Public release date: 11-Jun-2012 [ | E-mail | Share ]

Contact: Krista Conger kristac@stanford.edu 650-725-5371 Stanford University Medical Center

STANFORD, Calif. When most groups of mammalian cells are faced with a shortage of nutrients or oxygen, the phrase "every man for himself" is more apt than "all for one, one for all." Unlike colonies of bacteria, which often cooperate to thrive as a group, mammalian cells have never been observed to help one another out. But a new study led by a researcher at the Stanford University School of Medicine has shown that certain human embryonic stem cells, in times of stress, produce molecules that not only benefit themselves, but also help nearby cells survive.

"Altruism has been reported among bacterial populations and among humans and other animals, like monkeys and elephants," said Stanford postdoctoral scholar Bikul Das, MBBS, PhD. "But in mammalian cells at the cellular level the idea of altruism has never been described before." Das is the lead author of a paper, to be published online June 11 in Stem Cells, documenting altruistic behavior by human embryonic stem cells, or hESCs.

While altruism is generally thought of as a virtue, it can have a downside for hESCs: The altruistic cells appear to be more prone to accumulating mutations, a sign that they could lead to cancers. A better understanding of hESC altruism could provide new insights into cancer therapies, as well as improving scientists' ability to develop safe and effective stem cell treatments for other diseases.

The finding arose from Das' research into how hESCs react to low-oxygen environments, important because many cancerous tumors are low in oxygen. Embryonic stem cells have the capability to develop into many different cell types through a process called differentiation. Das found that when hESCs were placed for 24 hours in an environment with only one-tenth of a percent of oxygen (the air we breathe, by comparison, is almost 21 percent oxygen), free-radical molecules were generated that began causing internal damage in some cells. Ninety percent of the hESCs differentiated into other cell types or died, with only 10 percent maintaining their so-called "stemness," meaning they retained their ability to develop into any type of cell.

Das wanted to know what set these more hearty cells apart and so began sorting them based on what molecules they contained.

Das and his colleagues discovered that of the embryonic stem cells that had survived the oxygen deprivation, half had high levels of HIF2-alpha (a protein that turns up the production of antioxidant molecules) and low levels of p53 (a protein that normally encourages cells to die when they have too much DNA damage). These levels of HIF2-alpha and p53 are enough, Das showed, to keep the cells from differentiating by turning off cellular pathways typically involved in the process.

But the other half of the stem cells that had kept their "stemness" had relatively normal levels of HIF2-alpha and p53, he and his colleagues report in their paper. There was no clear explanation as to how they would remain undifferentiated without the help of high HIF2-alpha and low p53 unless the other cells were helping them out.

"When I saw this data, I began to suspect that maybe there was altruism going on," said Das.

Read more:
Stanford researcher identifies unusual 'altruistic' stem cell behavior with possible link to cancer

ScienceDaily (June 11, 2012) UCLA stem cell scientists purified a subset of stem cells found in fat tissue and made from them bone that was formed faster and was of higher quality than bone grown using traditional methods, a finding that may one day eliminate the need for painful bone grafts that use material taken from the patient during invasive procedures.

Adipose, or fat, tissue is thought to be an ideal source of cells called mesenchymal stem cells -- capable of developing into bone, cartilage, muscle and other tissues -- because they are plentiful and easily attained through procedures such as liposuction, said Dr. Chia Soo, vice chair for research at UCLA Plastic and Reconstructive Surgery. The co-senior authors on the project, Soo and Bruno Pault, are members of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

Traditionally, cells taken from fat had to be cultured for weeks to isolate the stem cells which could become bone, and their expansion increases risk of infection and genetic instability. A fresh, non-cultured cell composition called stromal vascular fraction (SVF) also is used to grow bone. However, SVF cells taken from adipose tissue are a highly heterogeneous population that includes cells that aren't capable of becoming bone.

Pault and Soo's team used a cell sorting machine to isolate and purify human perivascular stem cells (hPSC) from adipose tissue and showed that those cells worked far better than SVF cells in creating bone. They also showed that a growth factor called NELL-1, discovered by Dr. Kang Ting of the UCLA School of Dentistry, enhanced the bone formation in their animal model.

"People have shown that culture-derived cells could grow bone, but these are a fresh cell population and we didn't have to go through the culture process, which can take weeks," Soo said. "The best bone graft is still your own bone, but that is in limited supply and sometimes not of good quality. What we show here is a faster and better way to create bone that could have clinical applications."

The study appears June 11, 2012 in the early online edition of the peer-reviewed journal Stem Cells Translational Medicine, a new journal that seeks to bridge stem cell research and clinical trials.

In the animal model, Soo and Pault's team put the hPSCs with NELL-1 in a muscle pouch, a place where bone is not normally grown. They then used X-rays to determine that the cells did indeed become bone.

"The purified human hPSCs formed significantly more bone in comparison to the SVF by all parameters," Soo said. "And these cells are plentiful enough that patients with not much excess body fat can donate their own fat tissue."

Soo said if everything goes well, patients may one day have rapid access to high quality bone graft material by which doctors get their fat tissue, purify that into hPSCs and replace their own stem cells with NELL-1 back into the area where bone is required. The hPSC with NELL-1 could grow into bone inside the patient, eliminating the need for painful bone graft harvestings. The goal is for the process to isolate the hPSCs and add the NELL-1 with a matrix or scaffold to aid cell adhesion to take less than an hour, Soo said.

"Excitingly, recent studies have already demonstrated the utility of perivascular stem cells for regeneration of disparate tissue types, including skeletal muscle, lung and even myocardium," said Pault, a professor of orthopedic surgery "Further studies will extend our findings and apply the robust osteogenic potential of hPSCs to the healing of bone defects."

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A better way to grow bone: Fresh, purified fat stem cells grow bone better, faster

ScienceDaily (June 11, 2012) Studying mice and humans, researchers at Washington University School of Medicine in St. Louis and their collaborators in Paris have identified two proteins that are required to maintain a supply of stem cells in the developing kidney.

In the presence of the two proteins, FGF9 and FGF20, mouse kidney stem cells stayed alive outside the body longer than previously reported. Though the cells were maintained only five days (up from about two), the work is a small step toward the future goal of growing kidney stem cells in the lab.

In the developing embryo, these early stem cells give rise to adult cells called nephrons, the blood filtration units of the kidneys.

The results appear online June 11 in Developmental Cell.

"When we are born, we get a certain allotment of nephrons," says Raphael Kopan, PhD, the Alan A. and Edith L. Wolff Professor of Developmental Biology. "Fortunately, we have a large surplus. We can donate a kidney -- give away 50 percent of our nephrons -- and still do fine. But, unlike our skin and gut, our kidneys can't build new nephrons."

The skin and the gut have small pools of stem cells that continually renew these organs throughout life. Scientists call such pools of stem cells and their support system a niche. During early development, the embryonic kidney has a stem cell niche as well. But at some point before birth or shortly after, all stem cells in the kidney differentiate to form nephrons, leaving no self-renewing pool of stem cells.

"In other organs, there are cells that specifically form the niche, supporting the stem cells in a protected environment," Kopan says. "But in the embryonic kidney, it seems the stem cells form their own niche, making it a bit more fragile. And the signals and conditions that lead the cells to form this niche have been elusive."

Surprisingly, recent clues to the signals that maintain the embryonic kidney's stem cell niche came from studies of the inner ear. David M. Ornitz, MD, PhD, the Alumni Endowed Professor of Developmental Biology, investigates FGF signaling in mice. Earlier this year, Ornitz and his colleagues published a paper in PLoS Biology showing that FGF20 plays an important role in inner ear development.

"Mice without FGF20 are profoundly deaf," Ornitz says. "While they are otherwise viable and healthy, in some cases we noticed that their kidneys looked small."

Past work from his own lab and others suggested that FGF9, a close chemical cousin of FGF20, might also participate in kidney development. FGF20 and FGF9 are members of a family of proteins known as fibroblast growth factors. In general, members of this family are known to play important and broad roles in embryonic development, tissue maintenance, and wound healing. Mice lacking FGF9 have defects in development of the male urogenital tract and die after birth due to defects in lung development.

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Clues found to way embryonic kidney maintains its fleeting stem cells

ScienceDaily (June 11, 2012) When most groups of mammalian cells are faced with a shortage of nutrients or oxygen, the phrase "every man for himself" is more apt than "all for one, one for all." Unlike colonies of bacteria, which often cooperate to thrive as a group, mammalian cells have never been observed to help one another out. But a new study led by a researcher at the Stanford University School of Medicine has shown that certain human embryonic stem cells, in times of stress, produce molecules that not only benefit themselves, but also help nearby cells survive.

"Altruism has been reported among bacterial populations and among humans and other animals, like monkeys and elephants," said Stanford postdoctoral scholar Bikul Das, MBBS, PhD. "But in mammalian cells -- at the cellular level -- the idea of altruism has never been described before." Das is the lead author of a paper, published online June 11 in Stem Cells, documenting altruistic behavior by human embryonic stem cells, or hESCs.

While altruism is generally thought of as a virtue, it can have a downside for hESCs: The altruistic cells appear to be more prone to accumulating mutations, a sign that they could lead to cancers. A better understanding of hESC altruism could provide new insights into cancer therapies, as well as improving scientists' ability to develop safe and effective stem cell treatments for other diseases.

The finding arose from Das' research into how hESCs react to low-oxygen environments, important because many cancerous tumors are low in oxygen. Embryonic stem cells have the capability to develop into many different cell types through a process called differentiation. Das found that when hESCs were placed for 24 hours in an environment with only one-tenth of a percent of oxygen (the air we breathe, by comparison, is almost 21 percent oxygen), free-radical molecules were generated that began causing internal damage in some cells. Ninety percent of the hESCs differentiated into other cell types or died, with only 10 percent maintaining their so-called "stemness," meaning they retained their ability to develop into any type of cell.

Das wanted to know what set these more hearty cells apart and so began sorting them based on what molecules they contained.

Das and his colleagues discovered that of the embryonic stem cells that had survived the oxygen deprivation, half had high levels of HIF2-alpha (a protein that turns up the production of antioxidant molecules) and low levels of p53 (a protein that normally encourages cells to die when they have too much DNA damage). These levels of HIF2-alpha and p53 are enough, Das showed, to keep the cells from differentiating by turning off cellular pathways typically involved in the process.

But the other half of the stem cells that had kept their "stemness" had relatively normal levels of HIF2-alpha and p53, he and his colleagues report in their paper. There was no clear explanation as to how they would remain undifferentiated without the help of high HIF2-alpha and low p53 -- unless the other cells were helping them out.

"When I saw this data, I began to suspect that maybe there was altruism going on," said Das.

To test the theory, Das and his colleagues at the University of Toronto, where he began the work as a graduate student, let the cells with high levels of HIF2-alpha and low levels of p53 soak in a cell culture medium for 24 hours. Then, he removed the cells and added the other half -- those that didn't have high HIF2-alpha and low p53. Sure enough, when the mixture was deprived of oxygen, the cells retained their stemness. Molecules in the liquid had some property that kept them from differentiating. The team discovered that the important molecule in the liquid is an antioxidant called glutathione.

Scientists had previously shown that when embryonic stem cells are under stress, levels of HIF2-alpha and p53 increase and most cells differentiate or die. What makes this study unusual is that Das and colleagues were able to isolate the altruistic cells that exhibit low levels of p53, which helps them to escape death or differentiation.

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Unusual 'altruistic' stem cell behavior with possible link to cancer identified