Improved Method to Create Induced Pluripotent Stem Cells

Improved Method to Create Induced Pluripotent Stem Cells
Wednesday, 20 July 2011

University of Minnesota Medical School researchers have developed a new strategy to improve the development of induced pluripotent stem cells (iPS).

Currently, iPS cells are created by introducing four defined genes to an adult cell. The genes reprogram the adult cell into a stem cell, which can differentiate into many different types of the cells in the body. Typically, the four genes introduced are Oct4, Sox2, Klf4 and c-Myc, a combination known as OSKM.

The U of M researchers found that by fusing two proteins – a master stem cell regulator (Oct4) and a fragment of a muscle cell inducer (MyoD) – they succeeded in "powering up" the stem cell regulator, which can dramatically improve the efficiency and purity of reprogrammed iPS cells.

"Our team discovered that by fusing a fragment of the powerful protein MyoD to Oct4 we could create a 'super gene' which would improve the iPS reprogramming process," said senior author Dr. Nobuaki Kikyo, Stem Cell Institute researcher and University of Minnesota Medical School associate professor.

"The result is what we termed M3O, or 'super Oct4' – a gene that improves the creation of iPS cells in a number of ways. In the process we shed new light on the mechanism of making iPS cells."

The challenge with the previous method – OSKM – has been that very few cells actually become iPS cells during reprogramming. In fact, the rates currently stand at about 0.1 percent. Another issue has been tumor development. Because some of the reprogramming genes introduced are oncogenes, the risk of developing tumors grows.

The research, led by Kikyo and Dr. Hiroyuki Hirai, both from University of Minnesota Medical School and Stem Cell Institute, led to a new gene model that minimizes such complications while amplifying the benefits of the process.

According to Kikyo, the new gene model – called M3O-SKM – improves iPS development by:

Increasing efficiency. The efficiency of making mouse and human iPS cells was increased over 50-fold compared with the standard OSKM combination. Increasing purity. The purity of the iPS cells was much higher with the M3O-SKM gene introduction (98% of the colonies) compared with OSKM (5%).

Facilitating the reprogramming. iPS cell colonies appeared in around five days with M3O-SKM, in contrast to around two weeks with OSKM.

Decreasing the potential for tumor formation. M3O achieved high efficiency of making iPS cells without c-Myc, an oncogene that can potentially lead to tumor formation.

In addition, human iPS cells usually require co-culture with feeder cells typically prepared from mouse cells, obviously creating a problem when the cells are destined for human transplantation. The M3O model did not require such feeder cells, greatly simplifying the process.

The new process is outlined in the latest issue of the journal Stem Cells.

According to senior author Kikyo, this new strategy will dramatically speed up the process of making patient-specific iPS cells, which makes clinical applications via transplantation of the cells more feasible to treat many diseases incurable otherwise.

Many researchers are also examining how to reprogram one cell type into another without going through iPS cells; for instance, coaxing skin cells into becoming neurons or pancreas cells by introducing several genes.

The approach, called direct reprogramming, is thought to be the next generation approach beyond iPS cell technology.

The U of M approach – fusing a powerful protein fragment to other host proteins – can be widely applied to the direct reprogramming approach as well.

Source: University of Minnesota
Contact: Justin Paquette
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Precision Gene Targeting in Stem Cells Corrects Disease-causing Mutations

Precision Gene Targeting in Stem Cells Corrects Disease-causing Mutations 
Tuesday, 19 July 2011

Using two distinct methods, Whitehead Institute researchers have successfully and consistently manipulated targeted genes in both human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells (adult cells that have been reprogrammed to an embryonic stem cell-like state). In one case, scientists employed proteins known as zinc finger nucleases (ZFNs) to change a single base pair in the genome, allowing them either to insert or remove mutations known to cause early-onset Parkinson's disease (PD). The second method relies on proteins called transcription activator like effector nucleases (TALENs) capable of altering specific genes with similar efficiency and precision as ZFNs.

Both methods address a problem that has been plaguing human stem cell research – the ability to cleanly and site-specifically modify the genomes of human ES and iPS cells. Realizing the therapeutic promise of these cells depends on such changes to fix disease-causing mutations before the cells could be transplanted into patients or to create cell lines that researchers can use to study genetic diseases.

Using these two distinct methods, Whitehead Institute researchers have successfully and consistently manipulated targeted genes in both human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells (adult cells that have been reprogrammed to an embryonic stem cell-like state).

In one case, scientists employed proteins known as zinc finger nucleases (ZFNs) to change a single base pair in the genome, allowing them either to insert or remove mutations known to cause early-onset Parkinson's disease (PD). The second method relies on proteins called transcription activator like effector nucleases (TALENs) capable of altering specific genes with similar efficiency and precision as ZFNs. Both sets of experiments were conducted in close collaboration with scientists at Sangamo BioSciences.

Targeted genetic manipulation addresses a problem that has been plaguing human stem cell research – the ability to cleanly and site-specifically modify the genomes of human ES and iPS cells. Realizing the therapeutic promise of these cells depends on such changes to fix disease-causing mutations before the cells could be transplanted into patients or to create cell lines that researchers can use to study genetic diseases.

Such disease studies — the much-heralded "disease in a dish" approach — and the search for potentially disease-modifying drugs require the use of cells and controls that are genetically identical, except for a specific alteration whose impact can then be observed.

"This is very relevant for diseases like Parkinson's, which likely will display only subtle phenotypes in the Petri dish. It is very important that the cells be genetically identical and have the same history, then make or remove only that mutation," says Whitehead Founding Member Rudolf Jaenisch.

"If you use control cells from one person and a diseased cell from another person, it's like comparing apples and oranges."

As reported in a paper published July 22 in Cell, first author Frank Soldner used ZFNs created by Sangamo BioSciences to generate, from both normal and PD patients' cells, sets of mutated and control cell lines. By either removing or adding a mutation to the alpha-synuclein gene associated with PD, Soldner created lines of cells whose genomes differ only by a single base pair. Subsequent differences seen in comparative studies of the cells can therefore be attributed to the mutation in question.

"ZFNs can transfer a mutation without any other alterations to the genome, such as leaving in unwanted pieces of DNA that could be harmful," says Soldner, a postdoctoral researcher in Jaenisch's lab.

"This precision is ideal for drug research for PD and other diseases, but it is also one more step toward using ES or iPS cells therapeutically."

In its continual quest to refine human stem cell technology, the Jaenisch lab has also been investigating other gene targeting approaches. One option is to use TALENs, which use a type of DNA-binding domain originally found in some plant pathogens. TALENs can be designed and created in academic labs.

To compare TALENs' ability to alter genes to that of ZFNs', two postdoctoral researchers in Jaenisch's lab, Dirk Hockemeyer and Haoyi Wang, repeated an earlier ZFN experiment, this time using TALENs created by scientists at Sangamo BioSciences. In research reported earlier this month in Nature Biotechnology, Hockemeyer and Wang show that these TALENs can also modify genes as efficiently and precisely as ZFNs in ES and iPS cells.

"These are amazing proteins," says Wang.

"In theory, everything ZFNs do, they should be able to do as well."

"This opens up a lot of possibilities of what we will be able do because the generation of TALENs is extremely versatile," adds Hockemeyer.

"It appears they, along with ZFNs, will help us overcome the challenges of developing human ES and iPS cell technology."

Source: Whitehead Institute for Biomedical Research

Contact: Nicole Giese

Reference:

Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations
Frank Soldner, Josee Laganiere, Albert W Cheng, Dirk Hockemeyer, Qing Gao, Raaji Alagappan, Vikram Khurana, Lawrence I. Golbe, Richard H. Myers, Susan Lindquist, Lei Zhang, Dmitry Guschin, Lauren K Fong, Joe Vu, Xiangdong Meng, Fyodor D. Urnov, Edward J. Rebar, Philip D. Gregory, H. Steve Zhang, Rudolf Jaenisch
Cell, July 22, 2011
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Efficient Process Using microRNA Converts Human Skin Cells into Neurons

Efficient Process Using microRNA Converts Human Skin Cells into Neurons  
Tuesday, 19 July 2011

The addition of two particular gene snippets to a skin cell's usual genetic material is enough to turn that cell into a fully functional neuron, report researchers from the Stanford University School of Medicine. The finding, to be published online July 13 in Nature, is one of just a few recent reports of ways to create human neurons in a lab dish.

The new capability to essentially grow neurons from scratch is a big step for neuroscience research, which has been stymied by the lack of human neurons for study. Unlike skin cells or blood cells, neurons are not something that's easy for a living human to donate for research.

"A major problem in neurobiology has been the lack of a good human model," said senior author Gerald Crabtree, MD, professor of pathology and of developmental biology.

"Neurons aren't like blood. They're not something people want to give up."

Generating neurons from easily accessible cells, such as skin cells, makes possible new ways to study neuronal development, model disease processes and test treatments.

It also helps advance the effort, still in its infancy, to replace damaged or dead neurons with new ones.

Before succeeding at turning skin cells straight into neurons, scientists had discovered two years ago that they could get similar results if they transformed the skin cell first into a stem cell and then coaxed the stem cell into becoming a neuron. But Crabtree's new study and two studies by others show it's possible to go straight from skin cell to neuron without the stem-cell pit stop.

Crabtree's study is unique among the efforts because of the surprising identity of the molecules that nudged the cells to switch — short chains of genetic material called microRNA, best known for their ability to bind to specific genetic transcripts to turn off their activity.

"In this case, though, they're playing an instructive role," Crabtree said.

The discovery of the microRNAs' ability to switch the cells came to light when Andrew Yoo, PhD, then a postdoctoral researcher in Crabtree's lab (now on the faculty of Washington University in St. Louis), was trying to better understand what makes neural stem cells move on to become mature neurons. He found that two microRNAs, miR-9/9* and miR-124, trigger it by controlling a molecular machine (called the BAF chromatin remodeling complex) that shapes chromosomes so they'll direct the cell to remain a stem cell.

"When the microRNAs bind to one subunit of this 13-membered complex they turn this function off, and the cells begin to grow up and connect to one another — that is, they become mature, functioning neurons," said Crabtree. After they published this in Nature in 2009, Yoo went on to try to understand how the two microRNAs functioned. One way he did this was to watch what happened when he introduced them into cells that normally lacked them.

At first he didn't believe what he was seeing through the microscope: The cells with the additional microRNAs had started to look like neurons.

"It was very weird. We were astounded," said Crabtree, who is also the David Korn, MD, Professor of Pathology.

Yoo, one of the new report's lead authors, continued to study the phenomenon with others at Stanford. They used a virus to carry the snippets into skin cells and investigated whether the resulting cells really were neurons. They found that 2 to 3 percent of the skin cells reliably converted to neurons: The cells generated the electrical signals neurons use to communicate with one another, and they budded off small globules, called synaptic vesicles, just as the adult neurons ordinarily do.

"What we made are neurons that are characteristic of the frontal cortex — actually what you'd imagine would be the most difficult to make. They're the ones we think with, that we use to put two things together and see connections, not the ones involved in evolutionarily older emotional responses," said Crabtree.

"We also find inhibitory neurons among the converted cells, whose role is to keep the activity of other neurons at a resting, controlled state."

The team improved the efficiency of the transformation to 20 percent by adding two of the factors used in a similar experiment by colleague Marius Wernig, MD, assistant professor of pathology, in the first published account of converting a human skin cell directly to a neuron. In May this year, Wernig reported in Nature that the combination of four particular proteins can convert skin cells directly into functional neurons with 2 to 4 percent efficiency. (Even more recently, on July 3, Nature published a study led by a researcher at the San Raffaele Scientific Institute in Milan, Italy, showing a mix of three other proteins can set off the conversion.)

"It's been a long time in coming to this," said Crabtree.

"But science often progresses in leaps and starts, and then all of a sudden many scientists come to the same position at the same time. Now these studies have come out, and more will be coming, all of which are going to say that not only can you can make neurons different ways, but also you can make neurons of different types."

Wernig's study produced the same "thinking" neurons as Crabtree's did, but did not find inhibitory neurons. The Italian study produced neurons that release dopamine, a chemical that affects many behaviors, from moving, to learning, to sleeping.

Among the projects taking off from this finding is an effort to set up a model for Down syndrome. Stanford graduate student Alfred Sun, a co-leader of the study, has obtained skin cells from patients and converted them to neurons. Now he can try to see what's different about them.

"Our belief is there are certain biochemical abnormalities that might be correctable," Crabtree said.

Source: Stanford University Medical Center
Contact: Rosanne Spector
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Researchers Demystify a Fountain of Youth in the Adult Brain

Researchers Demystify a Fountain of Youth in the Adult Brain   Tuesday, 19 July 2011

Duke University Medical Center researchers have found that a "fountain of youth" that sustains the production of new neurons in the brains of rodents is also believed to be present in the human brain. The existence of a vital support system of cells around stem cells in the brain explains why stem cells by themselves can't generate neurons in a lab dish, a major roadblock in using these stem cells for injury repair.

"We believe these findings will have important implications for human therapy," said Chay Kuo, M.D., Ph.D., George Brumley Jr. assistant professor of Cell Biology, Pediatrics and Neurobiology, and senior author of the study.

The study is the cover story in the July issue of Neuron, published online July 14.

The scientists found that neighbouring "epithelial-like" ependymal cells – not stem cells themselves – maintain a special structure that keeps neural stem cells "neurogenic," able to make new neurons.

Currently, when neural stem cells are harvested for growth in culture, however, the ependymal cells are not removed along with them, and this can be a problem.

"Neural stem cells in a lab dish don't continue to make neurons as they do inside the brain," Kuo said.

"Instead, they often produce astrocytes, a cell type that may not be helpful to re-implant into a brain."

He said that uncontrolled astrocyte growth can lead to brain tumours.

In a series of experiments, the researchers found that the generation of new neurons depended on what he calls the "ugly sibling" of the stem cells, the ependymal cell that has long, moving, hair-like cilia that cover its surface. Kuo decided to study these cells because the lateral ventricles in the brain, where adult neural stem cells reside, are also the last area of a developing brain that grows ependymal cells.

"The common radial glial progenitors in the developing nervous system prior to birth give rise to both the ependymal cells and the adult stem cells," Kuo said.

"So it made sense to study these niche cells as well as the stem cells."

"There is this fountain of youth inside the adult brain that actively makes new neurons," Kuo said.

"Yet we don't know how this fountain is constructed or maintained."

Kuo and his colleagues found that the Foxj1 transcription factor, a class of master proteins that turn other genes on and/or off, is critical to instruct ependymal cells to change shape and assemble into pinwheel-like architecture surrounding stem cells. He said the lateral membranes of mature ependymal cells are shaped like machine cogs or fingers that lace together.

The researchers determined that the structural protein Ankyrin-3 was turned on by Foxj1 in these ependymal cells to provide structural support for the delicate neural stem cells. Signals generated by this structural support will probably be important for instructing introduced neural stem cells to make neurons in therapeutic settings, he said.

Kuo said he would not have examined the role of ependymal cell Foxj1 in relation to neural stem cells if not for his Cell Biology Chair, Brigid Hogan, Ph.D., whose lab next door is a world leader in understanding adult lung and airway stem cell function. Likewise, Kuo said pioneering work on ankyrins by Duke Cell Biology and Howard Hughes Medical Institute Investigator Vann Bennett, M.D., Ph.D., a co-author on the paper, paved the way for study of these proteins in the neural stem cell environment.

Future studies will look closely at the details of the niche environment to learn more.

"Understanding the environmental control of neuron production in the adult brain will be crucial for future therapeutic strategies using human stem cells to replace neurons," Kuo said.

Source: Duke University Medical Center

Contact: Mary Jane Gore
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Researchers Reprogram Brain Cells to Become Heart Cells

Researchers Reprogram Brain Cells to Become Heart Cells Saturday, 09 July 2011

 

For the past decade, researchers have tried to reprogram the identity of all kinds of cell types. Heart cells are one of the most sought-after cells in regenerative medicine because researchers anticipate that they may help to repair injured hearts by replacing lost tissue. Now, researchers at the Perelman School of Medicine at the University of Pennsylvania are the first to demonstrate the direct conversion of a non-heart cell type into a heart cell by RNA transfer. Working on the idea that the signature of a cell is defined by molecules called messenger RNAs (mRNAs), which contain the chemical blueprint for how to make a protein, the investigators changed two different cell types, an astrocyte (a star-shaped brain cell) and a fibroblast (a skin cell), into a heart cell, using mRNAs.

James Eberwine, PhD, the Elmer Holmes Bobst Professor of Pharmacology, Tae Kyung Kim, PhD, post-doctoral fellow, and colleagues report their findings online this week in the Proceedings of the National Academy of Sciences. This approach offers the possibility for cell-based therapy for cardiovascular diseases.

"What's new about this approach for heart-cell generation is that we directly converted one cell type to another using RNA, without an intermediate step," explains Eberwine.

tCardiomyocyte (center), showing

protein distribution (green and red

colors) indicative of a young

cardiomyocyte. Credit: Tae Kyung Kim,

PhD, Perelman School of Medicine,

University of Pennsylvania.

The scientists put an excess of heart cell mRNAs into either astrocytes or fibroblasts using lipid-mediated transfection, and the host cell does the rest. These RNA populations (through translation or by modulation of the expression of other RNAs) direct DNA in the host nucleus to change the cell's RNA populations to that of the destination cell type (heart cell, or tCardiomyocyte), which in turn changes the phenotype of the host cell into the destination cell.

The method the group used, called Transcriptome Induced Phenotype Remodeling, or TIPeR, is distinct from the induced pluripotent stem cell (iPS) approach used by many labs in that host cells do not have to be dedifferentiated to a pluripotent state and then re-differentiated with growth factors to the destination cell type. TIPeR is more similar to prior nuclear transfer work in which the nucleus of one cell is transferred into another cell where upon the transferred nucleus then directs the cell to change its phenotype based upon the RNAs that are made. The tCardiomyocyte work follows directly from earlier work from the Eberwine lab, where neurons were converted into tAstrocytes using the TIPeR process.

The team first extracted mRNA from a heart cell, then put it into host cells. Because there are now so many more heart-cell mRNAs versus astrocyte or fibroblast mRNAs, they take over the indigenous RNA population. The heart-cell mRNAs are translated into heart-cell proteins in the cell cytoplasm. These heart-cell proteins then influence gene expression in the host nucleus so that heart-cell genes are turned on and heart-cell-enriched proteins are made.

To track the change from an astrocyte to heart cell, the team looked at the new cells' RNA profile using single cell microarray analysis; cell shape; and immunological and electrical properties. While TIPeR-generated tCardiomyocytes are of significant use in fundamental science it is easy to envision their potential use to screen for heart cell therapeutics, say the study authors. What's more, creation of tCardiomyoctes from patients would permit personalized screening for efficacy of drug treatments; screening of new drugs; and potentially as a cellular therapeutic.

Source: University of Pennsylvania School of Medicine
Contact: Karen Kreeger  

Reference:
Transcriptome transfer provides a model for understanding the phenotype of cardiomyocytes

Tae Kyung Kim, Jai-Yoon Sul, Nataliya B. Peternko, Jae Hee Lee, Miler Lee, Vickas V. Patel, Junhyong Kim, and James H. Eberwine

PNAS July 5, 2011, July 5, 2011, doi: 10.1073/pnas.1101223108

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A Single Stem Cell Capable of Regenerating the Entire Blood System

'Pure' Human Blood Stem Cell Discovery Opens Door to Expanding Cells for More Clinical Use
Friday, 08 July 2011

For the first time since stem cells were discovered here 50 years ago, scientists have isolated a human blood stem cell in its purest form – as a single stem cell capable of regenerating the entire blood system. This breakthrough opens the door to harnessing the power of these life-producing cells to treat cancer and other debilitating diseases more effectively.

The research is published today in Science.

"This discovery means we now have an increasingly detailed road map of the human blood development system including the much sought after stem cell," says principal investigator John Dick, who holds a Canada Research Chair in Stem Cell Biology and is a Senior Scientist at the McEwen Centre for Regenerative Medicine and the Ontario Cancer Institute, University Health Network (UHN).

"We have isolated a single cell that makes all arms of the blood system, which is key to maximizing the potential power of stem cells for use in more clinical applications. Stem cells are so rare that this is a little like finding a needle in a haystack."

Dr. Dick, who pioneered the field of cancer stem cells with previous discoveries in human leukemia and colon cancer, also developed a way to replicate the entire human leukemia disease process using genetically engineered mice. As well as being a Senior Scientist at UHN's Princess Margaret and Toronto General Hospitals, he is a Professor in the Department of Molecular Genetics, University of Toronto, and Director of the Cancer Stem Cell Program at the Ontario Institute for Cancer Research.

Dr. Dick works out of UHN's Ontario Cancer Institute (OCI) – the venerable institution where stem-cell science began in 1961 with the original discovery of Drs. James Till and Ernest McCulloch – and McEwen Centre for Regenerative Medicine with the next generation of stem-cell scientists focused on developing better and more effective treatments for heart disease, diabetes, respiratory disease and spinal cord injury.

The 1961 Till and McCulloch discovery quickly led to using stem cells for bone marrow transplantation in leukemia patients, the most successful clinical application so far in what is now known as regenerative medicine and a therapy that is used to treat thousands of patients annually around the world.

"Ever since stem-cell science began," says Dr. Dick, "scientists have been searching for the elusive mother lode – the single, pure stem cell that could be controlled and expanded in culture prior to transplantation into patients. Recently scientists have begun to harness the stem cells found in the umbilical cord blood; however, for many patients a single donor sample is not large enough to use. These new findings are a major step to generate sufficient quantities of stem cells to enable greater clinical use and thus move closer to realizing the promise of regenerative medicine for patients."

Along the way, scientists have indeed mapped many vital signposts regarding stem-cell subsets and specialization. Last year, Dr. Dick's team reported isolating the more specialized progenitor cells that lie downstream of the stem cell. The discovery published today was enabled by hi-tech flow cytometry technology: a process that rapidly sorts, sifts and purifies millions of blood cells into meaningful bins for scientific analysis. Now, stem-cell scientists can start mapping the molecular switches that guide how "normal" stem cells behave and endure, and also characterize the core properties that distinguish them from all other blood cell types.

This discovery is the one Dr. Dick has personally been seeking ever since 1988 when he developed the first means of studying human blood stem cells by transplanting them into immune-deficient mice, research that was also published in Science.

"Back then, our goal was to define single human stem cells. With advances made in technology, twenty-three years later, we have."

Source: University Health Network
Contact: Jane Finlayson

Reference:
Isolation of Single Human Hematopoietic Stem Cells Capable of Long-Term Multilineage Engraftment
Faiyaz Notta, Sergei Doulatov. Elisa Laurenti, Armando Poeppl, Igor Jurisica and John E. Dick
Science 8 July 2011, Vol. 333 no. 6039 pp. 218-221, DOI: 10.1126/science.1201219
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Unexpected Cell Repairs the Injured Spinal Cord

Unexpected Cell Repairs the Injured Spinal Cord
Friday, 08 July 2011
 
Lesions to the brain or spinal cord rarely heal fully, which leads to permanent functional impairment. After injury to the central nervous system (CNS), neurons are lost and largely replaced by a scar often referred to as the glial scar based on its abundance of supporting glial cells. Although this process has been known to science for over a century, the function of the scar tissue has long been disputed. However, there are indications that it stabilizes the tissue and that it inhibits the re-growth of damaged nerve fibres.

In this present study, Professor Jonas Frisén and his team of researchers show that the majority of scar cells in the damaged spinal cord are not glial cells at all, but derive from pericytes, a small group of cells located along blood vessels. They reveal that these pericytes start to divide after an injury, giving rise to a mass of connective tissue cells that migrate towards the lesion to form a large portion of the scar tissue. Their paper also shows that these cells are needed to regain the tissue integrity, and that in the absence of this reaction, holes appear in the tissue instead of scarring.

For many years, scientists have tried to modulate scar formation after CNS damage in order to facilitate functional recovery, and have concentrated on glial cells. However, these new findings indicate a critical and previously unknown mechanism for scar formation following damage to the nerve system, and give reason for further investigation into whether the modulation of pericytes after CNS injury can stimulate functional recovery.

Source: Karolinska Institutet
Contact: Ulla Bredberg

Reference:
A pericyte origin of spinal cord scar tissue
C. Göritz, D. Dias, N. Tomilin, M. Barbacid, O. Shupliakov, J. Frisén
Science online 8 July 2011 Vol. 333 no. 6039 pp. 238-242, DOI: 10.1126/science.1203165
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Mesenchymal Stem Cells: A Drugstore Within

Mesenchymal stem cells protect and heal
Friday, 08 July 2011

A stem cell that can morph into a number of different tissues is proving a natural protector, healer and antibiotic maker, researchers at Case Western Reserve University and their peers have found.
Mesenchymal stem cells reaped from bone marrow had been hailed as the key to growing new organs to replace those damaged or destroyed by violence or disease, but have failed to live up to the billing.
Instead, scientists who'd been trying to manipulate the cells to build replacement parts have been finding the cells are innately potent antidotes to a growing list of maladies.
The findings are summarized in the July 8 issue of Cell Stem Cell.
The cell, referred to as an MSC, "is a drugstore that functions at the local site of injury to provide all the medicine that site requires for its successful regeneration," said Arnold Caplan, professor of biology at Case Western Reserve, and lead author of the paper.
Here's how:
MSCs sit on every blood vessel in the body. When a blood vessel is injured or enflamed, the cells detach and jump into action.
"From the front end, the cell puts up a curtain of molecules which stop an overaggressive immune system from sending in cells to survey the damage – which, if successful, would mount an autoimmune response," he said.
"The back face of the MSC secretes molecules that set up a regenerative microenvironment so that the damaged tissue can repair itself and not make scar tissue."
Researchers around the world have been using the cells in a broad range of preclinical animal models of disease and injury and in clinical trials during the last decade.
By injecting MSCs into damaged tissue or infusing them into the blood stream, the therapy appears to have muted damage or cured such diverse conditions and disorders as acute heart attack, stroke, kidney failure, tendonitis, juvenile diabetes, radiation syndrome, arthritis, amyotrophic lateral syndrome, burns, wounds and more.
The researchers have found that MSCs from one human do not cause an immune response in another, nor in animals injected with human MSCs.
Most of the research has been done using cells culled from bone marrow, but results using cells extracted from fat, placenta, umbilical cord and muscle have shown similar but not identical potential.
Which source of cell is the best for each disease or injury requires further investigation.
Recent work, led by the University of San Francisco scientists, shows the cell's arsenal is even greater. They found the cells produce a protein that kills bacteria including E. coli and Staphylococcus aureus, and enhance clearance of the microbes from the body.
Because MSCs are showing themselves capable of far more than a foundation for tissue engineering, Caplan suggests the acronym should now stand for medicinal signaling cells.

Source: Case Western Reserve University
Contact: Kevin Mayhood
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Stem Cells Know Where They Want to Go

Pluripotent cells are not all equal
Friday, 08 July 2011

Human stem cells have the ability to become any cell type in the human body, but when it comes to their destination they know where they want to go.
This finding by McMaster University researchers sheds new light on how these regenerative cells turn into more specialized cell types, such as neural or blood cells. Until now, the thought has been that stem cells keep all their options open and have no preference when it comes to becoming more specialized.
In a paper published in the scientific journal Cell Stem Cell, Mick Bhatia, director of the McMaster Stem Cell and Cancer Research Institute, led a team of investigators to discover the molecular underpinnings of how human pluripotent stem cells make decisions. Pluripotency is the ability of stem cells to turn into any one of the 226 cell types that make up the human body.
The researchers discovered the fate – or destination – of human pluripotent stem cells is encoded by how their DNA is arranged, and this can be detected by specific proteins on the surface of the stem cells.
"It's like going on secret trip," said Bhatia, a professor in the Department of Biochemistry and Biomedical Sciences at the Michael G. DeGroote School of Medicine. "When you decide to go to Jamaica, you pack your toothbrush, underwear, and of course shorts, t-shirts and swimsuits. But if, at the last minute, you get rerouted to Alaska, you unpack a few things but the basic elements, like your toothbrush, are going to be the same. You may just trade the shorts and swimsuits for long pants and a sweater."Until now, common scientific belief has been that all pluripotent stem cells are equivalent and keep all options open at the same time. But that's really not the case, Bhatia says.
"This study showed that pluripotent cells are not all equal," he said.
"They are all pluripotent. You can force a cell that normally would love to become a neural cell to turn into blood, just like you can force the vacationer to go Alaska instead of Jamaica. They'll do it, but not very well and not happily."
For the study, Bhatia and his research team found stem cells with roadmaps and specifically packed suitcases for the blood and neural destinations. The researchers discovered when they isolated these stem cells by new protein markers on the surface of cells, they were able produce a greater number of specialized cells – nearly five times as many blood cells and twelve times as many neural cells compared to when the stem cells had to be forced into those cell types.
The results open the door to tailoring stem cells and improving their ability for tissue and organ regeneration. The researchers now plan to investigate how the process works in induced pluripotent stem cells – the kind created from adult skin.

Source: McMaster University
Contact: Veronica McGuire
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