Unlocking the mysteries of brain regeneration: Breakthrough study offers new insight

Trajectories of neuron generation. Credit: BGI Genomics

First axolotl stereo-seq offers new insights into brain regeneration.

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

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

Type of tissue the Axolotl can regenerate

Type 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 research partners used Stereo-seq technology to recreate the architecture of the axolotl brain throughout development and regeneration processes at single-cell resolution. Examining the genes and cell types that allow axolotls to renew their brains could lead to better treatments for severe injuries and unlock the potential for human regeneration.

Images of cell regeneration after injury

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

The research team collected axolotl samples from six developmental stages and seven regeneration phases with the corresponding stereotemporal sequence data. The six stages of development include:

  • The first feeding stage after hatching (stage 44)
  • The development stage of the forelimbs (stage 54)
  • The stage of development of the hind limbs (stage 57)
  • Youth stage
  • Adulthood
  • metamorphosis

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

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

Development and regeneration of the axolotl brain

Processes of development and regeneration of the axolotl brain. Credit: BGI Genomics

Partial tissue attachment appeared in the wound, and after 20 to 30 days, new tissue had regenerated, but the cell type composition was significantly different from uninjured tissue. Cell types and distribution in the damaged area did not return to the state of uninjured tissue until 60 days post-injury.

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 a injury

What are the similarities and differences between neuron formation 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 features of the two processes, the researchers found that the process of neuron formation is very similar during regeneration and development, indicating that injury induces neural stem cells to transform into a state of rejuvenated development to start the regeneration process.

“Our team analyzed the cell types important in the regeneration process of the axolotl brain and tracked the changes in its spatial cell lineage,” said Dr. Xiaoyu Wei, first author of this article and senior researcher at BGI-Research. “The spatiotemporal dynamics of key cell types revealed by Stereo-seq provides us with a powerful tool to pave 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 species that self-regenerate, and the regeneration mechanisms are quite diverse. Using multi-omics methods, scientists at the whole 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, 2 Sep 2022, science.
DOI: 10.1126/science.abp9444

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

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