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Single-cell Stereo-seq reveals induced progenitor cells involved in axolotl brain regeneration
Xiaoyu Weia b✉, Sulei Fuc d e✉, Hanbo Lib f g✉, Yang Liub✉, Shuai Wangb h✉, Weimin Fengb h✉, Yunzhi Yangi j✉, Xiawei Liu
Xiaoyu Weia b✉, Sulei Fuc d e✉, Hanbo Lib f g✉, Yang Liub✉, Shuai Wangb h✉, Weimin Fengb h✉, Yunzhi Yangi j✉, Xiawei Liu
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The molecular mechanism underlying brain regeneration in vertebrates remains elusive. We performed spatial enhanced resolution omics sequencing (Stereo-seq) to capture spatially resolved single-cell transcriptomes of axolotl telencephalon sections during development and regeneration. Annotated cell types exhibited distinct spatial distribution, molecular features, and functions. We identified an injury-induced ependymoglial cell cluster at the wound site as a progenitor cell population for the potential replenishment of lost neurons, through a cell state transition process resembling neurogenesis during development. Transcriptome comparisons indicated that these induced cells may originate from local resident ependymoglial cells. We further uncovered spatially defined neurons at the lesion site that may regress to an immature neuron–like state. Our work establishes spatial transcriptome profiles of an anamniote tetrapod brain and decodes potential neurogenesis from ependymoglial cells for development and regeneration, thus providing mechanistic insights into vertebrate brain regeneration. Description Trade-offs in brain development Salamander brains share some, but not all, structures with the mammalian brain. They also have greater capacity to regenerate in response to damage. Three groups now come together with single-cell transcriptomics analyses that set the salamander brain in evolutionary context (see the Perspective by Faltine-Gonzalez and Kebschull). By comparing salamander brains with those of lizard, turtle, and mouse, Woych et al. track the evolutionary innovations that gave rise to the mammalian six-layered neocortex, which salamanders do not have. Lust et al. take a close look at why the axolotl brain is so much more capable of regeneration than is the mammalian brain. Finally, Wei et al. compare the developmental and regenerative processes in the axolotl brain. —PJH Developmental and regenerative processes in the axolotl brain are revealed by single-cell analyses. INTRODUCTION Brain regeneration requires the coordination of complex responses in a time- and region-specific manner. Identifying the cell types and molecules involved in this process would advance our understanding of brain regeneration and provide potential targets for regenerative medicine research. However, progress in this field has been hampered by the limited regeneration capacity of the mammalian brain and an incomplete mechanistic understanding of the regeneration process at both the cellular and molecular levels. Axolotls (Ambystoma mexicanum) can regenerate damaged appendages and multiple internal organs, including the brain. Therefore, axolotls may serve as a model for studying brain regeneration. RATIONALE If we are to understand the mechanism of brain regeneration, we need research tools that can achieve large-scale data acquisition and analyses to simultaneously decode complex cellular and molecular responses. It also seemed to us that a comparison between brain regeneration and developmental processes would help to provide new insights into the nature of brain regeneration. Accordingly, we removed a small portion of the lateral pallium region of the axolotl left telencephalon and collected tissue samples at multiple stages during regeneration. In parallel, we collected tissue samples of the axolotl telencephalon at multiple developmental stages. We then used high-definition and large-field Stereo-seq (spatial enhanced resolution omics sequencing) technology to generate spatial transcriptomic data from sections that covered both hemispheres of the axolotl telencephalon at single-cell resolution. Analyses of cell type annotation, cell spatial organization, gene activity dynamics, and cell state transition were performed for a mechanistic investigation of injury-induced regeneration compared to these cell attributes during development. RESULTS With the use of Stereo-seq, we generated a group of spatial transcriptomic data of telencephalon sections that covered six developmental and seven injury-induced regenerative stages. The data at single-cell resolution enabled us to identify 33 cell types present during development and 28 cell types involved in regeneration, including different types of excitatory and inhibitory neurons, and several ependymoglial cell subtypes. For development, our data revealed a primitive type of ependymoglial cells that may give rise to three subgroups of adult ependymoglial cells localized in separate areas of the ventricular zone, with different molecular features and potentially different functions. For regeneration, we discovered a subpopulation of ependymoglial cells that may originate from local resident ependymoglial cells activated by injury. This population of progenitor cells may then proliferate to cover the wound area and subsequently replenish lost neurons through a state transition to intermediate progenitors, immature neurons, and eventually mature neurons. When comparing cellular and molecular dynamics of the axolotl telencephalon between development and regeneration, we found that injury-induced ependymoglial cells were similar to developmental-specific ependymoglial cells in terms of their transcriptome state. We also observed that regeneration of the axolotl telencephalon exhibited neurogenesis patterns similar to those seen in development in molecular cascades and the potential cell lineage transition, which suggests that brain regeneration partially recapitulates the development process. CONCLUSION Our spatial transcriptomic data highlight the cellular and molecular features of the axolotl telencephalon during development and injury-induced regeneration. Further characterization of the activation and functional regulation of ependymoglial cells may yield insights for improving the regenerative capability of mammalian brains. Our single-cell spatial transcriptome of the axolotl telencephalon, a tetrapod vertebrate, also provides data useful for further research in developmental, regenerative, and evolutionary brain biology. All data are accessible in an interactive database (https://db.cngb.org/stomics/artista). Development and regeneration of axolotl telencephalon. The spatially resolved single-cell transcriptome of the adult axolotl telencephalon as determined by Stereo-seq analyses (left). Upon brain injury in the highlighted lateral pallium region of the left hemisphere, a neural progenitor subpopulation at the wound site was rapidly induced and subsequently replenished lost neurons (bottom right) through a process that partially resembles neurogenesis during development (top right). CREDIT: YUNZHI YANG, BGI
TL;DRThis work establishes spatial transcriptome profiles of an anamniote tetrapod brain and decodes potential neurogenesis from ependymoglial cells for development and regeneration, thus providing mechanistic insights into vertebrate brain regeneration. (Semantic Scholar)