Fight Aging!

Very shortly after birth, mammals are capable of far greater feats of regeneration than is the case for older individuals. The research community has put a fair amount of effort into determining why this is the case, though far less progress has been made here than in investigations of the biochemistry of highly regenerative species such as salamanders and zebrafish. This popular science article captures some of the present state of knowledge and uncertainty. Near future advances in medicine arising from this line of research seem unlikely at the present time, as by the look of it there is further to go yet in building a foundation of understanding sufficient to start talking about therapies.

Newborn mice are able to repair damaged heart tissue better than animals injured just a few days later in their lives. What accounts for this regenerative capacity, and exactly when and why it disappears, have been unanswered questions. A new report posits that the extracellular matrix (ECM) gets in the way of heart tissue renewal. The investigators also found that scarring was minimal in mice injured on their first day of life, but damage occurring after that, even just a day later, led to large fibrotic scars. Other scientists are skeptical that what the researchers observed is true regeneration, arguing that the team did not actually show the growth of new muscle. "There is a problem in this research field that we rely on this fibrosis hallmark because the extent of ventricle outgrowth is very hard to determine. If fibrosis is absent, people are very eager to conclude, 'OK, this is regeneration.' But it is not evidence of myocardial regrowth."

Because the adult mammalian heart cannot regenerate to any significant degree, an injury, such as that caused by a heart attack, damages the muscle irrevocably and can ultimately lead to heart failure and death. Following a 2011 paper that showed newborn mice could regenerate their hearts after having a chunk removed, some scientists began speculating that if they could figure out the mechanisms behind this renewal and recapitulate them in human heart attack victims, they might be able to prevent heart failure. The researchers reasoned that determining precisely when in the first week of life this capacity ceases might enable the identification of the factors involved. It was known that heart muscle cells continue to copy their DNA for a few days after birth, so one idea was that the heart's renewal capacity might be linked to this replication.

Researchers cut out the apical tips from the hearts of newborn mice on day 1, 2, 3, 4, or 9 after birth. Three weeks later, the researchers sacrificed the mice and reexamined their hearts. Animals whose hearts were resected on day 1 showed minimal scarring and the hearts were approximately the same size and shape as those of control animals. By contrast, animals who underwent heart surgery on day 2, 3, 4, or 9 exhibited large fibrotic scars in place of regrowth. Given the different recoveries of day 1 and day 2 mice, the team looked for differences between the animals' transcriptomes. "We were actually expecting to find differences in cell cycle genes, but that was not the case. The main difference that we found was in genes related to the extracellular matrix." The group saw a general upregulation of genes for ECM components and went on to show that the ECMs of day 2 mouse hearts were approximately 50 percent stiffer than those of day 1 hearts.

To determine whether ECM stiffness and regeneration were causally linked, researchers disrupted ECM formation in developing pups. They treated the pups with β-aminopropionitrile (BAPN) - an inhibitor of the ECM cross-linking enzyme LOX - during pregnancy (via the mothers' drinking water) and for three days after birth (through the mothers' milk). As a result, three-day-old pups were able to regenerate their hearts with significantly reduced fibrosis compared with controls whose ECMs were intact. Other researchers note that the proof that these mice are actually regenerating heart tissue wasn't provided, but the team is confident: "When there is no regeneration, you can see that the heart ventricular apex is missing a bit, and is replaced by a white patch (a scar). In contrast, it is not possible to distinguish, morphologically, a heart that completely regenerated from one that was not amputated."

Link: https://www.the-scientist.com/?articles.view/articleNo/52478/title/Study-Explains-How-Newborn-Mice-Can-Regrow-Damaged-Hearts/