Category Archives: Stem Cells

Discovery of stem cells in human ovaries overturns dogma

Web edition : 2:07 pm

A newly discovered type of stem cell in the ovary could mean big things for women’s health, possibly leading to new fertility treatments and maybe even a way to delay menopause.

Since the 1950s it has been thought that women are born with all of the egg cells they will ever have. But with the discovery of egg-producing stem cells in mice and humans, it now appears that the ovary can replenish its egg supply. Researchers led by Jonathan Tilly, a reproductive biologist at Massachusetts General Hospital in Boston, report the finding online February 26 in Nature Medicine.

Other researchers hail the discovery as a genuine breakthrough with huge implications. “This is like discovering a new planet in our solar system that has a bacterium on it,” says Kutluk Oktay, a reproductive biologist at the New York Medical College in Valhalla. At the very least, he says, the cells offer hope for extending a woman’s reproductive life span.

Tilly didn’t set out to overturn the accepted dogma that women don’t make new eggs. As part of their research into the onset of menopause, he and his colleagues developed ways to track the death of egg cells over time. When the researchers counted the number of healthy egg cells in mouse ovaries, they saw a steady decline with age as expected. But the team also found that dying cells greatly outnumber the starting population of eggs. “What we had was a math problem,” Tilly says. “We refocused all of our efforts on this glaring mathematical dilemma.”

In 2004, Tilly’s group reported the answer to their math problem: There are more dying eggs than healthy ones because stem cells in mouse ovaries are constantly making more eggs, which then die off. The discovery didn’t go over well. “The vast majority of our colleagues were not very receptive,” Tilly says. Many of those who did accept the existence of egg-forming stem cells in mice didn’t think humans would have similar cells.

Tilly and his colleagues isolated stem cells from ovaries that had been removed from six women during sex reassignment surgeries at Saitama Medical Center in Japan. Only about 1.5 percent of cells in the ovaries fit the stem cell profile. The researchers compiled molecular profiles of the cells and demonstrated that the stem cells are able to make precursors to eggs when transplanted into other ovaries. 

Tilly’s group convincingly demonstrates that stem cells in human ovaries can make egg cell precursors. But it remains to be seen if the cells can make mature gametes, says Evelyn Telfer, a reproductive biologist at the University of Edinburgh.

Stopping the depletion of eggs or keeping ovaries functioning could help stave off many of the health problems women experience after menopause, Tilly says. “If we can somehow control this biological clock, to me, the possibilities are endless.”

Found in: Genes & Cells

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Eggs may be made throughout adulthood

By Ryan Flinn - Sun Feb 26 18:00:00 GMT 2012

Stem cells taken from human ovaries can produce normal, healthy eggs, scientists demonstrated for the first time in an experiment that may lead to new methods to help infertile women.

The finding challenges a belief that women have a fixed number of eggs, or oocytes, from birth that are depleted by the time of menopause, and that their ovaries can't make make more. The research, led by Jonathan Tilly, director of Harvard University-affiliated Massachusetts General Hospital’s Vincent Center for Reproductive Biology, is published today in the journal Nature Medicine.

In 2004, Tilly discovered that ovarian stem cells in mice can create new eggs, similar to how stem cells in male testes produce sperm throughout a man’s life. The latest study proves the same is true in human ovaries, and may point to new ways to overcome infertility or preserve fertility by delaying the time when a woman’s ovaries stop functioning, he said.

“The 50-year-old belief in our field wasn’t actually based on data proving it was impossible, or not ongoing, it was simply an assumption made because there was no evidence indicating otherwise,” Tilly said in a telephone interview. “We have human cells that can produce new oocytes.”

A female is most endowed with oocytes as a fetus, when she has about 7 million. That number that drops to 1 million by birth, and around 300,000 by puberty. By menopause, the number is zero. Since the 1950’s, scientists thought that ovarian stem cells capable of producing new eggs are only active during fetal development.

Ovarian Stem Cells

In the study, healthy ovaries were obtained from consenting patients undergoing sex reassignment surgery. The researchers were able to identify ovarian stem cells because they express a rare protein that’s only seen in reproductive cells.

The stem cells from the ovaries were injected into human ovarian tissue that was then grafted under the skin of mice, which provided the blood supply that enabled the cells to grow. Within two weeks, early stage human follicles with oocytes had begun to form.

“This paper essentially opens the door to the ability to control oocyte development in human ovaries,” Tilly said.

About 10 percent of women of child-bearing age in the U.S., or 6.1 million, have difficulty getting pregnant or staying pregnant, according to the Centers for Disease Control and Prevention. Most cases of female infertility are caused by problems with ovulation, hormone imbalance or age.

Infertility Treatments

Infertility in women is now treated through drugs, surgery, artificial insemination or assisted reproductive technology, in which the woman’s eggs are mixed with sperm outside the body, then reinserted.

The study offers “a new model system for understanding the human egg cell,” according to David F. Albertini, director of the Center for Reproductive Services and professor in the department of molecular and integrative physiology at Kansas University. Still, “there’s a long way to go before this has real practical applications,” he said.

“I’ve spent 35 years of my life studying egg cells and this is a cell that is at least as complicated as a neuron in the brain, if not more,” Albertini said in an interview. “You will need to establish reproducibility from one lab to the next, and hopefully others will be able to confirm his work and extend it, make it into something that will make us confident that the cells are safe to use and we could actually use them to repopulate an egg-depleted ovary.”

New Therapies

The research is opening other therapeutic avenues in fertility treatment, Tilly said.

His team is exploring the development of a bank for ovarian stem cells, which can be cryogenically frozen and thawed without damage, unlike human oocytes. The researchers are also working to identify hormones and other growth factors for accelerating the production of eggs from human ovarian stem cells and ways to improve in-vitro fertilization.

“The problem we face with IVF is we don’t have many eggs to work with,” he said. “These cells are renewable. If we are successful -- and it’s a big if -- in generating functioning eggs from these cells, we can generate as many eggs as we need to on a per patient basis.”

Tilly is also collaborating with researchers at the University of Edinburgh in the U.K. to determine whether the oocytes can be developed into fully mature human eggs for fertilizing. The U.S bans creating or fertilizing embryos for experimental purposes, he said.

A company Tilly co-founded, Boston-based OvaScience Inc., has licensed the technology for potential commercial applications.

To contact the reporter on this story: Ryan Flinn in San Francisco at rflinn@bloomberg.net

To contact the editor responsible for this story: Reg Gale at rgale5@bloomberg.net

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Ovarian Stem Cells Produce Eggs in Method That May Aid Fertility Therapy

WASHINGTON — For 60 years, doctors have believed women were born with all the eggs they'll ever have. Now Harvard scientists are challenging that dogma, saying they've discovered the ovaries of young women harbor very rare stem cells capable of producing new eggs.

If Sunday's report is confirmed, harnessing those stem cells might one day lead to better treatments for women left infertile because of disease — or simply because they're getting older.

"Our current views of ovarian aging are incomplete. There's much more to the story than simply the trickling away of a fixed pool of eggs," said lead researcher Jonathan Tilly of Harvard's Massachusetts General Hospital, who has long hunted these cells in a series of controversial studies.

Tilly's previous work drew fierce skepticism, and independent experts urged caution about the latest findings.

A key next step is to see whether other laboratories can verify the work. If so, then it would take years of additional research to learn how to use the cells, said Teresa Woodruff, fertility preservation chief at Northwestern University's Feinberg School of Medicine.

Still, even a leading critic said such research may help dispel some of the enduring mystery surrounding how human eggs are born and mature.

"This is going to spark renewed interest, and more than anything else it's giving us some new directions to work in," said David Albertini, director of the University of Kansas' Center for Reproductive Sciences. While he has plenty of questions about the latest work, "I'm less skeptical," he said.

Scientists have long taught that all female mammals are born with a finite supply of egg cells, called ooctyes, that runs out in middle age. Tilly, Mass General's reproductive biology director, first challenged that notion in 2004, reporting that the ovaries of adult mice harbor some egg-producing stem cells. Recently, Tilly noted, a lab in China and another in the U.S. also have reported finding those rare cells in mice.

But do they exist in women? Enter the new work, reported in the journal Nature Medicine.

First Tilly had to find healthy human ovaries to study. He collaborated with scientists at Japan's Saitama Medical University, who were freezing ovaries donated for research by healthy 20-somethings who underwent a sex-change operation.

Tilly also had to address a criticism: How to tell if he was finding true stem cells or just very immature eggs. His team latched onto a protein believed to sit on the surface of only those purported stem cells and fished them out. To track what happened next, the researchers inserted a gene that makes some jellyfish glow green into those cells. If the cells made eggs, those would glow, too.

"Bang, it worked — cells popped right out" of the human tissue, Tilly said.

Researchers watched through a microscope as new eggs grew in a lab dish. Then came the pivotal experiment: They injected the stem cells into pieces of human ovary. They transplanted the human tissue under the skin of mice, to provide it a nourishing blood supply. Within two weeks, they reported telltale green-tinged egg cells forming.

That's still a long way from showing they'll mature into usable, quality eggs, Albertini said.

And more work is needed to tell exactly what these cells are, cautioned reproductive biologist Kyle Orwig of the University of Pittsburgh Medical Center, who has watched Tilly's work with great interest.

But if they're really competent stem cells, Orwig asked, then why would women undergo menopause? Indeed, something so rare wouldn't contribute much to a woman's natural reproductive capacity, added Northwestern's Woodruff.

Tilly argues that using stem cells to grow eggs in lab dishes might one day help preserve cancer patients' fertility. Today, Woodruff's lab and others freeze pieces of girls' ovaries before they undergo fertility-destroying chemotherapy or radiation. They're studying how to coax the immature eggs inside to mature so they could be used for in vitro fertilization years later when the girls are grown. If that eventually works, Tilly says stem cells might offer a better egg supply.

Further down the road, he wonders if it also might be possible to recharge an aging woman's ovaries.

The new research was funded largely by the National Institutes of Health. Tilly co-founded a company, OvaScience Inc., to try to develop the findings into fertility treatments.

Copyright 2012 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.

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Women have rare egg-producing stem cells

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Jonathan Tilly, director of the Vincent Center for Reproductive Biology, Massachusetts General Hospital, is shown in a handout photo.In research that could have far-reaching implications for female fertility, U.S. scientists have isolated stem cells from human ovarian tissue that give rise to what appear to be normal egg cells. THE CANADIAN PRESS/HO, Massachusetts General Hospital

In research that could have far-reaching implications for female fertility, U.S. scientists have isolated stem cells from human ovarian tissue that give rise to what appear to be normal egg cells.

The finding, published Sunday in the journal Nature Medicine, builds on earlier landmark papers by the Boston researchers, which suggest that female mammals continue producing egg cells, known as oocytes, into adulthood.

Since 2004, the scientists at Massachusetts General Hospital have produced a series of papers based on work in laboratory mice, which challenge the long-held belief that female mammals are born with a finite number of eggs that run out at a certain point in the life cycle.

The team was able to isolate stem cells from ovarian tissue taken from mice, from which they grew fully functional egg cells in the lab, which could then be fertilized and even produce healthy offspring.

"The primary objective of the current study was to prove that oocyte-producing stem cells do, in fact, exist in the ovaries of women during reproductive life, which we feel this study demonstrates very clearly," said lead author Jonathan Tilly, director of the Vincent Center for Reproductive Biology at Massachusetts General.

In their experiments, the team isolated the stem cells from ovarian tissue that had been removed from women in their 20s and early 30s.

When put in culture dishes in the lab, these stem cells gave rise to cells with the characteristic features of oocytes, including the physical appearance and gene expression patterns of those seen inside human ovaries.

"They spontaneously generate eggs in the dish," Tilly said in a phone interview, noting that they proliferate so well that a small number of stem cells could easily spawn a million egg cells in the lab.

The researchers next took stem cells they had genetically manipulated to glow green and injected them into snippets of human ovarian tissue. These prepared tissue bits were then grafted beneath the skin of specially bred mice, which have no immune system that can cause rejection of human tissue.

Within two weeks, researchers discovered the implanted ovarian tissue in the mice contained numerous immature human follicles with egg cells that originated from the injected stem cells. Follicles are small sacs within the ovary which contain maturing eggs.

Tilly said they knew the eggs cells had arisen from the injected stem cells "because they were all green."

Among the many potential clinical applications the researchers are exploring is whether these stem cells could produce oocytes that could play a role in in-vitro fertilization, as well as other applications to improve the outcomes of IVF and other infertility treatments.

"Can we use these cells for fertility reasons to maximize the opportunity for patients who are experiencing infertility to have different options available to them to have a genetically matched child?" asked Tilly.

"I think it's a fairly good possibility that at some point in the not-too-distant future there will be clinical protocols developed using some aspect of these cells or their properties that will have a significant impact on human reproduction."

Among them is the idea of extracting structures responsible for energy production in cells — called mitochondria — from the stem cells and injecting them into a woman's eggs at the time of in-vitro fertilization, with the hope of boosting the chances of conception and a successful birth.

But Tilly said another idea is to see whether these ovarian stem cells could be used to delay menopause — and the myriad health effects that can develop as women age.

"I've always been intrigued by the prospects of what if you could slow the rate at which the egg cell pool goes away and end up keeping an ovary functioning long past its normal time of failure," he said.

"With these egg stem cells, it raises the prospect that by harnessing the power of those cells, perhaps we can control the rate at which that precious reserve of egg cells is depleted and maybe even delay it ... And if you could achieve that, what would happen? Would we truly see a benefit or would there be unforeseen bad effects?"

More than a decade ago, Tilly's lab created a mouse through genetic manipulation that did not experience ovarian failure with age and was able to maintain an adequate reservoir of eggs.

"So it didn't undergo the equivalent of menopause," he said, or "mouseopause" as the scientists have dubbed it.

While normal mice as they reach old age experience health problems similar to those of postmenopausal women — including declining eyesight and hearing, hair loss, osteoporosis, diminished cognitive function and reduced muscle mass — these genetically modified mice did not. Nor did they have an increased risk of cancer.

So could these stem cells one day be used as the basis for an anti-aging treatment?

"There would be some pretty significant health benefits that would come out of it," said Tilly, if that were the case.

Even though every aspect of the human oocyte-producing stem cells have so far matched what the researchers have found in their mouse equivalents, Tilly conceded that "mouse is mouse — and perhaps human will be different."

"We don't know" if eggs generated from human ovarian stem cells will be normal and healthy, he said. "We will have to be very careful if and when we get to that stage."

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Human ovarian stem cells may hold promise for treating infertility: study

An experiment that produced human eggs from stem cells could one day be a boon for women who are desperate to have a baby, according to a study published on Sunday.

The work sweeps away the belief that a woman has only a limited stock of eggs and replaces it with the theory that the supply is continuously replenished from precursor cells in the ovary, its authors said.

"The prevailing dogma in our field for the better part of the last 50 or 60 years was that young girls at birth were given a bank account of eggs at birth that's not renewable," said Jonathan Tilly, director of the Vincent Center for Reproductive Biology at Massachusetts General Hospital, who led the research.

"As they become mature and become a woman, they use those eggs up (and) the ovaries will fail when they enter menopause."

Tilly first challenged the "bank account" doctrine eight years ago, suggesting female mammals continue producing egg-making cells into adulthood rather than from a stock acquired at birth.

His theory ran into a firestorm.

Other scientists challenged the accuracy of his experiments or dismissed their conclusions as worthless, given that they had only been conducted on lab mice.

But the new work, said Tilly, not only confirms his controversial idea, but takes it farther.

In it, his team isolated egg-producing stem cells in human ovaries and then coaxed them into developing oocytes, as eggs are called.

Building on a feat by Chinese scientists, they pinpointed the oocyte stem cells by using antibodies which latched onto a protein "handle" located on the side of these cells.

The team tagged the stem cells with a fluorescent green protein -- a common trick to help figure out what happens in lab experiments.

The cells were injected into biopsied human ovarian tissue which was then grafted beneath the skin of mice.

Within 14 days, the graft had produced a budding of oocytes. Some of the eggs glowed with the fluorescent tag, proving that they came from the stem cells. But others did not, which suggested they were already present in the tissue before the injection.

Tilly said "the hairs were standing up on my arm" when he saw time-elapse video showing the eggs maturing in a lab dish.

Further work needs to be done to test the viability of the eggs, and little is known about the hormones or other mechanisms by which oocytes emerge from the stem cells.

But the impact could be far-reaching, Tilly said.

"If we can guide the process correctly, I think it opens up a chance that sometime in the future, we might get to the point of actually having an unlimited source of human eggs," Tilly said in a video recording released to the press.

"A woman could come in, have a small biopsy taken from her ovary for us to retrieve these cells. Once we get these cells out, we can take a hundred of them and make a million of them.

"If we can get to the stage of generating functional human eggs outside the body, it would rewrite essentially human assisted reproduction."

According to a press release issued by Massachusetts General Hospital, Tilly's team are already exploring the idea of banks where oocyte stem cells can be frozen and stored, and then retrieved when a woman wants to have a baby.

Human eggs are extremely delicate and likely to suffer damage when frozen and thawed, but this risk does not apply to the egg cells that make them, it said.

Previous work has shown that around one in 10 women of reproductive age is at risk of premature ageing of the ovaries, a finding with repercussions in societies where women opt ever later to become mothers.

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Pioneering lab work aims to smash women's fertility barrier

February 26, 2012, 1:51 PM EST

By Ryan Flinn

Feb. 26 (Bloomberg) -- Stem cells taken from human ovaries can produce normal, healthy eggs, scientists demonstrated for the first time in an experiment that may lead to new methods to help infertile women.

The finding challenges a belief that women have a fixed number of eggs, or oocytes, from birth that are depleted by the time of menopause, and that their ovaries can't make make more. The research, led by Jonathan Tilly, director of Harvard University-affiliated Massachusetts General Hospital’s Vincent Center for Reproductive Biology, is published today in the journal Nature Medicine.

In 2004, Tilly discovered that ovarian stem cells in mice can create new eggs, similar to how stem cells in male testes produce sperm throughout a man’s life. The latest study proves the same is true in human ovaries, and may point to new ways to overcome infertility or preserve fertility by delaying the time when a woman’s ovaries stop functioning, he said.

“The 50-year-old belief in our field wasn’t actually based on data proving it was impossible, or not ongoing, it was simply an assumption made because there was no evidence indicating otherwise,” Tilly said in a telephone interview. “We have human cells that can produce new oocytes.”

A female is most endowed with oocytes as a fetus, when she has about 7 million. That number that drops to 1 million by birth, and around 300,000 by puberty. By menopause, the number is zero. Since the 1950’s, scientists thought that ovarian stem cells capable of producing new eggs are only active during fetal development.

Ovarian Stem Cells

In the study, healthy ovaries were obtained from consenting patients undergoing sex reassignment surgery. The researchers were able to identify ovarian stem cells because they express a rare protein that’s only seen in reproductive cells.

The stem cells from the ovaries were injected into human ovarian tissue that was then grafted under the skin of mice, which provided the blood supply that enabled the cells to grow. Within two weeks, early stage human follicles with oocytes had begun to form.

“This paper essentially opens the door to the ability to control oocyte development in human ovaries,” Tilly said.

About 10 percent of women of child-bearing age in the U.S., or 6.1 million, have difficulty getting pregnant or staying pregnant, according to the Centers for Disease Control and Prevention. Most cases of female infertility are caused by problems with ovulation, hormone imbalance or age.

Infertility Treatments

Infertility in women is now treated through drugs, surgery, artificial insemination or assisted reproductive technology, in which the woman’s eggs are mixed with sperm outside the body, then reinserted.

The study offers “a new model system for understanding the human egg cell,” according to David F. Albertini, director of the Center for Reproductive Services and professor in the department of molecular and integrative physiology at Kansas University. Still, “there’s a long way to go before this has real practical applications,” he said.

“I’ve spent 35 years of my life studying egg cells and this is a cell that is at least as complicated as a neuron in the brain, if not more,” Albertini said in an interview. “You will need to establish reproducibility from one lab to the next, and hopefully others will be able to confirm his work and extend it, make it into something that will make us confident that the cells are safe to use and we could actually use them to repopulate an egg-depleted ovary.”

New Therapies

The research is opening other therapeutic avenues in fertility treatment, Tilly said.

His team is exploring the development of a bank for ovarian stem cells, which can be cryogenically frozen and thawed without damage, unlike human oocytes. The researchers are also working to identify hormones and other growth factors for accelerating the production of eggs from human ovarian stem cells and ways to improve in-vitro fertilization.

“The problem we face with IVF is we don’t have many eggs to work with,” he said. “These cells are renewable. If we are successful -- and it’s a big if -- in generating functioning eggs from these cells, we can generate as many eggs as we need to on a per patient basis.”

Tilly is also collaborating with researchers at the University of Edinburgh in the U.K. to determine whether the oocytes can be developed into fully mature human eggs for fertilizing. The U.S bans creating or fertilizing embryos for experimental purposes, he said.

A company Tilly co-founded, Boston-based OvaScience Inc., has licensed the technology for potential commercial applications.

--With assistance from Sarah Frier in New York. Editors: Angela Zimm, Andrew Pollack

To contact the reporter on this story: Ryan Flinn in San Francisco at rflinn@bloomberg.net

To contact the editor responsible for this story: Reg Gale at rgale5@bloomberg.net

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Ovarian Stem Cells Produce Eggs in Method That May Aid Fertility