Geckos can regrow their tails, and salamanders can heal their brains. Humans often wonder why most mammals, including ourselves, don’t possess such “superpowers”. Recently, a research team jointly formed by the Beijing Institute of Genomics, BGI and the Beijing Institute of Life Sciences has made a significant breakthrough. Using the spatial – omics technology Stereo – seq and the high – throughput sequencing platform DNBSEQ – Tx series, they have discovered for the first time that insufficient retinoic acid synthesis, caused by the low expression of the Aldh1a2 gene, which is a rate – limiting enzyme in retinoic acid synthesis, is the core mechanism for the failure of mouse ear regeneration.
After activating this gene, the mouse ear was able to regenerate. This finding provides new insights into the loss of regenerative ability in mammals during evolution and offers important targets for the reconstruction and regeneration of damaged human organs. The relevant research results were recently published in the international academic journal Science.
The research team selected the ear pinna (outer ear), a unique organ of mammals, as the research model. Based on single – cell RNA sequencing and spatial – omics technology Stereo – seq, they depicted the high – resolution single – cell spatiotemporal dynamics of regeneration/repair in the ear pinnae of regenerative species (rabbits) and non – regenerative species (mice) after injury. By observing the changes in each cell type and the dynamics of gene expression at the wound site of the ear pinna, the research team accurately compared the regeneration process with the normal healing process.
The results showed that the failure of mouse ear pinna regeneration is related to insufficient retinoic acid synthesis. Retinoic acid, a metabolite of vitamin A, is closely related to cell development. As a key signaling molecule, it can regulate cell proliferation, differentiation, migration, and tissue remodeling. The insufficient retinoic acid in mice is mainly due to the low expression of the Aldh1a2 gene.
Why is the expression of the Aldh1a2 gene insufficient in mice? Through evolutionary biology comparison, the research team found that in the rabbit genome, some key DNA sequences responsible for regulating the Aldh1a2 gene are retained. These regulatory sequences are called enhancers, which can be regarded as the “switch” or “accelerator” of gene expression. The research team found six active enhancers (AE1 – AE6) near the rabbit Aldh1a2 gene. Among them, two enhancers, AE1 and AE5, are strongly activated when the rabbit ear pinna is injured and regenerating, which is equivalent to pressing the “switch” in a timely manner after the rabbit is injured, thus increasing the expression of the Aldh1a2 gene and producing more retinoic acid at the wound site to help tissue regeneration.
However, the research team has only found one active enhancer, AE3, in the corresponding gene region of mice. In other words, the “buttons” for regulating the Aldh1a2 gene in mice are relatively rare, and it is very difficult to significantly activate the expression of the Aldh1a2 gene after injury. This explains why the Aldh1a2 gene in the mouse ear pinna cannot be “awakened” after injury, the production of retinoic acid cannot be increased, and the ear pinna cannot regenerate like that of a rabbit.
If the Aldh1a2 gene is artificially activated, can mice regain their regenerative ability? The research team tried to directly activate the Aldh1a2 gene or supplement retinoic acid externally and found that both methods could make pluripotent cells appear at the wound site of the adult mouse ear pinna, which originally did not have the regenerative ability, thus reconstructing the cartilage and nerve tissue of the ear pinna. That is to say, the wound of the mouse ear no longer simply heals but regenerates.
In addition, the research team also introduced the rabbit enhancer AE1 into the mouse genome. As a result, they found that the expression of the Aldh1a2 gene in the injured mouse ear pinna was significantly increased, the amount of retinoic acid increased, and the regenerative ability of the ear pinna was also significantly enhanced.
Based on single – cell spatiotemporal omics technology and cross – species analysis, the research team systematically depicted the changes in cell composition and the spatiotemporal dynamics of gene expression in regenerative and non – regenerative species after organ injury, revealing the mechanism of the loss of organ regenerative ability in mammals and providing important targets and theoretical basis for exploring the reconstruction and regeneration of damaged human organs.
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