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By flipping an evolutionarily disabled genetic switch involved in vitamin A metabolism, researchers headed by a team at the National Institute of Biological Sciences, Beijing, have enabled ear tissue regeneration in mice.
The scientists, co-led by Wei Wang, PhD, and colleagues, performed a side-by-side genetic comparison between mammal species—including rabbits—that can regenerate ear tissue and those—including mice—that can’t. The team’s analyses identified a key difference in how wound-induced fibroblasts (WIF) respond following injury, and highlighted activation in regenerative animals of a specific gene, Aldh1a2, that is critical for producing vitamin A (retinoic acid; RA). The team subsequently found that administering RA externally or switching on the Aldh1a2 gene reactivated ear tissue regeneration in transgenic mice.
Co-senior author Wang, together with first author Weifeng Lin, PhD, and colleagues, reported on their studies in Science, in a paper titled “Reactivation of mammalian regeneration by turning on an evolutionarily disabled genetic switch.” In their report the research concluded, “Our findings may help in increasing understanding of the evolution of regeneration and provide a potential framework for dissecting mechanisms underpinning the failure of regeneration in different organs and species.”
Unlike some animals such as fish and salamanders, mammals have limited capacity to regenerate damaged tissues or organs fully. A variety of strategies have been explored to trigger regeneration in mammals, such as stem cell therapies, gene editing, and electrical stimulation. While these approaches have shown promise, none have fully restored organ function. This is likely due to the biological complexity of mammals and a limited understanding of the genetic factors that govern regenerative abilities. “…a complete rescue of organ regeneration has not been achieved, presumably owing to the complexity of mammalian organs, side effects of gene ectopic expression or inhibition, and lack of information on the linkage between the failure of regeneration and the genetic changes in the genome,” the investigators stated. They point out that understanding what has occurred during evolution to induce the loss or gain of regeneration could offer up valuable targets for regenerative medicine.
Some mammals, including rabbits, goats, and African spiny mice, can regenerate complex tissues, such as the ear pinna (the visible outer part of the ear), while others, including common rodents such as mice and rats, cannot. Because the ear pinna is a uniquely mammalian structure and varies widely in its ability to regenerate across species, Weifeng Lin and colleagues argue that it makes an ideal model for studying how regenerative capacity has evolved in mammals. And although there is a lot of variation in morphology and size, the ear pinnae of different placental mammals include similar cell types and have functions.
For their reported study Lin et al. first demonstrated that rabbits, which are regenerative mammals, could fill a full-thickness hole in the ear pinna and completely restore lost tissues. “This process requires the formation of a blastema, an injury-induced heterogeneous cell mass that prepares cells to regenerate new tissues,” they explained. In contrast, mice failed to close the holes, although the authors note that there was in these animals evidence of “extremely weak regeneration.”
The investigators then performed a side-by-side comparison between mammalian species that either can or cannot regenerate ear tissue. “We performed comparative single-cell and spatial transcriptomic analyses of rabbits and mice recovering from pinna damage,” they wrote. They found that failure of tissue regeneration in nonregenerative species is not due to an inability to form or proliferate the blastema, the early wound-healing structure. Instead, the key difference lies in how certain wound-induced fibroblasts (WIFs) respond after injury.
Their single-cell RNA sequencing and spatial transcriptomic analyses showed that regenerative species activate a gene called Aldh1a2, which is critical for producing vitamin A or retinoic acid (RA), a signaling molecule essential for regeneration. In nonregenerative species, they discovered, Aldh1a2 is insufficiently activated due to both reduced expression and enhanced breakdown of RA, which leads to regeneration failure.
“The inactivation of multiple Aldh1a2-linked regulatory elements accounted for the injury-dependent deficiency of Aldh1a2 in mice and rats,” they stated. Notably, the team found that supplying RA externally by injection, or activating Aldh1a2 using a gene enhancer from rabbits, was enough to restore regenerative ability in mice “An exogenous supplement of RA—but not the synthetic precursor retinol—was sufficient to induce regeneration by directing WIFs to form new ear pinna tissues,” they stated. “Importantly, activation of Aldh1a2 driven by a single rabbit enhancer was sufficient to promote ear pinna regeneration in transgenic mice.”
