Life isn't all about squid; mice also matter. I've been reading about the MRL mouse, a lab-bred strain which has been discovered to have an unusual property: amazing powers of regeneration. They weren't bred for that, though; instead, they were selected for large size, and were then discovered to have a defect in the cell death gene fas, which made them a useful model for autoimmune research—they had excessive proliferation of lymphatic cells.

Ear-hole closure after 30 days. Through-and- through 2 mm holes are punched in the middle of the ear pinnae in both MRL (a,b) C57BL/6 (black mouse) and (c,d ) MRL (white mouse) ears. The holes can be clearly seen in the C57BL/6 at days 0 (a,c) and 30 (b,d ). However, by day 30 in the MRL (d ) the holes have disappeared.

One way to mark individual mice is by punching small holes in their ears (it sounds cruel, I know…fathers with teenage daughters also think it is a terrible thing to do). The mice of the MRL strain do something remarkable, though, as you can see to the right: they heal right up. There is no detectable scar tissue, either—these mice regenerate.

Regrowing ears might be a very big deal to a mouse, but not so much to us. However, their powers of regeneration go deeper. Damage their livers, their kidneys, and many other tissues, and they grow right back. They can regrow lopped off toes and tails. Here's the big one: take a fine wire, stick it in their heart, and burn a hole in it with extreme cold, a process called cryo-damage which mimics the damage of a myocardial infarction, and in the MRL mouse, heart tissue regenerates.

Whoa.

MRL myocardium regenerates. Histological sections of the mouse heart are stained with trichrome and the collagen is stained in blue. Five to 7 days after cryo-injury to the RV of the heart, the injury can be seen in both the C57BL/6 (a) and MRL (b) hearts. By 60 days, an acellular scar can be seen in the C57BL/6 (c) and near complete myocardium has filled the injury site in the MRL (d ) heart.

This is biology that's getting a little personal. My father died of a series of heart attacks stretched out over more than a decade, each one killing muscle and leaving its little web of useless scar tissue, weakening his heart step by step. What we wouldn't have given to bestow this small property of a mouse's heart on him…

Alas, it's not going to be easy to transfer this ability to people. The good news is that the initial studies have found that the genes responsible for the MRL mouse's predilection for autoimmune diseases are different than the ones involved in fast healing; there isn't a horrible trade-off, where better recovery from heart attacks means one is likely to come down with lupus (there are almost certainly other trade-offs, however; for instance, the MRL mouse exhibits a greater inflammation response to injury). The bad news? At least 20 different genes are involved in the regeneration ability of the MRL mouse. This is a very complex characteristic, not one we're going to figure out how to turn on in ourselves next week.

How does the mouse do it? Among the factors that block regeneration in us is the formation of scar tissue and the secretion of a basement membrane around reforming tissues in the wound site. This might be a good thing in the short term; it represents a rapid response to injury that could prevent infection and further damage. However, it also blocks reorganization and more plastic responses that are needed in order to regenerate.

Among the genes affected in the MRL mouse are a pair of metalloproteinases, MMP-2 and MMP-9, which are upregulated. There are inhibitors of metalloproteinases, TIMP-2 and TIMP-3, that are also downregulated. The protein-digesting enzymes are present in the wound sites, and busily break down the basement membrane, keeping the tissues labile. When the MRL mice are treated with a metalloproteinase inhibitor (the antibiotic minocycline), the rate of regeneration is greatly slowed.

The authors also report improved ability of the MRL mouse to regenerate from spinal cord injury; again, one commonly reported obstacle to recovery from neural damage is the formation of scar tissue, and these mice have less of that. There are some suggestive observations here.

These spinal cord studies demonstrate that the scar plays a major role in blocking the regenerative response and that even in the C57BL/6 mouse, axonal regeneration occurs in its absence. Perhaps the same thing is true for humans. And perhaps, without the scar, the same type of healing and regeneration would be seen in the heart.

An evolutionary lesson from this animal is that it represents a more likely example of how advantageous novelties arise: not by abrupt transformations of single genes, but by fortuitous recombination of smaller, hardly noticeable variants that, when they come together in a single individual, interact to produce a new phenotype.

This is an exciting model for studying mechanisms of regeneration that might someday be applicable to us. One other weird thought: I'd like to see a combination of the MRL regenerating mouse with the Mighty Mouse myostatin mutant—then we'd have a Wolverine-like superhero mouse!

Heber-Katz E, Leferovich J, Bedelbaeva K, Gourevitch D, and Clark L (2004) The scarless heart and the MRL mouse. Phil. Trans. R. Soc. Lond. B 359:785-793.