A groundbreaking study in Science identifies vitamin A's metabolite, retinoic acid, as a critical regulator of organ regeneration, hair growth, and skin repair. It activates dormant regenerative pathways in mammals, balancing stem cell functions for tissue repair and hair follicle development, with implications for potential therapeutic applications.
In sci-fi movies, "organ regeneration" is often a standard feature of superhumans. However, in nature, organ regeneration is not an uncommon miracle. Starfish can regrow lost body parts, flatworms can become new individuals from each segment when cut, and even some amphibians can rebuild damaged eyes, hearts, and even brain tissues. These animals perform "regeneration" like copy-paste. But looking at humans, not to mention regrowing an organ, even a small ear piercing may leave a permanent scar. Why have we lost this amazing regenerative ability? Is there a "forgotten" switch hidden behind it?
A recent study published in Science provides a breakthrough clue to this puzzle: the key to determining whether the auricle can regenerate lies in the retinoic acid signal produced by vitamin A metabolism in the body. And by awakening this signal "forgotten" by mammals or supplementing retinoic acid exogenously, mice can also regrow complete ear tissue. It seems that the seemingly lost organ regenerative ability may not be completely lost, but merely sealed by a silent molecular switch.
DOI: 10.1126/science.adp0176
The Debut of WIFs: The "Regeneration Construction Team" Arrives After Injury
Researchers first focused on the "starting line": during the critical window of 5-10 days, whether it is regenerative rabbits, African spiny mice, goats, or mice and rats with poor regenerative ability, the prototype of blastema—an aggregation of undifferentiated cells crucial for regeneration—can be seen on the wound surface, and cell proliferation is also vigorous. This step shows that everyone can press the "start button", and the regeneration process does not fail from the beginning. All these species initiate the early stages of regeneration with similar cellular activity, indicating that the initial machinery for regeneration is still intact across different mammals.
The real dividing line appears in the subsequent 10-30 days. The blastema of regenerative animals maintains stable proliferation, continuing to grow and differentiate into the necessary tissues to rebuild the damaged area. In contrast, proliferation in mice and rats declined rapidly. By day 30, these non-regenerating species also had higher rates of apoptosis, leading to a rapid decline in blastema activity. This stark difference highlights that the problem is not in starting the regeneration process but in sustaining it to completion.
Transcriptome data—analyses of all RNA molecules expressed in cells—further revealed the differences at the genetic level. Mice and rats can indeed up-regulate classic regeneration genes such as Wnt5a, Fstl1, and Tgfb3, which are known to play roles in various developmental and repair processes. However, to truly "complete the project" of regeneration, there is a need to "ignite" a specific set of regeneration-associated genes (RAGs) that are only activated in species capable of full regeneration.
Evolution of regeneration in mammals.
Taking the rabbit-rat comparison as an example, rabbits have 469 such unique RAGs, which are concentrated in pathways such as "skeletal system morphogenesis" and "mesenchymal development"—both essential for forming complex structures like the auricle. Mice, on the other hand, show no response in these genes, leaving their regeneration efforts incomplete.
In other words, the auricle of mice can start the repair process, forming a blastema and initiating cell division, but it never receives the full "reconstruction blueprint" encoded in these RAGs. As a result, the "engineering project" of regeneration is forced to stop halfway, resulting in scarring rather than full tissue regrowth.
Further analysis found that those RAGs that are activated in rabbits but missing in mice are mainly concentrated in a special group of fibroblasts that only appear after tissue injury. The research team named these cells "wound-induced fibroblasts" (WIFs). These cells are not present in healthy tissue but are generated specifically in response to injury, making them unique to the regenerative process.
That is to say, RAGs are not expressed in every cell in the body. Only this group of newly generated WIFs after injury are the main force in performing the regeneration task, as they are the ones capable of activating and expressing the critical RAGs needed to drive regeneration to completion.
It's Not That the Gene is "Broken", But That the "Switch" is Gone
Next, the research team wanted to figure out which link of the regeneration process "gets stuck" in non-regenerative animals. To do this, they conducted gene overexpression experiments in the auricles of mice using AAV (adeno-associated virus) viral vectors, which can deliver and express specific genes in target tissues. The results of these experiments identified Aldh1a2, the rate-limiting enzyme in the retinoic acid synthesis pathway, as a key player. Once Aldh1a2 is stably expressed in the mouse auricle, it can almost induce the regeneration of mouse ear holes, demonstrating its crucial role in promoting regeneration.
Since the core enzyme Aldh1a2 works, the researchers wondered if directly supplementing retinoic acid— the end product of the pathway that Aldh1a2 regulates—could be a simpler way to induce regeneration. The answer is yes: exogenous supplementation of retinoic acid allows mice to completely close their ear holes within 30 days. Moreover, it makes wound-induced WIFs re-embark on the "rabbit-style" reconstruction route—starting from local chondrocytes, these cells diffuse and differentiate into various tissues such as blood vessels and cartilage, achieving true structural regeneration rather than just superficial healing. This means that the new tissue is functional and integrated, not just a scar covering the wound.
In fact, mice are not lacking the Aldh1a2 gene itself—their genome contains the gene. So why can't it be activated after injury to produce the necessary retinoic acid?
The research team compared the epigenetic markers of mice and rabbits before and after injury. Epigenetic markers are chemical modifications to DNA or associated proteins that affect gene expression without changing the underlying DNA sequence. They looked at the active promoter marker H3K4me3 and the active enhancer marker H3K27ac, both of which indicate regions of the genome that are actively being transcribed into RNA. The results are clear: after injury, rabbits have 6 activated enhancers (AE1-AE6) in the Aldh1a2 neighborhood, which boost the expression of the Aldh1a2 gene. In contrast, mice have almost no new activation signals in this region, meaning their Aldh1a2 gene remains "silent" after injury.
This indicates that although the mouse's "engine"—the Aldh1a2 gene—is present, the "igniter"—the epigenetic enhancers that turn the gene on after injury—is not working. Without these enhancers, the gene cannot be activated to produce the enzyme needed for retinoic acid synthesis.
To verify the function of these enhancers, the researchers inserted the rabbit's promoter or enhancer AE1 into the mouse genome. The results showed that a single AE1 enhancer can activate expression of Aldh1a2 in mouse epidermis and mesenchyme after injury, significantly reducing the size of the ear hole. Additionally, this enhancer also shows steady-state activity in multiple organs (brain, lung, kidney), suggesting that its role in activating gene expression is not limited to the auricle but could have broader implications for regeneration in other tissues.
It seems that even restoring just one of the "igniters"—the AE1 enhancer—is enough to increase retinoic acid synthesis and accelerate regeneration, highlighting the importance of these epigenetic regulators in controlling regenerative potential.
Specifically, in terms of mechanism, in species with regenerative ability, auricle injury will quickly activate the Aldh1a2 promoter-enhancer network. This activation leads to the synthesis of high levels of retinoic acid, which then helps WIFs complete tissue reconstruction by promoting their proliferation, differentiation, and the expression of RAGs. In contrast, mice and rats have lost the activity of these key enhancers during evolution, resulting in inherently insufficient retinoic acid production after injury. This low level of retinoic acid signals limits the morphogenetic potential of wound-induced WIFs—the ability to form complex tissues—leading to regeneration failure. However, by artificially activating Aldh1a2 through gene therapy or by exogenously supplementing retinoic acid, the regeneration process can be reactivated, bypassing the missing epigenetic "igniters".
In general, this study reveals that insufficient Aldh1a2 expression, caused by the loss of enhancer activity, and subsequent changes in the retinoic acid synthesis pathway are the direct causes of auricle regeneration failure in non-regenerative animals. This mechanism highlights the key role of the retinoic acid (RA) signaling pathway in mammalian regeneration and provides potential therapeutic targets for regenerative medicine, suggesting that manipulating this pathway could one day enable enhanced tissue regeneration in humans.
Also Beneficial for Hair Growth and Skin Repair
Vitamin A, this "versatile" substance, in addition to playing a significant role in organ regeneration, has recently been found to take on another important task—controlling the "identity switch" for stem cells. A previous study published in Science pointed out that vitamin A regulates the lineage plasticity of stem cells, maintaining a delicate balance between wound healing and hair growth, two processes that often compete for resources in the skin.
DOI: 10.1126/science.adi73
What is "lineage plasticity of stem cells"?
Simply put, stem cells are not limited to developing along a single predetermined path. When triggered by certain conditions, they can "change allegiance" and switch to another differentiation route, allowing them to adapt to the body's needs. Take lizards with amazing regenerative ability as an example. After their tails are broken, they can regrow muscles, bones, and even nerve tissues, which is a striking manifestation of cell "lineage plasticity".
The same is true for hair follicle stem cells. These stem cells are normally "specialized" in promoting hair growth, generating the cells that form the hair shaft and the surrounding follicle. However, when the skin is damaged, they can transform into epidermal stem cells, which are responsible for repairing the outer layer of the skin, to join the repair front. This ability to switch identities is what is called "lineage plasticity".
Retinoic acid orchestrates stem cell lineage plasticity during wound healing.
That is to say, for hair follicle stem cells to enter the state of "lineage plasticity", they need to temporarily express the transcription factors of both hair and epidermal stem cells. This dual expression allows them to be flexible in their fate, ready to commit to either hair growth or skin repair depending on the body's signals.
To find the key factors regulating this lineage plasticity, the research team used mammalian skin epithelium as a model and conducted a large-scale screening of small molecule compounds. In this screening, they accidentally found that retinoic acid (the active form of vitamin A) is the "valve" that allows stem cells to exit the plastic state and redifferentiate into either hair or epidermal cells in vitro. This means that retinoic acid controls when and how stem cells commit to a specific fate.
A series of subsequent in vivo and in vitro experiments further proved that only when the level of retinoic acid is maintained within a reasonable range can hair follicle stem cells effectively balance wound repair and hair growth. If the level of retinoic acid is too high, stem cells cannot enter the lineage plastic state at all. This means they remain committed to their original fate (e.g., hair growth) and thus cannot switch to epidermal stem cells to repair wounds, impairing the skin's ability to heal. Conversely, if the level of retinoic acid is too low, stem cells will focus almost exclusively on wound repair, continuously generating epidermal cells to close the wound, but this comes at the expense of hair regeneration, as the stem cells no longer produce the cells needed for hair growth.
Then, a "skin vs. hair" seesaw emerges, with vitamin A standing at the fulcrum. A slight tilt in either direction—too much or too little retinoic acid—will cause an imbalance on both sides, resulting in a situation where one cannot have both optimal skin repair and healthy hair growth.
Of course, retinoic acid does not work alone in this process. It joins forces with other signaling molecules such as BMP (bone morphogenetic protein) and WNT, which are known to play key roles in development and stem cell regulation. Together, these signals together form a network that builds the multiple cell lineages required for hair follicle formation and skin maintenance, and then accurately dispatches stem cells to "grow hair" or "replenish skin" according to the body's needs.
In general, this study is the first to clarify the important role of vitamin A in regulating stem cell lineage plasticity. It opens up new ideas for regenerative medicine, wound repair, and even tumor treatment—where abnormal lineage plasticity can contribute to cancer progression. Research suggests that precisely manipulating this “vitamin A balance” may one day allow us to both quickly restore skin to its original state after injury and regrow hair, solving two common problems in dermatology and aesthetics.
The human body cannot synthesize vitamin A directly, so it needs to be obtained from fresh foods or supplements. For ordinary people, to truly "use vitamin A for my own benefit", the first priority is not how much extra it should be consumed, but to ensure that the intake is just right - neither deficient nor excessive. Both deficiency and excess can lead to adverse effects: deficiency can impair regeneration and hair growth, while excess can be toxic, causing issues like liver damage or birth defects.
So, how to eat "appropriately"? According to the recommended intake (RNI) in China's dietary guidelines, adult men need 800 micrograms of retinol activity equivalents (RAE) per day, and women need 700 micrograms. RAE is a unit that accounts for the different biological activities of various forms of vitamin A, including both preformed vitamin A and provitamin A carotenoids.
Looking further, the sources of vitamin A intake mainly include two types of food: one is animal sources, which contain directly usable active vitamin A (i.e., retinol). Examples include animal liver (such as beef liver), egg yolks, and dairy products like milk and cheese. The other is plant sources, which are rich in the precursor of vitamin A—β-carotene. Representative foods include carrots, sweet potatoes, spinach, and pumpkins. β-carotene is converted into retinol in the body, but this conversion is not 100% efficient, which means that larger amounts of plant-based sources are needed to obtain the same amount of active vitamin A as from animal sources.
It should be noted that these two studies are mainly based on animal models—mice, rabbits, etc. While the findings are promising, their universality in humans still needs further verification through clinical trials and research. The regenerative processes and vitamin A metabolism in humans may differ in important ways from those in laboratory animals, so caution is needed when extrapolating these results to human health and potential treatments.
Summary
This article explores the multifaceted role of vitamin A, particularly its active form retinoic acid, in biological processes such as organ regeneration, hair growth, and skin repair. Key findings from Science studies show that retinoic acid signaling is critical for auricle regeneration in mammals, with non-regenerative species like mice lacking the necessary epigenetic enhancers to activate the pathway. Exogenous retinoic acid or activation of the Aldh1a2 gene can restore regenerative capacity. Additionally, vitamin A regulates stem cell lineage plasticity, balancing skin repair and hair growth—a delicate balance that relies on optimal retinoic acid levels. Human intake of vitamin A, obtained from animal and plant sources, must be moderate to avoid deficiency or excess. While animal studies are promising, further research is needed to confirm these effects in humans.