ScienceDaily (Feb. 6, 2012) — A University of Minnesota-led research team has proposed a mechanism for the control of whether embryonic stem cells continue to proliferate and stay stem cells, or differentiate into adult cells like brain, liver or skin.

The work has implications in two areas. In cancer treatment, it is desirable to inhibit cell proliferation. But to grow adult stem cells for transplantation to victims of injury or disease, it would be desirable to sustain proliferation until a sufficient number of cells have been produced to make a usable organ or tissue.

The study gives researchers a handle on how those two competing processes might be controlled. It was performed at the university's Hormel Institute in Austin, Minn., using mouse stem cells. The researchers, led by Hormel Institute Executive Director Zigang Dong and Associate Director Ann M. Bode, have published a report in the journal Nature: Structure and Molecular Biology.

"This is breakthrough research and provides the molecular basis for development of regenerative medicine," said Dong. "This research will aid in the development of the next generation of drugs that make repairs and regeneration within the body possible following damage by such factors as cancer, aging, heart disease, diabetes, or paralysis caused by traumatic injury."

The mechanism centers on a protein called Klf4, which is found in embryonic stem cells and whose activities include keeping those cells dividing and proliferating rather than differentiating. That is, Klf4 maintains the character of the stem cells; this process is called self-renewal. The researchers discovered that two enzymes, called ERK1 and ERK2, inactivate Klf; this allows the cells to begin differentiating into adult cells.

The two enzymes are part of a "bucket brigade" of signals that starts when a chemical messenger arrives from outside the embryonic stem cells. Chemical messages are passed to inside the cells, resulting in, among other things, the two enzymes swinging into action.

The researchers also discovered how the enzymes control Klf4. They attach a small molecule--phosphate, consisting of phosphorus and oxygen--to Klf4. This "tag" marks it for destruction by the cellular machinery that recycles proteins.

Further, they found that suppressing the activity of the two enzymes allows the stem cells to maintain their self-renewal and resist differentiation. Taken together, their findings paint a picture of the ERK1 and ERK2 enzymes as major players in deciding the future of embryonic stem cells--and potentially cancer cells, whose rapid growth mirrors the behavior of the stem cells.

Klf4 is one of several factors used to reprogram certain adult skin cells to become a form of stem cells called iPS (induced pluripotent stem) cells, which behave similarly to embryonic stem cells. Also, many studies have shown that Klf4 can either activate or repress the functioning of genes and, in certain contexts, act as either an oncogene (that promotes cancer) or a tumor suppressor. Given these and their own findings reported here, the Hormel Institute researchers suggest that the self-renewal program of cancer cells might resemble that of embryonic stem cells.

"Although the functions of Klf4 in cancer are controversial, several reports suggest Klf4 is involved in human cancer development," Bode said.

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The above story is reprinted from materials provided by University of Minnesota.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

Myoung Ok Kim, Sung-Hyun Kim, Yong-Yeon Cho, Janos Nadas, Chul-Ho Jeong, Ke Yao, Dong Joon Kim, Dong-Hoon Yu, Young-Sam Keum, Kun-Yeong Lee, Zunnan Huang, Ann M Bode, Zigang Dong. ERK1 and ERK2 regulate embryonic stem cell self-renewal through phosphorylation of Klf4. Nature Structural & Molecular Biology, 2012; DOI: 10.1038/nsmb.2217

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

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Key finding in stem cell self-renewal

Posted: Monday, February 6, 2012 10:00 am | Updated: 11:50 am, Mon Feb 6, 2012.

Researchers at Rice University and Texas Children's Hospital have turned stem cells from amniotic fluid into cells that form blood vessels.

Their success offers hope that such stem cells may be used to grow tissue patches to repair infant hearts.

"We want to come up with technology to replace defective tissue with beating heart tissue made from stem cells sloughed off by the infant into the amniotic fluid," said Rice bioengineer Jeffrey Jacot, who led the study. "Our findings serve as proof of principle that stem cells from amniotic fluid have the potential to be used for such purposes."

The results were published online by the journal Tissue Engineering Part A. The research was conducted at Texas Children’s Hospital.

According to the American Heart Association, about 32,000 infants a year in the United States are born with congenital heart defects, 10,000 of which either result in death or require some sort of surgical intervention before they're a year old.

Jacot, an assistant professor of bioengineering based at Rice's BioScience Research Collaborative and of the Pediatric Cardiac Bioengineering Laboratory at the Congenital Heart Surgery Service at Texas Children’s Hospital, hopes to grow heart patches from the amniotic stem cells of a fetus diagnosed in the womb with a congenital heart defect. He said, because the cells would be a genetic match, there would be no risk of rejection.

"Between 60 and 80 percent of severe heart defects are caught by ultrasound," he said. "Ultimately, when a heart defect is diagnosed in utero, we will extract amniotic cells. By birth, we will have made tissue for the repair out of the infant's own cells. The timing is critical because the surgery needs to be done within weeks of the infant's birth."

Surgeons currently use such nonbiological materials as Dacron or Teflon, which do not contract or grow with the patient, or native pericardium, the membrane that surrounds the heart. Pericardium generally forms scar tissue and can only be used in the first operation. Both solutions require further operations and raise the risk of cardiac arrest, Jacot said.

Stem cells, the focus of both great hope and great controversy, are the cells in every organism that differentiate into specialized cells in the body. Stem cells drawn from human embryos are known to have great potential for treatment of defects and disease, but research into their use has been limited by political and other concerns, Jacot said.

That isn't the case with cells found in amniotic fluid, he said. Amniotic fluid is the liquid that protects and nourishes a fetus in the womb. Fluid is sometimes taken from pregnant women through amniocentesis, but cells for the Jacot lab's studies were drawn from women undergoing treatment for twin-twin transfusion syndrome.

"This is where two identical twins share a placenta and one is getting more blood than the other. It's not common," he said, noting that Texas Children's is one of the few hospitals that treat the syndrome. "Part of the general treatment is to remove fluid with the goal of saving both lives, and that fluid is usually discarded."

Jacot said other labs have tested amniotic fluid as a source of stem cells with promising results.

"Our work is based on five years of work from other labs in which they've discovered a very small population of amniotic stem cells – maybe one in every 10,000 – that naturally express markers characteristic of embryonic and mesenchymal stem cells."

Jacot and his team created a population of amniotic stem cells through a complex process that involved extracting cells via centrifugation and fluorescence-activated sorting. They sequestered cells with a surface receptor, c-kit, a marker associated with stem cells.

The cells were cultured in endothelial growth media to make them suitable for growing into a network of capillaries, Jacot said. When the cells were placed in a bio-scaffold, a framework used for tissue engineering, they did just that.

"Anything we make will need a blood supply," he said. "That's why the first cell type we looked for is one that can form blood vessels. We need to know we can get a capillary network throughout tissue that we can then connect to the infant's blood supply."

Jacot said the cells they tested grow very fast.

"We've done calculations to show that, with what we get from amniocentesis, we could more than grow an entire heart by birth," he said. "That would be really tough, but it gives us confidence that we will be able to quickly grow patches of tissue outside of the body that can then be sewn inside."

He said construction of a functional patch is some years away, but his lab is making progress. While embryonic cells have the most potential for such a project, amniotic cells already show signs of an ability to turn into heart muscle, he said.

Co-authors are graduate students Omar Benavides and Jennifer Petsche, both of Rice; and Kenneth Moise Jr. and Anthony Johnson, now professors at the Texas Center for Maternal and Fetal Treatment at The University of Texas Health Science Center at Houston with appointments at Children's Memorial Hermann Hospital.

The research was supported by the National Institutes of Health, the National Science Foundation Graduate Research Fellowship and CAREER programs, the Houston-Rice Alliance for Graduate Education and the Professoriate, the Howard Hughes Medical Institute Med into Grad Program and the Virginia and L.E. Simmons Family Foundation.

(Submitted by Rice University; Posted by Emiy Moser, emoser@hcnonline.com)

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Rice University, Texas Children’s Hospital researchers makes strides towards fixing infants hearts

Public release date: 5-Feb-2012
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Contact: Charles Casey
charles.casey@ucdmc.ucdavis.edu
916-734-9048
University of California - Davis Health System

A research team led by UC Davis Health System scientists has developed a novel technique to enhance bone growth by using a molecule which, when injected into the bloodstream, directs the body's stem cells to travel to the surface of bones. Once these cells are guided to the bone surface by this molecule, the stem cells differentiate into bone-forming cells and synthesize proteins to enhance bone growth. The study, which was published online today in Nature Medicine, used a mouse model of osteoporosis to demonstrate a unique treatment approach that increases bone density and prevents bone loss associated with aging and estrogen deficiency.

"There are many stem cells, even in elderly people, but they do not readily migrate to bone," said Wei Yao, the principal investigator and lead author of the study. "Finding a molecule that attaches to stem cells and guides them to the targets we need is a real breakthrough."

Researchers are exploring stem cells as possible treatments for a wide variety of conditions and injuries, ranging from peripheral artery disease and macular degeneration to blood disorders, skin wounds and diseased organs. Directing stem cells to travel and adhere to the surface of bone for bone formation has been among the elusive goals in regenerative medicine.

The researchers made use of a unique hybrid molecule, LLP2A-alendronate, developed by a research team led by Kit Lam, professor and chair of the UC Davis Department of Biochemistry and Molecular Medicine. The researchers' hybrid molecule consists of two parts: the LLP2A part that attaches to mesenchymal stem cells in the bone marrow, and a second part that consists of the bone-homing drug alendronate. After the hybrid molecule was injected into the bloodstream, it picked up mesenchymal stem cells in the bone marrow and directed those cells to the surfaces of bone, where the stem cells carried out their natural bone-formation and repair functions.

"Our study confirms that stem-cell-binding molecules can be exploited to direct stem cells to therapeutic sites inside an animal," said Lam, who also is an author of the article. "It represents a very important step in making this type of stem cell therapy a reality."

Twelve weeks after the hybrid molecule was injected into mice, bone mass in the femur (thigh bone) and vertebrae (in the spine) increased and bone strength improved compared to control mice who did not receive the hybrid molecule. Treated mice that were normally of an age when bone loss would occur also had improved bone formation, as did those that were models for menopause.

Alendronate, also known by the brand name Fosamax, is commonly taken by women with osteoporosis to reduce the risk of fracture. The research team incorporated alendronate into the hybrid molecules because once in the bloodstream, it goes directly to the bone surface, where it slows the rate of bone breakdown. According to Nancy Lane, a co-investigator on the study and director of the UC Davis Musculoskeletal Diseases of Aging Research Group, the dose of alendronate in the hybrid compound was low and unlikely to have inhibited the compound's therapeutic effect.

"For the first time, we may have potentially found a way to direct a person's own stem cells to the bone surface where they can regenerate bone," said Lane, who is an Endowed Professor of Medicine and Rheumatology and an expert on osteoporosis. "This technique could become a revolutionary new therapy for osteoporosis as well as for other conditions that require new bone formation."

Osteoporosis is a major public health problem for 44 million Americans. One in two women will suffer a fracture due to osteoporosis in their lifetime. Although effective medications are available to help prevent fracture risk, including alendronate, their use is limited by potential harmful effects of long-term use.

The major causes for osteoporosis in women include estrogen deficiency, aging and steroid excess from treatment of chronic inflammatory conditions such as rheumatoid arthritis. Generally, the osteoporosis generated by these metabolic conditions results from change in the bone remodeling cycle that weakens the bone's architecture and increases fracture risk.

Mesenchymal stem cells from bone marrow induce new bone remodeling, which thicken and strengthen bone.

The authors noted that the potential use of this stem cell therapy is not limited to treating osteoporosis. They said it may prove invaluable for other disorders and conditions that could benefit from enhanced bone rebuilding, such as bone fractures, bone infections or cancer treatments.

"These results are very promising for translating into human therapy," said Jan Nolta, professor of internal medicine, an author of the study and director of the UC Davis Institute for Regenerative Cures. "We have shown this potential therapy is effective in rodents, and our goal now is to move it into clinical trials."

Funding for the study came from the Endowment on Healthy Aging and the National Institutes of Health. The California Institute for Regenerative Medicine has given the team a planning grant to develop a proposal for human clinical trials.

"This research was a collaboration of stem cell biologists, biochemists, translational scientists, a bone biologist and clinicians," said Lane. "It was a truly fruitful team effort with remarkable results."

###

The Nature Medicine article is titled "Directing mesenchymal stem cells to bone to augment bone formation and increase bone mass." Min Guan, who is affiliated with the UC Davis Department of Internal Medicine, was co-lead author of the paper. Other UC Davis authors were Ruiwu Liu, Junjing Jia, Liping Meng, Ping Zhou and Mohammad Shahnazari, from the departments of Internal Medicine, and Biochemistry and Molecular Medicine, as well as the UC Davis Institute for Regenerative Cures. Authors Brian Panganiban and Robert O. Ritchie are with the Department of Materials Science and Engineering at UC Berkeley.

UC Davis is playing a leading role in regenerative medicine, with nearly 150 scientists working on a variety of stem cell-related research projects at campus locations in both Davis and Sacramento. The UC Davis Institute for Regenerative Cures, a facility supported by the California Institute for Regenerative Medicine (CIRM), opened in 2010 on the Sacramento campus. This $62 million facility is the university's hub for stem cell science. It includes Northern California's largest academic Good Manufacturing Practice laboratory, with state-of-the-art equipment and manufacturing rooms for cellular and gene therapies. UC Davis also has a Translational Human Embryonic Stem Cell Shared Research Facility in Davis and a collaborative partnership with the Institute for Pediatric Regenerative Medicine at Shriners Hospital for Children Northern California. All of the programs and facilities complement the university's Clinical and Translational Science Center, and focus on turning stem cells into cures. For more information, visit http://www.ucdmc.ucdavis.edu/stemcellresearch.

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Researchers develop method of directing stem cells to increase bone formation and bone strength

SACRAMENTO — A research team led by UC Davis Health System scientists has developed a novel technique to enhance bone growth by using a molecule which, when injected into the bloodstream, directs the body's stem cells to travel to the surface of bones. Once these cells are guided to the bone surface by this molecule, the stem cells differentiate into bone-forming cells and synthesize proteins to enhance bone growth. The study, which was published online today in Nature Medicine, used a mouse model of osteoporosis to demonstrate a unique treatment approach that increases bone density and prevents bone loss associated with aging and estrogen deficiency.

"There are many stem cells, even in elderly people, but they do not readily migrate to bone," said Wei Yao, the principal investigator and lead author of the study. "Finding a molecule that attaches to stem cells and guides them to the targets we need is a real breakthrough."

Researchers are exploring stem cells as possible treatments for a wide variety of conditions and injuries, ranging from peripheral artery disease and macular degeneration to blood disorders, skin wounds and diseased organs. Directing stem cells to travel and adhere to the surface of bone for bone formation has been among the elusive goals in regenerative medicine.

The researchers made use of a unique hybrid molecule, LLP2A-alendronate, developed by a research team led by Kit Lam, professor and chair of the UC Davis Department of Biochemistry and Molecular Medicine. The researchers' hybrid molecule consists of two parts: the LLP2A part that attaches to mesenchymal stem cells in the bone marrow, and a second part that consists of the bone-homing drug alendronate. After the hybrid molecule was injected into the bloodstream, it picked up mesenchymal stem cells in the bone marrow and directed those cells to the surfaces of bone, where the stem cells carried out their natural bone-formation and repair functions.

"Our study confirms that stem-cell-binding molecules can be exploited to direct stem cells to therapeutic sites inside an animal," said Lam, who also is an author of the article. "It represents a very important step in making this type of stem cell therapy a reality."

Twelve weeks after the hybrid molecule was injected into mice, bone mass in the femur (thigh bone) and vertebrae (in the spine) increased and bone strength improved compared to control mice who did not receive the hybrid molecule. Treated mice that were normally of an age when bone loss would occur also had improved bone formation, as did those that were models for menopause.

Alendronate, also known by the brand name Fosamax, is commonly taken by women with osteoporosis to reduce the risk of fracture. The research team incorporated alendronate into the hybrid molecules because once in the bloodstream, it goes directly to the bone surface, where it slows the rate of bone breakdown. According to Nancy Lane, a co-investigator on the study and director of the UC Davis Musculoskeletal Diseases of Aging Research Group, the dose of alendronate in the hybrid compound was low and unlikely to have inhibited the compound's therapeutic effect.

"For the first time, we may have potentially found a way to direct a person's own stem cells to the bone surface where they can regenerate bone," said Lane, who is an Endowed Professor of Medicine and Rheumatology and an expert on osteoporosis. "This technique could become a revolutionary new therapy for osteoporosis as well as for other conditions that require new bone formation."

Osteoporosis is a major public health problem for 44 million Americans. One in two women will suffer a fracture due to osteoporosis in their lifetime. Although effective medications are available to help prevent fracture risk, including alendronate, their use is limited by potential harmful effects of long-term use.

The major causes for osteoporosis in women include estrogen deficiency, aging and steroid excess from treatment of chronic inflammatory conditions such as rheumatoid arthritis. Generally, the osteoporosis generated by these metabolic conditions results from change in the bone remodeling cycle that weakens the bone's architecture and increases fracture risk.

Mesenchymal stem cells from bone marrow induce new bone remodeling, which thicken and strengthen bone.

The authors noted that the potential use of this stem cell therapy is not limited to treating osteoporosis. They said it may prove invaluable for other disorders and conditions that could benefit from enhanced bone rebuilding, such as bone fractures, bone infections or cancer treatments.

"These results are very promising for translating into human therapy," said Jan Nolta, professor of internal medicine, an author of the study and director of the UC Davis Institute for Regenerative Cures. "We have shown this potential therapy is effective in rodents, and our goal now is to move it into clinical trials."

Funding for the study came from the Endowment on Healthy Aging and the National Institutes of Health. The California Institute for Regenerative Medicine has given the team a planning grant to develop a proposal for human clinical trials.

"This research was a collaboration of stem cell biologists, biochemists, translational scientists, a bone biologist and clinicians," said Lane. "It was a truly fruitful team effort with remarkable results."

The Nature Medicine article is titled "Directing mesenchymal stem cells to bone to augment bone formation and increase bone mass." Min Guan, who is affiliated with the UC Davis Department of Internal Medicine, was co-lead author of the paper. Other UC Davis authors were Ruiwu Liu, Junjing Jia, Liping Meng, Ping Zhou and Mohammad Shahnazari, from the departments of Internal Medicine, and Biochemistry and Molecular Medicine, as well as the UC Davis Institute for Regenerative Cures. Authors Brian Panganiban and Robert O. Ritchie are with the Department of Materials Science and Engineering at UC Berkeley.

UC Davis is playing a leading role in regenerative medicine, with nearly 150 scientists working on a variety of stem cell-related research projects at campus locations in both Davis and Sacramento. The UC Davis Institute for Regenerative Cures, a facility supported by the California Institute for Regenerative Medicine (CIRM), opened in 2010 on the Sacramento campus. This $62 million facility is the university's hub for stem cell science. It includes Northern California's largest academic Good Manufacturing Practice laboratory, with state-of-the-art equipment and manufacturing rooms for cellular and gene therapies. UC Davis also has a Translational Human Embryonic Stem Cell Shared Research Facility in Davis and a collaborative partnership with the Institute for Pediatric Regenerative Medicine at Shriners Hospital for Children Northern California. All of the programs and facilities complement the university's Clinical and Translational Science Center, and focus on turning stem cells into cures. For more information, visit http://www.ucdmc.ucdavis.edu/stemcellresearch.

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Directing stem cells to boost bone formation, strength