.

Images of cell regeneration following injury

Images of cell regeneration at seven different time points after injury; the control image is on the left. Credit: BGI Genomics

The research team collected axolotl samples at six developmental stages and seven regeneration stages with corresponding spatio-temporal Stereo-seq data. The six stages of development include:

  • The first feeding stage after hatching (stage 44)
  • The stage of forelimb development (stage 54)
  • The stage of development of the hind limbs (stage 57)
  • Juvenile stage
  • Adulthood
  • Metamorphosis

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

In the third part of the study, the researchers generated a set of spatial transcriptomic data from forebrain sections covering seven stages of injury-induced regeneration. After 15 days, a new neural stem cell subtype, reaEGC (reactive ependymoglial cells), appeared in the wound area.

Axolotl brain development and regeneration

Axolotl brain development and regeneration process. Credit: BGI Genomics

A partial tissue connection appeared at the wound and after 20-30 days new tissue had been regenerated, but the cell type composition was significantly different from that of the uninjured tissue. Cell types and their distribution in the damaged area did not return to the state of uninjured tissue until 60 days after injury.

The key neural stem cell subtype (reaEGC) involved in this process is derived from the activation and transformation of resting neural stem cell subtypes (wntEGC and sfrpEGC) near the wound after being stimulated by a wound.

What are the similarities and differences between the formation of neurons during development and regeneration? The researchers discovered a similar pattern between development and regeneration, which goes from neural stem cells to progenitor cells, then to immature neurons and finally to mature neurons.

Axolotl brain development

Spatial and temporal distribution of axolotl brain development. Credit: BGI Genomics

By comparing the molecular characteristics of the two processes, the researchers found that the process of neuron formation is very similar during regeneration and development, indicating that injury prompts neural stem cells to transform into a rejuvenated developmental state. to initiate the regeneration process.

“Our team analyzed cell types important in the axolotl brain regeneration process and tracked changes in its spatial cell lineage,” said Dr. Xiaoyu Wei, first author of this paper and principal investigator of BGI-Research. “The spatio-temporal dynamics of key cell types revealed by Stereo-seq provides us with a powerful tool to open up new research directions in the life sciences.”

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 quite diverse. Thanks to multi-omics methods, scientists around the world can work together more systematically.”

Reference: “Single-cell Stereo-seq Reveals Induced Progenitor Cells Involved in Axolotl Brain Regeneration” by Xiaoyu Wei, Sulei Fu, Hanbo Li, Yang Liu, Shuai Wang, Weimin Feng, Yunzhi Yang, Xiawei Liu, Yan-Yun Zeng, Mengnan Cheng, Yiwei Lai, Xiaojie Qiu, Liang Wu, Nannan Zhang, Yujia Jiang, Jiangshan Xu, Xiaoshan Su, Cheng Peng, Lei Han, Wilson Pak-Kin Lou, Chuanyu Liu, Yue Yuan, Kailong Ma, Tao Yang, Xiangyu Pan, Shang Gao, Ao Chen, Miguel A. Esteban, Huanming Yang, Jian Wang, Guangyi Fan, Longqi Liu, Liang Chen, Xun Xu, Ji-Feng Fei and Ying Gu, September 2, 2022, Science.
DOI: 10.1126/science.abp9444

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

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