Researchers find stem cells remember prior substrates

6 hours ago by Bob Yirka Mesenchymal stem cell displaying typical ultrastructural characteristics. Credit: Robert M. Hunt/Wikipedia

(Phys.org) A team of researchers working at the University of Colorado has found that human stem cells appear to remember the physical nature of the structure they were grown on, after being moved to a different substrate. In their paper published in the journal Nature Materials, the researchers describe how they grew human stem cells on different substrates. In so doing, they discovered that the stem cells continued to express certain proteins related to a substrate even after its hardness was changed.

Scientists have known for some time that stem cells respond to their environment as they growthose grown on hard material, such as glass or metal for example, are more amenable to growing into bone cells. In this new effort, the researchers sought to discover if changes to a stem cell brought about by environment are retained if the stem cell is moved to a different environment.

To find out, the researchers used mesenchymal cells which are known to be able to grow into almost any human body part. They placed the stem cells on a stiff substrate then moved them to one less stiff over differing numbers of days. In so doing, they found that the longer the cells were left on the stiff substrate the more a protein connected to bone growth (RUNX2) was expressed. Conversely, cells that were first placed on a soft surface and subsequently moved to a hard surface demonstrated a tendency to develop either bone or adipogenic tendencies.

In another experiment, the researchers applied the stem cells to a substrate coated with a phototunable hydrogelit grows softer when exposed to lightusing it allowed for changing the stiffness of the substrate without having to move the cells. Using this approach the team found that if the cells were allowed to grow on the gel in its stiff state, for just one day, switching to a soft state caused the expression of RUNX2 to cease immediately. When they allowed the cells to grow for ten days on the stiff base, however, before switching to a soft one, expression of RUNX2 continued for another ten days before finally ceasing. This shows, the researchers contend, that stem cells have a memory component that is not yet understood.

The researchers note that their findings could be applied to other stem cell research areas such as cases where unintentional consequences may be arising in experiments due to the stiffness of the substrate in which they are being grown. It also raises the question of whether other environmental factors might be impacting cell growth and if so, if they have a memory component as well.

Explore further: Heart cells respond to stiff environments

More information: Mechanical memory and dosing influence stem cell fate, Nature Materials (2014) DOI: 10.1038/nmat3889

Abstract We investigated whether stem cells remember past physical signals and whether these can be exploited to dose cells mechanically. We found that the activation of the Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding domain (TAZ) as well as the pre-osteogenic transcription factor RUNX2 in human mesenchymal stem cells (hMSCs) cultured on soft poly(ethylene glycol) (PEG) hydrogels (Young's modulus E ~ 2 kPa) depended on previous culture time on stiff tissue culture polystyrene (TCPS; E ~ 3 GPa). In addition, mechanical dosing of hMSCs cultured on initially stiff (E ~ 10 kPa) and then soft (E ~ 2 kPa) phototunable PEG hydrogels resulted in either reversible orabove a threshold mechanical doseirreversible activation of YAP/TAZ and RUNX2. We also found that increased mechanical dosing on supraphysiologically stiff TCPS biases hMSCs towards osteogenic differentiation. We conclude that stem cells possess mechanical memorywith YAP/TAZ acting as an intracellular mechanical rheostatthat stores information from past physical environments and influences the cells' fate.

Journal reference: Nature Materials

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Researchers find stem cells remember prior substrates

Nobel laureate calls handing of stem cell research data 'sloppy'

The Nobel Prize-winning head of a Japanese institute whose scientists' work on stem cells was hailed as a game-changer in the field of medical biology called the lead researcher's handling of the data "extremely sloppy" and "irresponsible".

Two papers published in the journal Nature in January detailed a simple way to reprogram mature animal cells back into an embryonic-like state that allows them to generate many types of tissue, offering hope for a simpler way to replace damaged cells or grow new organs in humans.

But other scientists have been unable to replicate the research's results since then and there have been indications of problems with its data and images.

"The problem here is one immature researcher collected a huge amount of research data, and her handling of data was extremely sloppy and irresponsible," president of Japanese research institute RIKEN Ryoji Noyori told a news conference.

"I would like to offer my apology for the Nature articles, having brought into question the credibility of the science community," said Noyori, bowing deeply.

Noyori, who won a Nobel prize for chemistry in 2001, was referring to Haruko Obokata, 30, a lead author of the papers who became an instant celebrity in Japan after they were published.

A written statement from Obokata and two other RIKEN researchers made available at the news conference said they are discussing the possible withdrawal of the papers with other co-authors.

Another scientist on the team, Teruhiko Wakayama of the University of Yamanashi, has already called for the papers to be withdrawn.

"It is no longer clear what's right," Wakayama told public broadcaster NHK on Monday.

The news conference was called to release the interim findings of investigation on the controversy by a panel of experts from within and outside RIKEN.

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Nobel laureate calls handing of stem cell research data 'sloppy'

Riken Apologizes for Errors in Two Stem Cell Studies

Japans Riken center apologized for errors in a pair of studies that had outlined a simpler, quicker way of making stem cells and said the institute is considering urging the scientists to retract it.

Riken will impose a penalty if misconduct is proven, President Ryoji Noyori said in news conference today. Haruko Obokata, who led the research, and two other Riken researchers in a separate statement on the centers website said they are in talks with co-writers to discuss a retraction.

Government-funded Riken on March 11 said is investigating the two studies that were published in journal Nature in January and said ordinary cells taken from newborn mice could be transformed into stem cells without adding genes. The institute today said it was investigating six images and methods in the research after claims that they looked unnatural or were plagiarized from other studies.

We are communicating with other authors and considering the possibility of retracting the studies, Obokata and the two other researchers, Yoshiki Sasai and Hitoshi Niwa, said in a joint statement on Rikens website today.

Two areas were handled inappropriately, though researchers didnt have intent to falsify data, the institute said on its website. The center is still investigating the rest, it said.

Images used in the studies to show the establishment of the method resemble photos from Obokatas previous studies, Kyodo News reported this week. Another scientist, Teruhiko Wakayama at the University of Yamanashi in Japan who worked on the research said he was no longer sure of the premise of the data he used to establish the experiments and that the studies should be withdrawn for review, public broadcaster NHK reported on March 10.

The probe is a setback for Japan as it tries to push into stem-cell science following Shinya Yamanakas 2012 Nobel Prize. Japan aims to cement its leadership in the field of research, and has pushed through bills that fast-track regulatory approval for cell-based products.

Researchers led by Obokata at the Riken Center for Developmental Biology shocked the cells with a dose of sublethal stress such as mechanical force to trigger a transformation. Obokata worked with institutions including Charles Vacantis laboratory at Brigham and Womens Hospital, Harvard Medical School.

In an embryos early stages, stem cells are pluripotent, meaning they can become any type of tissue in the body. As the embryo develops, the cells begin to specialize, or differentiate, into units for the bodys different structures.

There are several ways to regenerate pluripotent stem cells, including one that uses embryos and one that reprograms matured cells by inserting genes. Last year, Japans Health Ministry cleared the way for the worlds first clinical trial with stem cells made using a separate technique established by Yamanaka, the Nobel Prize winner from Kyoto University.

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Riken Apologizes for Errors in Two Stem Cell Studies

Riken Considers Retracting Two Stem-Cell Studies

Research that outlined a simpler, quicker way of making stem cells may be retracted after one of the scientists involved expressed doubts about the basis for the experiments.

Japans Riken research center is investigating two studies published in the journal Nature in January and is considering options including retracting them, the government-funded organization said in a statement on its website today. Riken will give a briefing on the probe March 14.

Teruhiko Wakayama, who worked on the research at the University of Yamanashi in Japan, said in an interview with public broadcaster NHK yesterday that he was no longer sure of the premise of the data he used to establish the experiments and that the studies should be withdrawn for review. The comments underscore the pressure researchers face amid Japans push into stem-cell science following Shinya Yamanakas 2012 Nobel Prize.

Its a disappointment for the community when such high profile papers may possibly be retracted, said Nissim Benvenisty, director of the stem-cell unit at the Hebrew University in Jerusalem, in an interview. Its reassuring that the investigators in this institute are themselves taking the initiative to look into what might have gone wrong.

The studies found that ordinary cells taken from newborn mice could be transformed into stem cells, the versatile building blocks of the body, without adding genes. Researchers led by Haruko Obokata at the Riken Center for Developmental Biology shocked the cells with a dose of sublethal stress such as mechanical force to trigger a transformation.

The study surprised me when it came out because it contradicted the common sense that we have acquired so far in the field, Benvenisty said. At the same time, this is the beauty of the scientific world, that editors allow publications of papers that contradict common sense to allow novel data to be discussed and understood.

Obokata worked with Wakayama and institutions including Charles Vacantis laboratory at Brigham and Womens Hospital, Harvard Medical School.

Rikens media relations department couldnt immediately be reached. An e-mail to Obokata wasnt immediately answered.

Im not sure what Riken will decide to do, Wakayama said in an e-mail responding to a request for comments.

Japans Prime Minister Shinzo Abe aims to cement the countrys leadership in the field of research and has pushed through bills that fast-track regulatory approval for cell-based products and set new research guidelines. Last year, Japans Health Ministry cleared the way for the worlds first clinical trial with stem cells made using a separate technique fromYamanaka, the Nobel Prize winner from Kyoto University.

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Riken Considers Retracting Two Stem-Cell Studies

Protein synthesis studied in stem cells for the first time

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A new breakthrough in stem cell research has occurred, thanks to scientists at the Children's Medical Center Research Institute at UT Southwestern Medical Center in Dallas, Texas.

The researchers claim that protein synthesis - an essential biological process - can be studied in adult stem cells. This is something that scientists have been previously unable to accomplish.

It is believed that many degenerative diseases and some cancers are linked with mutations that affect the process of protein synthesis. But experts have been unable to pinpoint why this happens.

Therefore, the team's discovery is important in improving understanding of protein synthesis and why changes in the process are linked with the development of disease.

The research built on previous work that used a modified antibiotic, called puromycin, to make it possible to see and measure the amount of protein that is being synthesized in the body.

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Protein synthesis studied in stem cells for the first time

Stem cell study opens door to undiscovered world of biology

13 hours ago This photo shows Dr. Sean Morrison, Director of the Children's Research Institute and senior author of the study, right, and Dr. Robert A.J. Signer, a postdoctoral research fellow and the study's first author. Credit: University of Texas Southwestern Medical Center

For the first time, researchers have shown that an essential biological process known as protein synthesis can be studied in adult stem cells something scientists have long struggled to accomplish. The groundbreaking findings from the Children's Medical Center Research Institute at UT Southwestern (CRI) also demonstrate that the precise amount of protein produced by blood-forming stem cells is crucial to their function.

The discovery, published online today in Nature, measures protein production, a process known as translation, and shows that protein synthesis is not only fundamental to how stem cells are regulated, but also is critical to their regenerative potential.

"We unveiled new areas of cellular biology that no one has seen before," said Dr. Sean Morrison, Director of the Children's Research Institute, Professor of Pediatrics, and the Mary McDermott Cook Chair in Pediatric Genetics at UT Southwestern Medical Center. "No one has ever studied protein synthesis in somatic stem cells. This finding not only tells us something new about stem cell regulation, but opens up the ability to study differences in protein synthesis between many kinds of cells in the body. We believe there is an undiscovered world of biology that allows different kinds of cells to synthesize protein at different rates and in different ways, and that those differences are important for cellular survival."

Dr. Adrian Salic's laboratory at Harvard Medical School chemically modified the antibiotic puromycin in a way that made it possible to visualize and quantify the amount of protein synthesized by individual cells within the body. Dr. Robert A.J. Signer, a postdoctoral research fellow in Dr. Morrison's laboratory and first author of the study, realized that this reagent could be adapted to measure new protein synthesis by stem cells and other cells in the blood-forming system.

What they came across was astonishing, Dr. Morrison said. The findings suggested that different types of blood cells produce vastly different amounts of protein per hour, and stem cells in particular synthesize much less protein than any other blood-forming cells.

"This result suggests that blood-forming stem cells require a lower rate of protein synthesis as compared to other blood-forming cells," said Dr. Morrison, the paper's senior author.

Researchers applied the findings to a mouse model with a genetic mutation in a component of the ribosome the machinery that makes proteins and the rate of protein production was reduced in stem cells by 30 percent. The scientists also increased the rate of protein synthesis by deleting the tumor suppressor gene Pten in blood-forming stem cells. In both instances, stem cell function was noticeably impaired.

Together, these observations demonstrate that blood-forming stem cells require a highly regulated rate of protein synthesis, such that increases or decreases in that rate impair stem cell function.

"Amazingly, when the ribosomal mutant mice and the Pten mutant mice were bred together, stem cell function returned to normal, and we greatly delayed, and in some instances entirely blocked, the development of leukemia," Dr. Morrison said. "All of this happened because protein production in stem cells was returned to normal. It was as if two wrongs made a right."

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Stem cell study opens door to undiscovered world of biology

New OHSU center aims to speed cures for Parkinson’s …

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OHSU's Dr. Shoukhrat Mitalipov will lead the hospital's new Center for Embryonic Stem Cell and Gene Therapy.

Oregon Health & Science University has launched a new Center for Embryonic Cell and Gene Therapy.

Led by renowned researcher Dr. Shoukhrat Mitalipov, a senior scientist at OHSU's Oregon National Primate Research Center, the center could help accelerate cures and treatments for Parkinson's disease, multiple sclerosis and other conditions caused by diseased or injured cells.

"Our continuing work and discoveries can be revolutionary in how we cure and treat many diseases and injuries," said Mitalipov in a statement. "This new center will allow us to put together a comprehensive program where we can share our expertise, answer new questions and train the scientists needed to move this important work forward."

Mitalipov and his team have succeeded in preventing transmission of genetic defects in mitochondrial DNA in the cells of monkeys, in 2009, and in human cells in 2012. Thousands of babies are born every year in the U.S. with mutated mitochondrial DNA, which can cause brain damage, muscle weakness, cardiac disease and damage to other organs. Most children with mitochondrial disease don't live past their teenage years.

Mitalipov just returned from a two-day Food and Drug Administration hearing in Maryland that reviewed his gene therapy research for consideration of human clinical trials.

Mitalipov and his team are also global leaders in embryonic stem cell research. Last year, the journal Cell published a Mitalipov paper that detailed how his team had reprogrammed human skin cells to become embryonic stem cells capable of transforming into any cell type in the body.

Stem cell therapies may eventually allow damaged cells to be replaced and could be key contributors to treating Parkinson's disease, cardiac disease and spinal cord injuries, among other conditions. Mitalipov's procedure is among a very few alternatives to the controversial use of stem cells derived from fertilized human embryos. His lab is the only one in the world currently capable of producing these embryonic human stem cells.

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Man fights the flab to be cell donor -Eastday

A LOCAL man on Tuesday celebrated his 39th birthday by becoming Shanghais 294th hematopoietic stem cell donor after shedding 22 kilograms to meet the eligibility requirements.

Pan Weizhong, a team leader for Sinopec, joined the China Bone Marrow Bank in 2007 after one of his colleagues successfully donated his stem cells. Last October, Pan received a call from the Shanghai Red Cross Society telling him his blood was a match for a 28-year-old woman suffering from leukemia in Wuhan, capital of central Chinas Hubei Province.

He was really excited when he found out and couldnt wait to tell me when I came home from work,Pans wife Wang Aiping, who works as an accountant at a community health care center, told Shanghai Daily yesterday.

I was also very happy because I had always supported his decision to become a donor.

But when Pan, who weighed about 90 kilograms at the time, went for a preliminary medical examination, doctors told him he had a fatty liver and needed to lose weight, Wang said.

Determined to qualify for the scheme, Pan switched to a vegetarian diet and began exercising for two hours every day. He even quit smoking and drinking alcohol, his wife said.

My son and I also became vegetarians to support him,she said.

After two months of no meat and lots of exercise, doctors gave Pan the green light.

After Tuesdays operation Pan said he was delighted to have been able to help someone he had never even met.

It feels great to celebrate my birthday by giving this woman a fresh start in life,he said.Its the best present Ive ever had.

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Man fights the flab to be cell donor -Eastday

New neurons generated in brains, spinal cords of living adult mammals

UT Southwestern Medical Center researchers created new nerve cells in the brains and spinal cords of living mammals without the need for stem cell transplants to replenish lost cells.

Although the research indicates it may someday be possible to regenerate neurons from the body's own cells to repair traumatic brain injury or spinal cord damage or to treat conditions such as Alzheimer's disease, the researchers stressed that it is too soon to know whether the neurons created in these initial studies resulted in any functional improvements, a goal for future research.

Spinal cord injuries can lead to an irreversible loss of neurons, and along with scarring, can ultimately lead to impaired motor and sensory functions. Scientists are hopeful that regenerating cells can be an avenue to repair damage, but adult spinal cords have limited ability to produce new neurons. Biomedical scientists have transplanted stem cells to replace neurons, but have faced other hurdles, underscoring the need for new methods of replenishing lost cells.

Scientists in UT Southwestern's Department of Molecular Biology first successfully turned astrocytes -- the most common non-neuronal brain cells -- into neurons that formed networks in mice. They now successfully turned scar-forming astrocytes in the spinal cords of adult mice into neurons. The latest findings are published today in Nature Communications and follow previous findings published in Nature Cell Biology.

"Our earlier work was the first to clearly show in vivo (in a living animal) that mature astrocytes can be reprogrammed to become functional neurons without the need of cell transplantation. The current study did something similar in the spine, turning scar-forming astrocytes into progenitor cells called neuroblasts that regenerated into neurons," said Dr. Chun-Li Zhang, assistant professor of molecular biology at UT Southwestern and senior author of both studies.

"Astrocytes are abundant and widely distributed both in the brain and in the spinal cord. In response to injury, these cells proliferate and contribute to scar formation. Once a scar has formed, it seals the injured area and creates a mechanical and biochemical barrier to neural regeneration," Dr. Zhang explained. "Our results indicate that the astrocytes may be ideal targets for in vivo reprogramming."

The scientists' two-step approach first introduces a biological substance that regulates the expression of genes, called a transcription factor, into areas of the brain or spinal cord where that factor is not highly expressed in adult mice. Of 12 transcription factors tested, only SOX2 switched fully differentiated, adult astrocytes to an earlier neuronal precursor, or neuroblast, stage of development, Dr. Zhang said.

In the second step, the researchers gave the mice a drug called valproic acid (VPA) that encouraged the survival of the neuroblasts and their maturation (differentiation) into neurons. VPA has been used to treat epilepsy for more than half a century and also is prescribed to treat bipolar disorder and to prevent migraine headaches, he said.

The current study reports neurogenesis (neuron creation) occurred in the spinal cords of both adult and aged (over one-year old) mice of both sexes, although the response was much weaker in the aged mice, Dr. Zhang said. Researchers now are searching for ways to boost the number and speed of neuron creation. Neuroblasts took four weeks to form and eight weeks to mature into neurons, slower than neurogenesis reported in lab dish experiments, so researchers plan to conduct experiments to determine if the slower pace helps the newly generated neurons properly integrate into their environment.

In the spinal cord study, SOX2-induced mature neurons created from reprogramming of astrocytes persisted for 210 days after the start of the experiment, the longest time the researchers examined, he added.

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New neurons generated in brains, spinal cords of living adult mammals

Researchers Generate New Neurons in Brains, Spinal Cords of Living Adult Mammals Without the Need of Stem Cell …

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Newswise DALLAS, Feb. 25, 2014 UTSouthwestern Medical Center researchers created new nerve cells in the brains and spinal cords of living mammals without the need for stem cell transplants to replenish lost cells.

Although the research indicates it may someday be possible to regenerate neurons from the bodys own cells to repair traumatic brain injury or spinal cord damage or to treat conditions such as Alzheimers disease, the researchers stressed that it is too soon to know whether the neurons created in these initial studies resulted in any functional improvements, a goal for future research.

Spinal cord injuries can lead to an irreversible loss of neurons, and along with scarring, can ultimately lead to impaired motor and sensory functions. Scientists are hopeful that regenerating cells can be an avenue to repair damage, but adult spinal cords have limited ability to produce new neurons. Biomedical scientists have transplanted stem cells to replace neurons, but have faced other hurdles, underscoring the need for new methods of replenishing lost cells.

Scientists in UTSouthwesterns Department of Molecular Biology first successfully turned astrocytes the most common non-neuronal brain cells into neurons that formed networks in mice. They now successfully turned scar-forming astrocytes in the spinal cords of adult mice into neurons. The latest findings are published today in Nature Communications and follow previous findings published in Nature Cell Biology.

Our earlier work was the first to clearly show in vivo (in a living animal) that mature astrocytes can be reprogrammed to become functional neurons without the need of cell transplantation. The current study did something similar in the spine, turning scar-forming astrocytes into progenitor cells called neuroblasts that regenerated into neurons, said Dr. Chun-Li Zhang, assistant professor of molecular biology at UTSouthwestern and senior author of both studies.

Astrocytes are abundant and widely distributed both in the brain and in the spinal cord. In response to injury, these cells proliferate and contribute to scar formation. Once a scar has formed, it seals the injured area and creates a mechanical and biochemical barrier to neural regeneration, Dr. Zhang explained. Our results indicate that the astrocytes may be ideal targets for in vivo reprogramming.

The scientists' two-step approach first introduces a biological substance that regulates the expression of genes, called a transcription factor, into areas of the brain or spinal cord where that factor is not highly expressed in adult mice. Of 12 transcription factors tested, only SOX2 switched fully differentiated, adult astrocytes to an earlier neuronal precursor, or neuroblast, stage of development, Dr. Zhang said.

In the second step, the researchers gave the mice a drug called valproic acid (VPA) that encouraged the survival of the neuroblasts and their maturation (differentiation) into neurons. VPA has been used to treat epilepsy for more than half a century and also is prescribed to treat bipolar disorder and to prevent migraine headaches, he said.

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Researchers Generate New Neurons in Brains, Spinal Cords of Living Adult Mammals Without the Need of Stem Cell ...