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 心筋細胞は長い間再生しないと考えられてきたが、Karolinska研究所のDr. Jonas Frisenにより、心筋細胞は25才では年に約1%が入れ替わり、その率は歳とともに下がり75才では0.5%以下程度まで低下すると断定された。最終的には心筋細胞は生涯の内に約半分が入れ替わることになると計算される。
 心筋細胞は新しく再生できないと言う教義は、1987年以来ずっとハーバード・メディカル・スクールのDr. Piero Anversaによって問題にされてきた。Dr. Anversaは、心筋細胞はとても早く更新されるので80才で亡くなるまでに4回心臓を交換していると主張している。しかし、多くの他の研究者はこの主張を疑っていた。
 細胞回転率は、放射性物質でラベルすることで動物では測定可能であるが、人では倫理的に測定ができなかった。
 しかし、Dr. Frisen は数年前、1963年以来大気中の核兵器実験で、全世界の人々の細胞がラベルされることになったのに気づいた。炭素14という炭素の放射性体が生成され、植物や動物、海洋中にも拡散し、その後大気圏内での実験が禁止されたため、大気中の炭素14は1963年以来徐々に減少している。このためDNAにおける炭素14の量は細胞の生年月日を示すのに役立つと気づいた。
 4年前に、彼は新たな方法でいろいろな体組織の回転率を調べたところ、成人では平均して7-10年若い可能性があると結論したが、器官による大きな差があり、血液や腸管は回転率が早く、脳はほぼ半永久的であった。Anversa博士が予測したよりかなり遅い率だが心筋セルが再生するという発見は「激しく争われた問題への妥当な結論」である。
 インディアナ大のDr. Loren Fieldは、マウスの心筋細胞の再生率は人と同じとわかったと言う。
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Heart Muscle Renewed Over Lifetime, Study Finds
http://www.nytimes.com/2009/04/03/science/03heart.html
By NICHOLAS WADE
Published: April 2, 2009

In a finding that may open new approaches to treating heart disease, Swedish scientists have succeeded in measuring a highly controversial property of the human heart: the rate at which its muscle cells are renewed during a person’s lifetime.
画像

Tests of nuclear weapons in the atmosphere, which lasted until 1963, generated a radioactive form of carbon, carbon-14. The carbon-14 in carbon dioxide is breathed in by plants, turned into glucose (see equation) and enters the human diet. In the body, the carbon-14 is incorporated into new DNA, and once a new cell is made, its DNA does not change. The level of carbon-14 in the atmosphere has dropped each year since 1963 (see graph), so the exact amount in a cell marks the year the cell was born. From a cell's birth date, researchers can calculate how quickly different tissues such as the intestine, brain and heart are renewed.
Dr. Jonas Frisén of the Karolinska Institute in Stockholm.

The finding upturns what has long been conventional wisdom: that the heart cannot produce new muscle cells and so people die with the same heart they were born with.

About 1 percent of the heart muscle cells are replaced every year at age 25, and that rate gradually falls to less than half a percent per year by age 75, concluded a team of researchers led by Dr. Jonas Frisen of the Karolinska Institute in Stockholm. The upshot is that about half of the heart’s muscle cells are exchanged in the course of a normal lifetime, the Swedish group calculates. Its results are to be published Friday in the journal Science.

“I think this will be one of the most important papers in cardiovascular medicine in years,” said Dr. Charles Murry, a heart researcher at the University of Washington in Seattle. “It helps settle a longstanding controversy about whether the human heart has any ability to regenerate itself.”

If the heart can generate new muscle cells, researchers can hope to develop drugs that might accelerate the process, since the heart fails to replace cells that are killed in a heart attack.

The dogma that the heart cannot generate new muscle cells has been challenged since 1987 by a somewhat lonely skeptic, Dr. Piero Anversa, now of the Harvard Medical School. Dr. Anversa maintains that heart muscle cells are renewed so fast that a person dying at age 80 has replaced the heart four times over. Many other researchers have doubted this assertion.

Cell turnover rates can easily be measured in animals by making their cells radioactive and seeing how fast they are replaced. Such an experiment, called pulse-labeling, could not ethically be done in people. But Dr. Frisen realized several years ago that nuclear weapons tested in the atmosphere until 1963 had in fact labeled the cells of the entire world’s population.

The nuclear blasts generated a radioactive form of carbon known as carbon-14. The amount of carbon-14 in the atmosphere has gradually diminished since 1963, when above-ground tests were banned, as it has been incorporated into plants and animals or diffused into the oceans.

In the body, carbon-14 in the diet gets into the DNA of new cells and stays unchanged for the life of the cell. Because the level of carbon-14 in the atmosphere falls each year, the amount of carbon-14 in the DNA can serve to indicate the cell’s birth date, Dr. Frisen found.

Four years ago he used his new method to assess the turnover rate of various tissues in the body, concluding that the average age of the cells in an adult’s body might be as young as 7 to 10 years. But there is a wide range of ages ― from the rapidly turning over cells of the blood and gut to the mostly permanent cells of the brain.

Dr. Frisen has successfully applied his method to the heart muscle cells, but had to navigate a series of technical obstacles created by the special behavior of the cells. Many have two nuclei, instead of the usual one, and within these double nuclei the DNA may be duplicated again. “I was really impressed at the level of rigor they put into this analysis,” Dr. Murry said, calling it a “scientific tour de force.”

The finding that heart muscle cells do regenerate, though at a considerably slower rate than Dr. Anversa predicted, is a “reasonable conclusion to a hotly contested issue,” Dr. Murry said. “Anversa went out on a limb, and I think he was partly right.”

Dr. Loren Field, a heart expert at the Indiana University School of Medicine, said he had found that heart muscle cells regenerated in mice at the same rate that Dr. Frisen had found in people. Despite the controversy created by Dr. Anversa’s claims, there has long been agreement that there is a low but detectable rate of cell renewal in the heart, Dr. Field said. The goal now, in his view, is “to try to tickle the system to enhance it.”

Dr. Anversa, for his part, said he was “ecstatic” at Dr. Frisen’s confirmation of his view that the heart could generate new muscle cells, but suggested that the new measurements might have underestimated the rate at which new cells are formed. Since heart muscle cells contract 70 times a minute, they seem likely to need renewing more often than Dr. Frisen’s measurements suggest, he said. “Now let’s discuss the magnitude of the process, and that will let us think about how we can apply this concept to heart failure,” Dr. Anversa said.

Dr. Frisen said he did not agree that the rate of regeneration had been underestimated. He said it would now be worth trying to understand how the regeneration of heart muscle cells was regulated.

A zebrafish, for instance, can regenerate large regions of its heart after injury, and possibly a similar response could be induced in people. It could also be that the heart does generate many new muscle cells after a heart attack but that the cells fail to establish themselves. Drugs that kept any such new cells alive could be helpful, Dr. Frisen said.

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Science 3 April 2009:
Vol. 324. no. 5923, pp. 98 - 102
DOI: 10.1126/science.1164680

Evidence for Cardiomyocyte Renewal in Humans
Olaf Bergmann,1* Ratan D. Bhardwaj,1* Samuel Bernard,2 Sofia Zdunek,1 Fanie Barnabé-Heider,1 Stuart Walsh,3 Joel Zupicich,1 Kanar Alkass,4 Bruce A. Buchholz,5 Henrik Druid,4 Stefan Jovinge,3,6 Jonas Frisén1{dagger}

It has been difficult to establish whether we are limited to the heart muscle cells we are born with or if cardiomyocytes are generated also later in life. We have taken advantage of the integration of carbon-14, generated by nuclear bomb tests during the Cold War, into DNA to establish the age of cardiomyocytes in humans. We report that cardiomyocytes renew, with a gradual decrease from 1% turning over annually at the age of 25 to 0.45% at the age of 75. Fewer than 50% of cardiomyocytes are exchanged during a normal life span. The capacity to generate cardiomyocytes in the adult human heart suggests that it may be rational to work toward the development of therapeutic strategies aimed at stimulating this process in cardiac pathologies.

1 Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
2 CNRS UMR5208, Institut Camille Jordan, Université Claude Bernard Lyon 1, 69622 Villeurbanne cedex, France.
3 Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, SE-221 84 Lund, Sweden.
4 Department of Forensic Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
5 Center for Accelerator Mass Spectrometry, Lawrence Livermore National Laboratory, 7000 East Avenue, L-397, Livermore, CA 94551, USA.
6 Department of Cardiology, Lund University Hospital, SE-221 85 Lund, Sweden.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: jonas.frisen@ki.se

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