麻豆淫院

Research led by the National Institute of Biological Sciences in Beijing has discovered that switching on a single dormant gene enables mice to regenerate ear tissue.

Some vertebrates such as salamanders and fish can regenerate complex tissue structures with precision. A lost limb can be regrown, a damaged heart or eye can be repaired. Salamanders are so remarkable at reconstructing damaged tissues that even a spinal cord injury with severed neural motor connectivity can be restored.

Mammals occasionally showcase the ability to regenerate. Deer antlers and goat horns are examples of living tissue regeneration. Mice can regrow fingertips if they are lost. A healthy human liver can experience up to 70% loss of tissue and regrow to near full size within several weeks.

However, for the most part, mammals have seemingly replaced the ancient capacity for tissue regeneration with scarring, a trade-off that increases immediate survival of an injury by closing and sealing the wound.

Ear tissue punch regeneration has previously been studied in specific strains of Murphy Roths Large mice that have the ability to close 2-mm ear punches with scar-free regeneration. They can regenerate cartilage, dermis, epidermis, hair follicles, and even nerves in the ear tissue, and have shown some capacity to repair heart damage as well. Rabbits too have this ability to regenerate holes in ear tissue, suggesting that the capacity may have been shared by a common ancestor.

Rabbits and mice are related species that share a common ancestor around 90 million years ago which had previously diverged from the human primate ancestor around the same time. Millions of years of separate evolution have left the regeneration gene itself intact, but rewired its expression, extinguishing an ancestral regenerative response in most rodents that a few mice and the rabbit lineage still deploy.

In the study, "Reactivation of mammalian regeneration by turning on an evolutionarily disabled genetic switch," in Science, researchers conducted comparative genomic analyses of regenerative mammals, rabbits, goats, and African spiny mice, and nonregenerative mice and rats.

Analyzing ear pinna injury recovery in these mammals, researchers used single-cell RNA sequencing, spatial transcriptomic profiling, bulk RNA sequencing, ChIP-seq, ATAC-seq, and Micro-C to identify gene activity differences in wound-induced fibroblasts, specialized cells crucial to tissue regeneration.

Regeneration outcomes were evaluated in 10 rabbits and 10 non-regenerating lab mice. Molecular analyses pooled tissue from six animals per replicate across three replicates per time point. Mice did form initial blastema-like cell clusters indicative of regeneration potential, but proceeded to light scarring without regeneration.

Genetic analysis pointed to a potential difference in the mouse and rabbit models. Retinoic acid buildup in the rabbits preceded regeneration, synthesized from retinaldehyde by an enzyme called Aldehyde Dehydrogenase 1 Family Member A2 (Aldh1a2). Mice also expressed the Aldh1a2 enzyme, but it was nearly absent and insufficient to produce significant retinoic acid.

Testing found that supplementing retinoic acid alone (notably not its precursor retinol) fully restored regeneration of cartilage and other ear structures in mice and rats. Conversely, inhibiting RA production impeded regeneration in rabbits, verifying its critical role.

Researchers created transgenic mice carrying a rabbit-derived regulatory enhancer known as AE1. Insertion of this single genetic element increased Aldh1a2 expression after injury and induced regrowth of cartilage and other ear structures.

Regrowth in transgenic mice was incomplete compared to the fully restored ears of retinoic acid-infused mice, suggesting that additional enhancers and promoter interactions may be required to continue the process beyond initial injury.

Genetic analysis identified regulatory elements required for regeneration after injury that have become inactive in nonregenerative species. Reactivation of this genetic switch induced regeneration of damaged structures, and skipping the genetic mechanism by supplying the retinoic acid worked even better.

Results and findings should inspire a wave of regenerative medicine research into the untapped capacity to circumvent scarring by tapping into the potentially dormant mechanisms already prepared to regrow damaged hair, skin, nerve and cartilage tissues.