Muscle cells are one of the types of cells that have lost the ability to divide. Biologists call such cells post-mitotic because normal cell division is called mitosis. Knock out of the p38 gene in rats and mice allows muscle cells to divide.
It has long been believed that after initial development, the heart muscle cells can no longer proliferate. The new findings demonstrate that by eliminating a brake that halts the division of the muscle cells, researchers can then trigger the proliferation of the cells by adding specific cardiac growth factors.
The researchers will publish their findings in the May 15, 2005, issue of the journal Genes & Development. The paper was published online on May 3.
The research team was led by Howard Hughes Medical Institute investigator Mark T. Keating at Children's Hospital Boston and Harvard Medical School. Keating and his colleagues collaborated with researchers from the University of California, Los Angeles and Boehringer Ingelheim Pharmaceuticals in Ridgefield, Conn.
“There has been a longstanding controversy going back more than a hundred years about whether cardiomyocytes (cardiac muscle cells) in adult mammals have the capacity to proliferate,” said Keating. “While there have been occasional studies indicating this possibility, the dogma has been that they can't.” According to Keating, researchers thought that once an animal's heart has fully developed, cardiomyocytes lose the molecular plasticity that allows them to divide.
Whenever you read a scientist claim that some cell type X can't be made to do something that another cell type Y can do translate that statement into "We do not yet know how to make cell type X act like cell type Y". Cells in your body are like different computers running the same computer program. The different copies of the computer program may be in different states. But it is inevitable that ways will be found to get cells in one state to change into the state that another cell type uses. This wil be achieved for just about any pairs of cell types that exist in the body (exceptions being red blood cells that have lost their DNA and egg and sperm cells that no longer have full copies of their DNA).
The researchers accomplished their feat by knocking out a gene in rat cells for a protein called p38.
In their studies, Keating and his colleagues explored whether an enzyme called p38 acted as a brake on proliferation of adult cardiomyocytes. Although p38 is known to be involved in regulating cell division, very little is understood about its possible role in cardiomyocytes, said Keating.
In their experiments, the researchers explored whether knocking out p38 activity in cultures of rat cardiomyocytes could induce proliferation. The researchers found that knocking out p38 in the cell cultures of both infant and adult rats — in the presence of a cardiomyocyte growth factor protein called FGF1 — induced DNA synthesis, an important component in cell proliferation.
They also found other indications that the p38-knockout cells were undergoing mitotic proliferation. For example, they found that the proliferating cells dedifferentiated, meaning they temporarily lost the characteristics of mature heart muscle cells and reverted to a more fetal type of proliferating cell. Additional genetic studies of p38 inhibition showed that it regulates genes thought to be critical for cardiomyocyte proliferation.
Importantly, they found that the cardiomyocytes lacking p38 activity could continue to proliferate through many rounds of cell division in the presence of FGF1. “The fact that we could show that were multiple rounds of division is important, because clinical regeneration of cardiac muscle would require the cells to divide again and again,” said Keating.
We wouldn't want to have p38 permanently knocked out in our heart muscle cells. The heart muscle cells might grow too much and possibly even become cancerous. Also, p38 might serve some other as yet undiscovered purposes. But this result demonstrates that the process by which cells become unable to divide (post-mitotic) is reversible.
The scientists also raised mice with the p38 gene knock-out.
“As a result of these experiments, we felt quite confident that we could induce cardiomyocytes to proliferate, at least in vitro,” said Keating. “However, an in vitro system is quite artificial, and there could be many reasons why it would not be relevant in vivo.” So, in further experiments in collaboration with co-author Yibin Wang and his colleagues at UCLA, the researchers tested whether a genetic knockout mouse lacking p38 would show evidence of cardiomyocyte proliferation. Those experiments did yield significant evidence for such proliferation, said Keating.
Keating says a drug that would temporarily knock out p38 activity might enable heart repair after a heart attack. If heart cells could temporarily be given the ability to divide they could grow replacements for lost cells.
“These findings represent the first step toward showing that drugs that eliminate p38 activity could reduce scar tissue formation and enhance cardiac regeneration after cardiac injury,” said Keating. The formation of scar tissue in damaged hearts is the major reason myocardial infarctions lead to subsequent abnormalities and compromised heart function, he said.
A drug aimed at knocking out p38 might also induce regular muscles to grow. But for an old person who has lost a lot of muscle cells throughout the body due to aging such a side effect might even be a benefit. But does p38 also prevent other types of cells from dividing? If a drug that suppresses p38 activity also caused, for example, nerve cells to divide then that would be a very problematic side effect.
Adult and embryonic stem cells are the other major alternatives being investigated for replacing lost heart muscle cells. But if existing muscle cells can be induced to divide they'd offer a few advantages. Most notably, they are already located where the replacement cells are needed. Also, as compared to adult stem cells their DNA might be in better shape because they haven't been dividing for decades collecting errors on each cell division. Though muscle cell DNA does accumulate damage.
We need complete understanding and mastery of the mechanisms which govern cell division both to replenish lost cells and also to cure cancer and other diseases which are caused by excessive cell division. This latest report provides yet another piece of the puzzle.
|Share |||Randall Parker, 2005 May 04 01:47 PM Biotech Organ Replacement|