Regeneration in Mammals–Ancient Capacity is Not Lost, but Actively Suppressed

It was 1995, and Ellen Heber-Katz ran a busy lab at the Wistar Institute in Philadelphia, at the top of a thriving career in auto-immunity.  Her lab used standard practice to identify individual mice with tiny holes punched in their ears.  In the midst of one experiment, she discovered some un-labeled mice, and she spoke to her post-doc about it.  But Lise Clark said she was sure she had punched their ears.  So Heber-Katz punched their ears herself, and checked back a few weeks later.  She could hardly see the holes she had punched.  Within a few weeks, the ears had healed over, smooth skin, seamless cartilage with nary a scar.  Mice aren’t supposed to be able to do this.

She might have continued the project with an alternate labeling method, but Heber-Katz was more curious than that.  She learned that this particular strain of mouse (MRL mice from Jackson Labs in Bar Harbor) was known for healing over their ear punches.  Other researchers had noticed the “problem” and dealt with the inconvenience, without giving a second thought to the larger implications.

Heber-Katz couldn’t wait to study the phenomenon in depth. But her colleagues counseled against it, urging her not to waste her expertise in the field of autoimmune disease and transplant rejection. They advised her to pursue the disappearing ear holes as “an aside,” like a hobby. But Heber-Katz knew she had stumbled onto something big, and she just had to go after it full force. “I realized, since I didn’t know anything about wound healing, I had better go to a meeting about it,” she says. So she did, and there an expert told her: “Oh no, mouse ear holes absolutely do not close.” So Heber-Katz kept her finding secret. “I was really on cloud nine,” she says.    – Katie Moisse, [Sci Am (2006)]

In early studies with regeneration, she and colleagues found that the hearts of MRL mice heal scarlessly from injury.  When humans suffer heart attacks, heart tissue dies and usually the damage becomes permanent.  Normal mice can’t repair their own hearts either.

Salamanders and zebrafish are among the species that can regenerate limbs and even large portions of vital organs after injury, and the regrown portions of their anatomy are just the same as the original. We mammals cannot do this: we can manage fingernails, occasionally fingertips at a very early age, and portions of the liver, but that is about it. One line of modern regenerative research asks whether it is possible to somehow induce the regenerative biochemistry of salamanders and zebrafish in mammals. Is mammalian incompetence in healing a matter of lost capabilities that originally evolved in a distant shared ancestor species, and thus the necessary biochemistry still exists, but is in some way dormant? [Reason at]

Juan Carlos Belmonte’s Group at the Salk Inst has gotten normal mice to perform the same trick, using a micro-RNA signal to turn normal heart (muscle) cells back into the stem cells from whence they came, so they can make new heart cells. They were able to reactivate

long dormant molecular machinery found in the animals’ cells, a finding that could help pave the way to new therapies for heart disorders in humans. The new results suggest that although adult mammals don’t normally regenerate damaged tissue, they may retain a latent ability as a holdover, like their distant ancestors on the evolutionary tree.
In a [2010 paper in Nature], the researchers described how regeneration occurred in the zebrafish. Rather than stem cells invading injured heart tissue, the cardiac cells themselves were reverting to a precursor-like state (a process called ‘dedifferentiation’), which, in turn, allowed them to proliferate in tissue…

The team decided to focus on microRNAs, in part because these short strings of RNA control the expression of many genes. They performed a comprehensive screen for microRNAs that were changing in their expression levels during the healing of the zebrafish heart and that were also conserved in the mammalian genome.

 Their studies uncovered four molecules in particular–MiR-99, MiR-100, Let-7a and Let-7c–that fit their criteria. All were heavily repressed during heart injury in zebrafish and they were also present in rats, mice and humans.

[News Release from the Salk Inst]

In other words, the surprise is that we didn’t lose something in the advance from fish to mammal, rather we acquired a response that suppresses regeneration.  The ability to regenerate remains intact in mammals, but it is switched off.  This raises the possibility that if we want our bodies to be able to regenerate damaged tissue without scarring, we don’t have to acquire a new mechanism or even re-acquire one that has been lost; all we have to do is to fiddle with biochemical switches.  Switching on or off particular genes in particular tissues has become a reliable technology, using any of several techniques (e.g. CRISPR, RNAi, retroviruses).

the team used adeno-associated viruses specific for the heart to target each of those four microRNAs, suppressing their levels experimentally.

Injecting the inhibitors into the hearts of mice that had suffered a heart attack triggered the regeneration of cardiac cells, improving numerous physical and functional aspects of the heart, such as the thickness of its walls and its ability to pump blood. The scarring caused by the heart attack was much reduced with treatment compared to controls, the researchers found. The improvements were still obvious three and six months after treatment – a long time in a mouse’s life.

In the same vein, Heber-Katz’s group has also concluded that the capacity to regenerate has not been lost in mammals, but is actively suppressed.  Four years ago, they had already identified a gene called p21 which is defective in their MRL mice.  They knocked the p21 gene out of normal mice and discovered that those mice could heal their ears similarly to MRL mice.

Animals capable of regenerating multiple tissue types, organs, and appendages after injury are common yet sporadic and include some sponge, hydra, planarian, and salamander (i.e., newt and axolotl) species, but notably such regenerative capacity is rare in mammals. The adult MRL mouse strain is a rare exception to the rule that mammals do not regenerate appendage tissue…Using the ear hole closure phenotype, a genetically mapped and reliable quantitative indicator of regeneration in the MRL mouse, we show that the unrelated Cdkn1atmi/Tyj/J p21-/- mouse (unlike the B6129SF2/J WT control) closes ear holes similar to MRL mice, providing a firm link between cell cycle checkpoint control and tissue regeneration.  [Ref]

Although Heber-Katz’s group was based on genetically engineered mice, there is no reason to expect they could not do the same with normal mice, using one of the three in vivo techniques I mentioned above to shut off the p21 gene temporarily and locally.  I know of no one who is trying this in humans, but it seems to me that this technology is ready, and if I were a heart attack patient, I would eagerly volunteer for early trials.

This story of regeneration not being lost but suppressed fits beautifully with the song that I have sung so often on these pages and elsewhere–that there is no fundamental limit to life span in our metabolisms, but that evolution has programmed a fixed length of life for the purpose of stabilizing ecologies.

One thing that doesn’t fit so well is the story that Heber-Katz has been focusing on the last two years: inflammation is an essential part of the regeneration process [ref, ref, ref].  This could be an example of antagonistic pleiotropy.  Suppressing inflammation is an important anti-aging strategy, and it may have to be pried apart from wound healing in order to make further progress.


Porpoises and other marine mammals

Adult porpoises can repel a large shark, but are frequently injured in the encounter.  It is estimated that 40% of poropoises in the ocean have survived a shark bite, but they don’t carry scars from the event.  Porpoise skin and the blubber layer underneath recover in a matter of days from lacerations up to a foot long.

A Georgetown University pediatrician published this information a few years ago in a dermatology journal.  “Reports of the survival after severe traumatic injury of other marine mammals, such as the southern elephant seal [ref] and the Hawaiian monk seal [ref], suggest that efficient healing of soft-tissue injury might be widespread among marine mammals.”

What do the porpoises have that we don’t have?  I think the proper question is likely to be, by what signals have we suppressed the porpoise’s capacity to heal?


9 thoughts on “Regeneration in Mammals–Ancient Capacity is Not Lost, but Actively Suppressed

  1. Why are you concerned about inflammation as an impediment to regeneration (if I’ve read you correctly)? If you can locally and temporarily disable P21 as you suggest doing, why not allow inflammation to take place locally and temporarily being that you don’t get an EMT w/o it.

  2. So that is very interesting- imagine having genes that prevent us from regenerating lost parts? Imagine having genes that result in our eventual demise? We know this to be the case and if we believe in ‘wear and tear’ aging, (aging as a result of damage accumulation and information loss) then we cannot imagine that Nature could select an organism bent on its own destruction so the concept of ‘antagonistic pleiotropy came to be – people who could only believe that lifespan is limited by poor choices in enzymes that are valuable in youth and the opposite at old age. I don’t know how an species can ‘tune’ its lifecycle based on figuring out when it’s good enzyme will go bad. Clearly there are enzymes that shorten lifespan when they’re working correctly so their mutations increase lifespan though – I believe there are a number of very positive life limiting reactions that don’t depend on ‘antagonistic pleiotropy’ – for example the age-related involution of the thymus gland, and the age-related increase in low-grade, generalized inflammation. Now, while generalized, low-grade inflammation is a characteristic of aging, and leads to the diseases of aging, if not aging itself (whatever that is), the localized acute inflammation associated with the regeneration of a limb is not the same thing.
    What really interested me however is the use of miRNAs to dedifferentiate tissues allowing them to regenerate – what they did was to insert viruses carrying templates for miRNA complements to show that they were responsible for the ability of the cells to de-differentiate – but this is not really feasible with human beings – however miRNA is passed between cells in membrane-bound ‘exosomes’. And these exosomes have been show to be taken up by cells and altering their behaviors. So I’m thinking if we can make exosomes capable of being taken up by particular cells, we can use them to introduce the proper miRNAs into cells. I’m afraid that like the ‘wear and tear’ ers, I’d have to guess that a gene that prevented de-differentiation would likely prevent cancers?

  3. Do MRL mice live much longer than ordinary mice ?
    Regeneration would be a tremendous medical advance, but if all I could do is regenerate my organs, limbs etc to my current age, it sort of misses the point.
    What I want is not only to regenerate my damage body but have the regenerated tissue and ultimately my entire body into a younger state than before.
    Having said that I will happily accept any form of regeneration over what we have now. So how do we go about inhibiting P21?


    • Regeneration is related to longevity, but indirectly. A species that has a long internally-programmed life span has a greater chance of suffering major injury from accident or encounter with a predator, etc, and having the ability to regenerate is more useful to a long-lived species than a short-lived species.

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