Genes & Development

The Jerusalem Post

Nature

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Nature

For the first time in the world, Jerusalem researchers have discovered that pregnancy has the remarkable ability to promote the regeneration in elderly mice of damaged livers and muscles. They have also managed to mimic the state of pregnancy using specific molecules that trigger the regeneration and growth of livers in older rodents.This basic new concept from Hadassah University Medical Center and the Hebrew University-Hadassah Medical School could eventually be relevant to other tissues and organs and lead to the ability to stimulate their regeneration in elderly, sick patients.An article on the research by Dr. Yuval Gielchinsky, Prof. Neri Laufer, Prof. Yehudit Bergman and colleagues has just been published in the prestigious journaland aroused much interest among scientists.Laufer, who is chairman of the department of obstetrics and gynecology at the medical center in Jerusalem’s Ein Kerem, toldon Wednesday evening that the research began soon after he read an article five years ago in the journalThe authors of that article had connected young mice to other young mice by uniting their blood vessels; old mice to old mice; and young mice to old mice (this procedure is called parabiosis).If a mouse was either young or old and attached to a young mouse – and it suffered liver damage – the connection via blood circulation led to regeneration of tissue in the damaged organ. In aging rodents and elderly people, regeneration of the liver and other tissue is slow or even impossible.Bergman, an expert in molecular immunology, developmental biology and gene expression at the medical school, told the: “One day about four years ago, a young gynecologist named Dr. Yuval Gielchinsky came into my office and said Neri suggested he come to me to do his Ph.D. and for me to be his supervisor.“I asked if he knew what I do in my lab – epigenetics [the study of changes in the appearance or gene expression caused by mechanisms other than changes in the underlying DNA sequence]. He said he didn’t.“We thought of all kinds of ideas, until Neri came and told us about the article in. It seemed to him that pregnancy was a kind of parabiosis in which a mother is connected by blood vessels to its young fetus. Investigating this was appealing, and this is what Yuval set off to do.”Also involved in the research was Dr. Eli Pikarsky of the medical school’s pathology department and Lautenberg Center for Immunology, as well as Efi Weitman, Dr. Rinat Abramovitch and Dr. Zvi Granot.The team studied mice and indeed found that damage to tissue in the foot muscle (and later liver) of an older but pregnant mouse was quickly repaired, as if it had been connected to a live young animal. The researchers knew there was something in the blood that was doing this, but couldn’t explain what it was and how it worked.Laufer said that when a young animal loses two-thirds of its liver, it can regenerate the lost tissue in a few days. But if it is old, half of the mice would die due to stress on the organ. Of those that survive, much less tissue would be regenerated.But if the mouse is older and pregnant, its tissue regenerates as if it were young.The regenerative capacity of tissue declines with age, and healing in response to injury is delayed, he said. This effect is observed in liver, skin, bones, blood vessels, nerves, muscles and other tissue. The reason is that ageing alters the function of many biological processes such as changes in growth factors, the accumulation of damage to DNA in the cells and the increase in oxygen free radicals in the cells.They learned that the repair mechanism was a kind of switch within the cells, and that it can be made to work with specific molecules (drugs) to stimulate and repair them.The significance of this, explained Laufer, “is that part of the liver can be removed from old animals, they can be given drugs and this will cause the remaining liver to regenerate as if they were pregnant but without actually being pregnant.”The new research shows that pregnancy causes a switch from regeneration based on proliferation (an increase in the number of cells due to cell division) to regeneration caused by hypertrophy (the increase in the volume of an organ or tissue due to the enlargement of its component cells). Certain molecules given to aged mice induced hypertrophy in their livers, thus mimicking the state of pregnancy and lengthening their lifespan.The fountain of youth, he said, “is pregnancy. That is the new concept we developed. It has rejuvenating ability.“But the advantages of pregnancy can be produced in non-pregnant animals. We are now working to see if this affects their longevity. If this concept can be transferred to humans, it could allow people to recover from illness or disease naturally and more quickly and weaken the effects of old age.”Bergman said they first worked on muscle tissue but then switched to the liver, as it is already a very well-studied organ model. In the future, the team will work on skin and other tissues.“It was very surprising to see how pregnancy affects the regeneration of the liver,” she said.The team has already received a preliminary patent – registered throughHadasit (the Hadassah Medical Organization’s technology transfercompany) and Yissum (that of HU) – for the development of medicationbased on their findings.The researchers concluded that it’s possible that similar means couldbe used to enhance the ability of the liver to regenerate in oldpeople. Such advances could have considerable impact on those who areeligible for and/or in need of liver surgery, yet are at significantrisk of surgical complications.