Wyva
Senior Member (Voting Rights)
Structured Abstract
INTRODUCTION
Regeneration, an apparently beneficial trait, is well maintained in some animal lineages but has been lost in many others during evolution and speciation. A complete rescue of organ regeneration in mammals with limited regenerative capacity has not yet been achieved, primarily because of limited information on the linkage between the failure of regeneration and the genetic changes in the genome. Understanding what has occurred during animal evolution to drive the loss or gain of regeneration will shed new light on regenerative medicine.RATIONALE
Identification of the causal mechanism underlying the failure of regeneration in mammals through comparative strategies is usually entangled by the large phylogenetic distance from highly regenerative species (mostly lower vertebrates). Exploration of principles in the evolution of regeneration demands an organ with easy accessibility and diverse regenerative capacities. One such mammalian organ is the ear pinna, which evolved to funnel sound from the surrounding environment for better distinguishing between ambient noise and predators or prey. The ear pinna possesses complex tissues such as skin and cartilage and exhibits remarkable diversity in the ability to regenerate full-thickness holes punched through this organ in placental mammals.RESULTS
By performing a side-by-side comparison between regenerative species (rabbits, goats, and African spiny mice) and nonregenerative species (mice and rats), we found that the failure of regeneration in mice and rats was not due to the breakdown of tissue-loss triggered blastema formation and proliferation. Single-cell RNA sequencing and spatial transcriptomic analyses of rabbits and mice identified the response of wound-induced fibroblasts (WIFs) as a key difference between the regenerating and nonregenerating ear pinna. Gene overexpression studies discovered that Aldehyde Dehydrogenase 1 Family Member A2 (Aldh1a2), encoding a rate-limiting enzyme for the synthesis of retinoic acid (RA) from retinaldehyde, was sufficient to rescue mouse ear pinna regeneration. The activation of Aldh1a2 upon injury was correlated with the regenerative capacity of the tested species. Furthermore, we demonstrated that the deficiency of Aldh1a2 expression, together with the augmented activity of the RA degradation pathway, contributed to insufficient RA production after injury and eventually the failure of regeneration. 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. The inactivation of multiple Aldh1a2-linked regulatory elements accounted for the injury-dependent deficiency of Aldh1a2 in mice and rats. Importantly, activation of Aldh1a2 driven by a single rabbit enhancer was sufficient to promote ear pinna regeneration in transgenic mice.CONCLUSION
Our study identified a direct target involved in the evolution of regeneration and provided a potential framework for dissecting mechanisms underpinning the failure of regeneration in other organs or species. RA signaling is broadly involved in different contexts of regeneration including bone, limb, skin, nerve, and lung regeneration. The crosstalk between the RA pathway and the crucial regeneration regulator, AP-1 complex, further highlights the impact of RA deficiency on regeneration in some lineages. We propose that modulation of the RA pathway may be a hot spot for the evolution of regeneration in vertebrates.Abstract
Mammals display prominent diversity in the ability to regenerate damaged ear pinna, but the genetic changes underlying the failure of regeneration remain elusive. We performed comparative single-cell and spatial transcriptomic analyses of rabbits and mice recovering from pinna damage. Insufficient retinoic acid (RA) production, caused by the deficiency of rate-limiting enzyme Aldh1a2 and boosted RA degradation, was responsible for the failure of mouse pinna regeneration. Switching on Aldh1a2 or RA supplementation reactivated regeneration. Evolutionary inactivation of multiple Aldh1a2-linked regulatory elements accounted for the deficient Aldh1a2 expression upon injury in mice and rats. Furthermore, the activation of Aldh1a2 by a single rabbit enhancer was sufficient to improve ear pinna regeneration in transgenic mice. Our study identified a genetic switch involved in the evolution of regeneration.Paywall: https://www.science.org/doi/10.1126/science.adp0176
