Stem Cell Research

Virus-Free Technique Enables Researchers To Easily Make Fat Stem Cells Pluriotent

Stem cells from human fat are multipotent to begin with, meaning they are basically designed to turn into fat, bone or muscle tissue. While skin cells have been extensively used to create induced pluripotent (iPS) cells in the two plus years since iPS cells were first demonstrated, the ready multipotency and available supply of fat stem cells were seen by Stanford researchers as perhaps an easier approach.

Tiny circles of DNA turned out to ve the key to a new and easier way to transform stem cells from human fat into induced pluripotent stem (iPS) cells.  Unlike other commonly used techniques, the method, which is based on standard molecular biology practices, does not use viruses to introduce genes into the cells or permanently alter a cell's genome.

The new technique is the first example of reprogramming adult cells to pluripotency in this manner, and is hailed by the researchers as a major step toward the use of such cells in humans. They hope that the ease of the technique and its relative safety will smooth its way through the necessary FDA approval process.

"This technique is not only safer, it's relatively simple," said Stanford surgery professor Michael Longaker, MD, and co-author of the paper. "It will be a relatively straightforward process for labs around the world to begin using this technique. We are moving toward clinically applicable regenerative medicine."

The Stanford researchers used the so-called minicircles - rings of DNA about one-half the size of those usually used to reprogram cells - to induce pluripotency in stem cells from human fat. Pluripotent cells can then be induced to become many different specialized cell types. Although the researchers plan to first use these cells to better understand - and perhaps one day treat - human heart disease, induced pluripotent stem cells, or iPS cells, are a starting point for research on many human diseases.

"Imagine doing a fat or skin biopsy from a member of a family with heart problems, reprogramming the cells to pluripotency and then making cardiac cells to study in a laboratory dish," said cardiologist Joseph Wu, MD, PhD. "This would be much easier and less invasive than taking cell samples from a patient's heart." Wu is the senior author of the research.  Research assistant Fangjun Jia, PhD is the lead author of the work.
      
The minicircle reprogramming vector works so well because it is made of only the four genes needed to reprogram the cells (plus a gene for a green fluorescent protein to track minicircle-containing cells). Unlike the larger, more commonly used DNA circles called plasmids, the minicircles contain no bacterial DNA, meaning that the cells containing the minicircles are less likely than plasmids to be perceived as foreign by the body. The expression of minicircle genes is also more robust, and the smaller size of the minicircles allows them to enter the cells more easily than the larger plasmids. Finally, because they don't replicate they are naturally lost as the cells divide, rather than hanging around to potentially muck up any subsequent therapeutic applications.
      
The researchers chose to test the reprogramming efficiency of the minicircles in stem cells from human fat because previous work in Wu and Longaker's lab has shown that the cells are numerous, easy to isolate and amenable to the iPS transformation, probably because of the naturally higher levels of expression of some reprogramming genes. They found that about 10.8 percent of the stem cells took up the minicircles and expressed the green fluorescent protein, or GFP, versus about 2.7 percent of cells treated with a more traditional DNA plasmid.
      
When the researchers isolated the GFP-expressing cells and grew them in a laboratory dish, they found that the minicircles were gradually lost over a period of four weeks. To be sure the cells got a good dose of the genes, they reapplied the minicircles at days four and six. After 14 to 16 days, they began to observe clusters of cells resembling embryonic stem cell colonies - some of which no longer expressed GFP.
      
They isolated these GFP-free clusters and found that they exhibited all of the hallmarks of induced pluripotent cells: they expressed embryonic stem cell genes, they had similar patterns of DNA methylation, they could become multiple types of cells and they could form tumors called teratomas when injected under the skin of laboratory mice. They also confirmed that the minicircles had truly been lost and had not integrated into the stem cells' DNA.
      
Altogether, the researchers were able to make 22 new iPS cell lines from adult human adipose stem cells and adult human fibroblasts. Although the overall reprogramming efficiency of the minicircle method is lower than that of methods using viral vectors to introduce the genes (about 0.005 percent vs. about 0.01-0.05 percent, respectively), it still surpasses that of using conventional bacterial-based plasmids. Furthermore, stem cells from fat, and, for that matter, fat itself, are so prevalent that a slight reduction in efficiency should be easily overcome.

Adapted from the Stanford University School of Medicine announcement.

New Form of Stem Cell Communication Rescues Diseased Neurons

Researchers using mouse models have determined that transplanted stems cells, when in direct contact with diseased neurons, send signals through specialized channels that rescue the neurons from death. These direct cell-to-cell connections may also play a role in normal development by laying down the blueprint for more mature electrical connections between neurons and other cells.

While it was already known that stem cells will seek out diseased cells in the brain, this international research group of scientists showed -- both in tissue culture and in mice -- that the stem cells actively bring diseased neurons back from the brink via cross-talk through gap junctions, the connections between cells that allow molecular signals to pass back and forth. The international team included researchers from Sanford-Burnham Medical Research Institute (Sanford-Burnham, formerly Burnham Institute for Medical Research), the Karolinska Institutet, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School and Université Libre de Bruxelles.

Significantly, the stem cells do not need to differentiate into the specific type of neuron to provide this therapeutic effect.

Possibility Of Embryonic Stem Cell Transplant Rejection Narrowed

Researchers have discovered a new strategy for making embryonic stem cell transplants less likely to be rejected by a recipient's immune system. The new strategy involves fusing bone marrow cells to embryonic stem cells. Once fused, the hybrid cells have DNA from both the donor and recipient, raising hopes that immune rejection of embryonic stem cell therapies can be avoided without drugs.

"Our study shows that transplanted bone marrow cells fuse not only with bone marrow cells of the recipient, but with non-hematopoietic cells, suggesting that if we can understand the process of cell fusion better, we may be able to target certain organ injuries with the patient's own bone marrow cells and repair the tissues," said Nicholas Zavazava, M.D., Ph.D., a University of Iowa researcher involved in the work.

Although the study holds promise for future embryonic stem cell therapies, the results may be even more far reaching. Zavazava and colleagues used two different mouse strains, one as the donor and the other as the recipient. When bone marrow cells were engrafted into the recipient, they tested for the presence of both donor and recipient cells and found three different types of cells: donor cells, recipient cells, and fused cells that had DNA from the donor and recipient. They then discovered that these cells could fuse with many different types of cells in addition to embryonic stem cells, including those from the liver, kidney, heart, and gut. Although more work is necessary to determine the exact clinical outcomes, the discovery raises the possibility that bone marrow cells could be fused to transplant organs to reduce the likelihood of rejection. They could also be fused to failing organs to support regeneration.

Adapted from the Federation of American Societies for Experimental Biology announcement.

Researchers Transform Mouse Skin Cells Into Neurons, Skipping Induced Pluripotent Stem Cell Stage

The future of regenerative medicine continues to depend on the type of stem cell that is proven most effective, most scalable, and most time and cost efficient to produce.  Approaches include embryonic stem cells, adult stem cells, Induced pluripotent stem cells, from both autologous and allogeneic sources.  One of our Sector Companies, International Stem Cell Corp., is attempting to create a stem cell bank based on parthenogenic stem cells derived from unfertilized eggs (oocytes).  Such a bank would have the following advantages:

1. A scalable bank would contain a manageable number of stem cell lines that will be immunological matches for large patient populations of different ethnic origin.


2. Unlike induced pluripotent stem (iPS) cells these would not involve extensive gene manipulation, which to this point in time have largely unknown biological impact.

We point this out in order to ask ourselves what the potential impact on such a stem cell bank might be from new study results obtained by researchers at Stanford University.  Since human iPS cells were first created in late 2007, the emphasis has been on developing these cells in a faster, cheaper way that also provides safe and predictable biological results when used in regenerative therapies.

But what if the iPS phase can be skipped entirely?  Will adult cells converted, for example, directly  into nerve cells be an eventual solution to Parkinson's Disease?  Or will parthenogenic, or some other more basic, more embryonic-like, cell provide the answer.  Perhaps both will be a solution and success in the market, as well as in therapy, will be a function of efficiency from origin to therapeutic use, and resultant lower cost. Perhaps neither will be universally useful in general therapy, but will be more effective for therapies in particular parts of the body.  At this stage no one knows for sure.  What we do know is that knowledge is expanding rapidly as shown in this current Stanford study.

Stanford researchers have succeeded in transforming mouse skin cells in a laboratory dish directly into functional nerve cells with the application of just three genes. The cells make this transition without first becoming a pluripotent type of stem cell.

Mesenchymal Stem Cells: A New Understanding Of How We Age

Throughout adulthood stem cells work to replace mature cells lost to turnover, injury or disease. Some of the genes responsible for keeping stem cells active and productive modify the chromatin, the complex combination of DNA and fibers that make up chromosomes.

Now, researchers from the Sbarro Institute for Cancer Research and Molecular Medicine at Temple University and the Human Health Foundation in Spoleto, Italy have studied the impact of MECP2 on mesenchymal stem cells, or MSCs, multipotent stem cells that can differentiate into a variety of cell types.  MECP2 is one of the chromatin modifier genes whose mutations underlie RETT syndrome, a severe X-linked neurodevelopmental disorder.

The study's conclusion is that inhibition of MECP2 induces senescence, or aging, in MSCs. In general, MSCs are of particular interest to researchers, because of the multiple roles they perform (They are the stem cell utilized in stem cell therapies being developed by Aastrom Biosciences, Athersys Inc., Opexa Therapeutics and Osiris Therapeutics, among others) . MSCs support hematopoiesis, or blood production, and contribute to the maintenance of many organs and tissues. Their aging has profound consequences on body physiology.

“Our studies suggest that MECP2 is a factor whose expression must be tightly regulated to avoid alteration in the cell’s function,” said Dr. Umberto Galderisi, Department of Experimental Medicine, Biotechnology and Molecular Biology Section, Second University of Naples, Italy and lead author of the study.

“Studies on in vitro stem cell senescence (aging) can be of interest in order to dissect molecular events leading to a decline of stem cell functions with advancing of age,” said Dr. Antonio Giordano, director of the Sbarro Institute and the Center for Biotechnology at Temple University.

Adapted from the S.H.R.O. announcement.

Researchers Generate Abundant Functional Blood Vessel Cells From Embryonic And Induced Pluripotent Stem Cells

Researchers have developed a new technique -- and described a novel mechanism -- for turning human embryonic and pluripotent stem cells into plentiful, functional endothelial cells, which are critical to the formation of blood vessels. Endothelial cells form the interior "lining" of all blood vessels and are the main component of capillaries, the smallest and most abundant vessels.

The new approach allows scientists to generate virtually unlimited quantities of durable endothelial cells -- more than 40-fold the quantity possible with previous approaches.

"This technique is the first of its kind with serious potential as a treatment for a diverse array of diseases, especially cardiovascular disease, stroke and vascular complications of diabetes," said Dr. Shahin Rafii, the study's senior author and Arthur B. Belfer Professor in Genetic Medicine and co-director of the Ansary Stem Cell Institute at Weill Cornell Medical College. Dr. Rafii is also an investigator of the Howard Hughes Medical Institute.

Researchers first screened for molecular factors that come into play when stem cells turn into endothelial cells. Their findings led them to a strategy that significantly boosts the efficiency of producing these cells.

They then tracked the differentiation process in real-time using a green fluorescent protein marker developed by Dr. Daylon James, the study's first author and assistant research professor in the Department of Reproductive of Medicine at Weill Cornell Medical College. They found that when they exposed stem cells to a compound that blocks TGF-beta (a growth factor involved in cell specialization) at just the right time during cell culturing, the propagation of endothelial cells dramatically increased.

Molecule Identified That Inhibits Stem Cell Differentiation

It turns out that stem cells have need for long-term memory to help them know who they are and what they should become. Researchers at the Stanford University School of Medicine have now identified a molecule involved in keeping skin stem cells on the straight and narrow path.

“We’re starting to understand the molecular mechanism of cellular memory,” said Paul Khavari, MD, PhD, professor of dermatology. “How a stem cell remembers what it is, and why it might go astray.”

The molecule, called DNMT1, helps the stem cells know whether to self-renew to create more stem cells, or to differentiate into specialized, non-dividing adult skin cells. It’s important because too much self-renewal can lead to cancer, and too little can inhibit wound healing.

Much ado is made over pluripotent cells — such as embryonic stem cells and their laboratory doppelgangers, induced pluripotent stem (iPS) cells — which have the potential to differentiate into any of the body’s different cell types. But adult stem cells, while more limited in their ability to create new types of cells, still have important roles in the body. They’re particularly vital in skin, blood and other tissues that must constantly regenerate new cells.

Biologists Develop Efficient Genetic Modification Of Human Embryonic Stem Cells

One of the non-ethical problems with embryonic stem cell research has been the lack of efficient ways to study genetics using these cells.  Now, using bacterial artificial chromosomes  (BACs) to swap in defective copies of genes, researchers have successfully transferred a defective copy of the gene p53, which suppresses cancer, into a human embryonic stem cell line.

"This will help open up the whole human embryonic stem cell field. Otherwise, there are really few efficient ways you can study genetics through them," said Yang Xu, professor of biology at the University of California, San Diego who directed the research.

BACs are synthesized circles of human DNA, which bacteria will replicate just like their own native chromosomes. Commercially available BACs can be modified within bacterial cells to insert altered copies of specific genes. Once the modified BACs are introduced into human cells, they will sometimes pair up with a matching segment of a human chromosome and swap segments of DNA, a process called homologous recombination.

Ethnic Origin Of Stem Cells Found Important To Safety And Effectiveness Of Specific Future Drugs

Analysis of a variety of human embryonic stem cell lines determined that the cells originated largely from Caucasian and East Asian populations, with little representation from populations originating in Africa.  The lines analyzed are currently in use in research laboratories around the world.  In response to these results, scientists from Scripps Research Institute used skin cells from an individual of West African Yoruba heritage to create a new stem cell line, the first to carry the genetic profile of this ethnic group.

Why is this important? Research has shown that discordance between the ethnic origin of organ donors and recipients can influence medical outcomes for tissue transplantation, and that the safety and effectiveness of specific drugs can vary widely depending on ethnic background.

"Ethnic origin is a critical piece of information that should come with every cell line," said Scripps Research Professor Jeanne Loring, who is senior author of the paper resulting from this research. "Everyone who works with stem cells should be doing this kind of analysis."

One of our Sector Companies, International Stem Cell Corp. (ISCO) announced a collaboration with Dr. Jeanne Loring and Scripps Research in November of last year.  ISCO has developed a parthenogenetic homozygous stem cell line and is hopeful that this research will provide immune-matched stem cells for human transplant which will allow the building of a "stem cell bank" that could offer on-demand delivery of stem cells matched to a patient’s own immune system.

"Knowing that a big push in the future is using stem cell lines in the clinic and in drug development, there's a need to have an ethnically diverse population of cells," added Louise Laurent, assistant professor at the University of California, San Diego (UCSD) and research associate at Scripps Research, who is first author of the paper with Caroline Nievergelt, also an assistant professor at UCSD.

Umbilical Cord May Be Source Of Far Greater Number Of Stem Cells Than Previously Thought

Just as the blood that goes through the umbilical cord provides precursor cells to treat blood disorders, the tissue of the umbilical can easily supply stem cells that could one day provide therapeutic options for muscle and bone disorders according to a new study.

In the study, Umbilical cord tissue cells were obtained from the gelatinous material in the cord known as Wharton's jelly and from blood vessel walls. These cells can be expanded to greater number, are remarkably stable and might not trigger strong immune responses, according to senior investigator Bridget M. Deasy, Ph.D., assistant professor in the Department of Orthopaedic Surgery, Pitt School of Medicine.

"Our experiments indicate also that at least 21 million stem cells, and possibly as many as 500 million, could be banked from a single umbilical cord after the birth of a baby," said Deasy. "So, the cord could become an accessible source of a multitude of stem cells that overcome many of the restrictions, such as limited quantity as well as donor age and donor sex issues, that come with other adult stem cell populations."

Immune System Protein Found To Be Important In Reprogramming Adult Cells Into iPS Cells

Researchers at Stanford’s School of Medicine have discovered a protein required to quickly and efficiently reprogram human skin cells to express embryonic stem cell genes. The finding could eliminate a major bottleneck in the generation of iPS and embryonic stem cells — that of removing molecular tags called methyl groups from specific regions of cellular DNA. Without this process of demethylation, the stem cell genes are silent in adult, or differentiated, cells.

Since the first human skin cell was reprogrammed into an embryonic-like cell in 2007, scientists have believed there is much promise for induced pluripotent stem cells, considering them to have the potential to be used to repair damaged tissue and treat the ravages of disease.  The problem has been that making these so-called iPS cells is both time-consuming and inefficient.

“The mechanism of DNA demethylation in mammals has eluded us for decades,” said Helen Blau, PhD, the Donald E. and Delia B. Baxter Professor and member of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine. “Now we’ve identified a protein involved in targeted DNA demethylation, and we’ve also shown that it’s critically important in reprogramming adult cells to function more like their stem cell predecessors.” Blau is the senior author of the research.

The researchers used a high-efficiency cell fusion strategy to identify the protein, called activation-induced cytidine deaminase, or AID. This protein is most commonly known for its involvement in the immune system in generating germ-fighting antibodies. But Blau and her colleagues uncovered an unexpected presence — and an unanticipated role — of the protein in embryonic stem cells.

Researchers anticipate that harnessing the activity of AID and other proteins with which it may work could revolutionize the generation of iPS cells. It may also help in creating embryonic stem cells through a process called somatic cell nuclear transfer. Both methods rely on the removal of the molecular tags from specific regions of DNA.

Researchers Demonstrate Stem Cell Therapy To Kill HIV

Researchers from  have for the first time demonstrated that human blood stem cells can be engineered into cells that can target and kill HIV-infected cells — a process that potentially could be used against a range of chronic viral diseases.

The study, accomplished by UCLA AIDS Institute researchers and colleagues, provides a proof-of-principle that human stem cells can be engineered into the equivalent of a genetic vaccine.

"We've demonstrated in this proof-of-principle study that this type of approach can be used to engineer the human immune system -- particularly the T-cell response -- to specifically target HIV-infected cells," said lead investigator Scott G. Kitchen, assistant professor of medicine in the division of hematology and oncology at the David Geffen School of Medicine at UCLA and a member of the UCLA AIDS Institute. "These studies lay the foundation for further therapeutic development that involves restoring damaged or defective immune responses toward a variety of viruses that cause chronic disease, or even different types of tumors."

So It Turns Out Stem Cells Have To Battle For Space?

Apparently cells constantly compete with one another for space and dominance.  To tackle the stem cell competition quandary, a research team looked at fruit fly testes where two different stem cells exist: germline stem cells which give rise to sperm, and somatic stem cells which develop into non-reproductive cell types.

Using genetics, the researchers grew flies lacking the SOCS protein, which controls other molecules that promote stem cell growth. SOCS normally ensures that the right numbers of stem cells are present in the stem cell niche, a region at the far end of the fly testis where new cells are born. In a normal testis, the germline stem cells are surrounded by somatic stem cells at a ratio of about one germline stem cell for every two somatic stem cells.

Researchers from the Johns Hopkins School of Medicine isolated testes from flies lacking SOCS and, under a microscope, counted the number of germline stem cells and somatic stem cells. They found that nearly half of the germline stem cells were gone and the somatic stem cells appeared to be occupying that space.

"The somatic stem cells almost look like they've invaded the niche area," says Melanie Issigonis, a graduate student in the Biochemistry, Cellular, and Molecular Biology graduate program at Johns Hopkins. "I saw that image and said, 'Wow, it's right there. Germline stem cell loss.'"

To figure out where the lost germline stem cells went and how they lost the battle for space, the research team returned to the microscope. This time, they examined the cells for whether they contained integrin, a protein that helps cells stick to each other. They found that somatic stem cells from flies lacking SOCS seemed to contain more integrin than somatic stem cells from flies with functional SOCS. According to Matunis, it's the increase in integrin that allows somatic stem cells to gain the upper hand because they can stick to the niche better than neighboring germline stem cells.

Though the somatic stem cells were invading the niche, germline stem cells were not dying. In the microscope images, the team found that all remaining germline stem cells still looked alive and healthy, but had simply been elbowed out of their niche by somatic stem cells. Says Matunis, no matter how healthy a germline stem cell is, if it cannot stick, it will eventually be pushed out of the niche by somatic cells. Issigonis found the discovery remarkable: "The germline stem cells are perfectly fine," she says. "They're just leaving the niche and differentiating."

"Our work exemplifies how one signal coordinately maintains two types of stem cells in a single niche, or microenvironment," says Erika Matunis, Ph.D., associate professor of cell biology at the Johns Hopkins School of Medicine. "What we found may emerge as common themes of mammalian stem cell niches as they become better characterized."

The research team believes this model can be applied to other stem cell niches such as cancer. Just like the somatic stem cells overrunning the fly testes, cancer stem cells in mammalian systems become a danger when they become the stickiest cell in the niche. In both cases, the important control protein, SOCS, is lost. Knowing what is necessary for some stem cells to thrive and others to dwindle could have great importance to understanding the roots of stem cell diseases.  

Adapted from the Johns Hopkins announcement.

Another Twist On Potential Mesenchymal Stem Cell Therapies

In terms of our Sector Companies, Aastrom Biosciences, Athersys, Inc., Opexa Therapeutics and Osiris Therapeutics, all are relying on some combination of mesenchymal stem cells and various growth factors as potential stem cell therapies.  Osiris is further along in clinical trials and has had its share of problems in demonstrating the efficacy of mesenchymal cells in attempting extremely difficult therapeutic solutions.

Osiris has sponsored a study led by cardiologist Joshua M. Hare, director of the stem cell institute at the University of Miami Miller School of Medicine, with colleagues at nine other medical centers, about which results were released yesterday. "Stem cell-treated patients had ... significant improvements in heart, lung, and global function,” Hare said in a news release. "Echocardiography showed improved heart function, particularly in those patients with large amounts of cardiac damage."

It's not the first time heart attack patients have been treated with stem cells. But previous studies used bone marrow cells extracted from the patient and then injected directly into the heart. The Hare study enrolled 53 heart attack patients treated within 10 days of their first heart attack. None of the patients required bypass. A fourth of the patients got infusions of an inactive placebo; the others got various doses of the Prochymal cells.

"Stem cell-treated patients had ... significant improvements in heart, lung, and global function,” Hare said in a news release. "Echocardiography showed improved heart function, particularly in those patients with large amounts of cardiac damage."

At another point on the mesenchymal spectrum, the use of mesenchymal stem cells (MSCs, or multipotent stem cells that can differentiate into a variety of cell types) has been claimed to be a promising biological therapy that could be used to treat complicated fractures and other disorders in the skeleton. These cells constitute a unique population of adult stem cells that can readily be isolated from various sites in the human body, especially from bone marrow and adipose (fat) tissues. Following isolation, MSCs can be utilized to repair a variety of injured tissues including bone, cartilage, tendon, intervertebral discs and even the heart muscle.

The conventional method of MSC isolation, using prolonged periods of growth in designated incubators, has proved to be laborious, costly and also possibly injurious to the therapeutic quality of the cells. Therefore, an alternative method involving the immediate use of these stem cells was an unmet need in the field of regenerative medicine.

Now, a Hebrew University group has developed a technology called immuno-isolation in which MSCs are sorted out from the other cells residing in a bone marrow sample, using a specific antibody. In the resultant paper it was shown that the immuno-isolated cells could be immediately used to form new bone tissue when implanted in laboratory animals, without having to undergo a prolonged incubator growth period.

Autologous Stem Cell Transplants Can Treat Heart Disease Study Finds

Out of the estimated 1 million people in the U.S. who suffer from chronic, severe angina — chest pain due to blocked arteries — about 300,000 cannot be helped by any traditional medical treatment such as angioplasty, bypass surgery or stents. This is called intractable or severe angina, the severity of which is designated by classes. This study included class 3 or 4 patients, meaning they had chest pain from normal to minimal activities, such as from brushing their teeth or even resting.

Consisting of 25 sites totalling 167 subjects, this Phase II study claims to be the largest national stem cell study for heart disease.   it also claims to be the first to show evidence that transplanting a potent form of adult stem cells into the heart muscle of subjects with severe angina results in less pain and an improved ability to walk.  We use the word 'claims' not to disparage in any way these results achieved by Feinberg School of Medicine at Northwestern University researchers. It is used simply because several other studies, perhaps smaller, have achieved similar positive results.

In this 12-month, double-blind trial, autologous (taken from the subject) purified stem cells (hematopoietic stem cells), referred to as CD34+ cells, were injected into the subjects' hearts in an effort to spur the growth of small blood vessels that constitute the microcirculation of the heart muscle. Researchers believe the loss of these blood vessels contributes to the pain of chronic, severe angina.

Unraveling The Mechanisms Behind Organ Regeneration

The search for the holy grail of regenerative medicine—the ability to "grow back" a perfect body part when one is lost to injury or disease—has been under way for years, yet the steps involved in this seemingly magic process are still poorly understood.

Some time ago we posted about Max Planck Institute research on Salamanders.  Salamanders regrow lost limbs and Elly Tanaka at Planck has been studying how they do so. Tanaka and colleagues found that salamander regeneration begins when a clump of cells called a blastema forms at the tip of a lost limb. From the blastema come skin, muscle, bone, blood vessels and neurons, ultimately growing into a limb virtually identical to the old one.

But here's the surprise: Rather than having their cellular clocks fully reset and reverting to an embryonic state, cells in the salamanders’ stumps became slightly less mature versions of the cells they’d been before.  In other words they don't revert to pluripotency.

Now researchers at the Salk Institute for Biological Studies have identified an essential cellular pathway in zebrafish that paves the way for limb regeneration by unlocking gene expression patterns last seen during embryonic development. They found that a process known as histone demethylation switches cells at the amputation site from an inactive to an active state, which turns on the genes required to build a copy of the lost limb.

Salk Institute researchers, lead by Juan Carlos Izpisúa Belmonte Ph.D, used zebrafish, a small fish from the minnow family, to study limb regeneration. "If you amputate the tail of the zebrafish, it regenerates in about a week, seemingly with no effort and leaving no scar," explains Scott Stewart Ph.D. "What's more, it regenerates a perfect copy and—like growing grass—it will do this over and over again." In other words, the zebrafish has the same regenerative capacity as the salamander.

Johns Hopkins and Harvard Add To Previous 2009 Findings On Differnces Between Induced Pluripotent And Embryonic Stem Cells

In July 2009, UCLA and Broad Institute researchers analyzed induced pluripotent stem cell lines derived with newer methods that didn't require integration of the reprogramming factors. Their analysis showed different molecular signatures between iPS cells and their embryo-derived counterparts, and these signatures showed a significant degree of overlap with those generated with integrative methods.

"We can’t explain this, but it appears something is different about iPS cells and embryonic stem cells,” said Bill Lowry, a researcher with the Broad Stem Cell Research Center. “The differences are there, no matter whose lab the cells come from, whether they’re human or mouse cells or the method used to derive the iPS cells. Perhaps most importantly, many of these differences are shared amongst lines made in various ways.”

Then in September came work regarding the differences between induced and embryonic stem cells done by UCSD and the Salk Institute. 

By creating iPSCs from human neural stem cells without the use of viruses, UCSD and Salk scientists learned something that moved toward an explaination of some of the questions raised by the UCLA/Broad Institute results. What they found was this: While the genetic transcriptional profile of the new iPSCs was closer to that of embryonic stem cells than to human neural stem cells, the iPSCs still carried a transcriptional "signature" of the original neural cell.

"While most of the original genetic memory was erased when the cells were reprogrammed, some was retained," said lead researcher Alysson R. Muotri, UCSD Stem Cell Program researcher who added that in the past it wasn't known if this retinue was caused by the use of viral vectors.

Although genetically identical to the mature body cells from which they are derived, induced pluripotent stem cells (iPSCs) are notably special in their ability to self-renew and differentiate into all kinds of cells. Now researchers from Johns Hopkins and Harvard have detected a remarkable if subtle molecular disparity between the two: Turns out they have distinct "epigenetic" signatures; that is, they differ in what gets copied when the cell divides, even though these differences aren't part of the DNA sequence.

Gladstone And Stanford To Develop Induced Pluripotent Stem (IPS) Cells For Cardiac Stem Cell Treatments

Researchers from the Gladstone Institute of Cardiovascular Disease (GICD), led by Director Deepak Srivastava, MD, will collaborate with a Stanford research team led by Robert Robbins, MD, professor and chair of cardiothoracic surgery, to investigate the use of induced pluripotent stem cells (iPS cells) to repair damaged heart muscle. The research consortium will be funded by the National Heart, Lung and Blood Institute (NHLBI).

iPS cells result from the “reprogramming” of adult cells into cells closely resembling embryonic stem cells. Like ESCs, they can develop into any cell type in the body. This technology was developed by Gladstone investigator Shinya Yamanaka, MD, PhD. the 2009 Lasker Award Recipient for Biomedical Research.

"Important gaps remain in our understanding of stem and progenitor cells," said NHLBI director Elizabeth Nabel, MD. "This consortium holds great promise to expand our knowledge and uncover therapeutic applications of great public impact.”

Neural Stem Cells In Mice Affected By Gene Associated With Longevity

A gene associated with longevity in roundworms and humans has been shown to affect the function of stem cells that generate new neurons in the adult brain.  The study suggests the gene may play an important role in maintaining cognitive function during aging.

Unlike skin or intestine, the adult human brain doesn’t make a lot of new cells. But those it does are critical to learning, memory and spatial awareness. To meet these demands, the brain maintains two small caches of neural stem cells. In each cache, stem cells can self-renew and give rise to neurons and other cells known as oligodendrocytes and astrocytes. Properly balancing these functions allows the generation of new nerve cells as needed while also maintaining a robust neural stem cell pool.

“It’s intriguing to think that genes that regulate life span in invertebrates may have evolved to control stem cell pools in mammals,” said Anne Brunet, PhD, assistant professor of genetics at the Stanford University School of Medicine.

As mice and other organisms age, the pool of neural stem cells in the brain shrinks and fewer new neurons are generated. These natural changes correlate with the gradual loss of cognitive ability and sensory functions that occur as we approach the end of our lives. However, the life span of some laboratory animals can be artificially extended by mutating genes involved in metabolism, and some humans outlive their life expectancy (about 70 years for someone born in 1960) by decades. Brunet and her colleagues wanted to know why.

Small Molecule Platform For Commercial-Scale Reprogramming Announced

Fate Therapeutics, Inc. claims to have significantly improved the speed and efficiency of reprogramming adult cells into human induced-pluripotent stem cells (iPSCs) using a combination of small molecules.

The discovery, which was made by Sheng Ding, Ph.D. under a research collaboration between Fate Therapeutics and The Scripps Research Institute (TSRI), represents a more than 200-fold improvement in reprogramming efficiency and reduces the reprogramming period to two weeks as compared to methods using only the four reprogramming factors (Oct 3/4, Sox2, Klf4 and c-Myc).

This advancement has implications for the creation of "pharmaceutical grade" iPSCs, reprogrammed cells that can be produced without genetic modification at commercial scale quantity, quality and consistency.

China And California Announce Collaboration To Advance Stem Cell Research toward Stem Cell Therapy

In a step taken to broaden the potential pool of expertise that can be applied toward research in a specific area, a new agreement between the California Institute for Regenerative Medicine (CIRM) and the Chinese Ministry of Science and Technology (MOST) will make it easier for researchers in both California and China to obtain joint stem cell research funding. 

Researchers in both jurisdictions will be invited to form teams that will apply jointly for funding through a process that builds upon routine CIRM and MOST procedures. For those that are approved, CIRM will fund the California researchers and MOST will fund the Chinese researchers.

“One of CIRM’s primary goals is to accelerate the field of stem cell research as a whole, and in some instances we can do this more effectively through collaborations that involve the best scientific endeavors, regardless of geography,” said Alan Trounson, President of CIRM. “China is developing a major national program in stem cells and regenerative medicine that can be effectively matched with California’s excellence in stem cell science that is rapidly evolving in academic and biotechnology settings. I would expect major developments for patients to occur through this new partnership.”

Study Gains New Insight Into Stem Cell Regenerative Process And Organism Death

Stem Cell Regenerative Medicine is the controlled differentiation of stem cells into the functionally defined cells required to mend or replace sick or damaged tissue or organs.  Our bodies do this naturally, generating rather than regenerating a complete body from a single cell, growing and maintaining the body during our early years, maintaining it during adulthood, and then somehow allowing the process to deteriorate as the body ages and finally dies.

Shedding some new light on the process of aging and death, It turns out that the loss of two proteins,  the tumor-suppressor protein p53 and the DNA-maintenance protein ATR, results in tissues deteriorating rapidly generally resulting in death.

Essentially, argued senior author Eric Brown, PhD, Assistant Professor of Cancer Biology at the University of Pennsylvania School of Medicine, the findings highlight the fact that day-to-day maintenance required to keep proliferative tissues like skin and intestines functional is about more than just regeneration, the stem cell-based process that forms the basis of tissue renewal. It's also about housekeeping, the clearing away of damaged cells.

Harvard Stem Cell Research Team Reports Major Step In Producing Induced Pluripotent Stem Cells

Finding a way to produce safe iPS cells that are the biological equivalent of embryonic stem cells is especially important because the cells can then be created from the cells of individual patients for transplantation into those patients. Once accomplished, a patient with Parkinson’s disease might be treated with neurons created from his own cells, theoretically eliminating the need for immunosuppressive drugs, or the possibility of rejection of the transplanted cells. Similarly, patient-specific iPS cells could be used to create muscle for damaged hearts, or other individualized treatments.

A team of Harvard Stem Cell Institute (HSCI) researchers has made a major advance toward producing induced pluripotent stem cells, or iPS cells, that are safe enough to use in treating diseases in patients.

“We’re halfway home, and remarkably we got halfway home with just one chemical,” said Kevin Eggan, a Harvard Stem Cell Institute principal faculty member who is the senior author of this study.

Bioengineered 'Patch' Formed To Create Heart Stem Cell Treatment

In addition to combining appropriatly selected stem cells with necessary growth factors, one of the problems in coming up with stem cell treatments has been the necessity of providing a 'structure,' or 'scaffold' to give cells and growth factors a framework that fools them into thinking they're in a natural environment for growth.  This is particularly true where organ regeneration is concerned.  While generally in the very early stages, organ regeneration remains the holy grail of stem cell research.  A fair amount of the initial effort in this regard, both by academic labs and both private and publicly traded stem cell companies, has been directed to regenerating portions of the heart, in particular that damaged by scar tissue.

To that end, Duke University bioengineers have created a novel mold of unique design to fashion a three-dimensional "patch" made up of heart muscle cells, known as cardiomyocytes. The new tissue grown in the mold exhibited the two most important attributes of heart muscle cells -– the ability to contract and the ability to conduct electrical impulses. The mold looks much like a piece of Chex cereal in which researchers varied the shape and length of the pores to control the direction and orientation of the growing cells.

As a result, Duke bioengineers believe they have taken an important first step toward growing a living "heart patch" to repair heart tissue damaged by disease.

NHLBI Awards $170 Million To Create The Progenitor Cell Biology Consortium And Fund Related Stem Cell Research

The National Heart, Lung, and Blood Institute (NHLBI), one of the National Institutes of Health, has awarded $170 million to be paid over seven years to 18 teams of research scientists to develop the high-potential field of stem and progenitor cell tools and therapies.

The awards create the NHLBI Progenitor Cell Biology Consortium, which will bring together researchers from the heart, lung, blood, and technology research fields. A seven-year project, the consortium assembles nine research hubs with multidisciplinary teams of principal investigators and an administrative coordinating center to focus on progenitor cell biology.

“This is a grand experiment,” said Irving Weissman, MD, director of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine. “By forming this consortium, the NHLBI is encouraging a dialogue between scientific groups that would otherwise be competing with one another. I am very excited, and have high hopes that this will accelerate the understanding of stem and progenitor cells to the point of medical therapies.”

Umbilical Cord Blood Found To Be Ready Source For Off-The-Shelf, Patient-Specific, Induced Pluripotent Stem cells

Umbilical cord blood cells can successfully be reprogrammed to function like embryonic stem cells, thus setting the basis for a comprehensive bank of tissue-matched, cord blood-derived induced pluripotent stem (iPS) cells for off-the-shelf applications.

Worldwide, there are already more than 400,000 cord blood units banked along with immunological information. Cells found in umbilical cord blood contain a minimal number of cell mutations and possess the immunological immaturity of newborn cells, allowing the HLA donor-recipient match to be less than perfect without the risk of immune rejection of the transplant.

Human leukocyte antigen (HLA) typing is used to match patients and donors for bone marrow or cord blood transplants. HLAs are special surface markers found on most cells in the body and help the immune system to distinguish between "self" and "non-self." Selecting common HLA haplotypes from among already banked cord blood units to create iPS cell would significantly reduce the number of cell lines needed to provide a HLA match for a large percentage of the population.

Since the first adult cells were converted into iPS cells, they have generated a lot excitement as an uncontroversial alternative to embryonic stem cells and as a potential source for patient-specific stem cells. Unfortunately, taking a patient's cells back in time is not only costly, but could be difficult when those cells are needed right away to mend injured spinal cords or treat acute diseases, and outright impossible when the effects of aging or chronic disease have irrevocably damaged the pool of somatic cells.

Researchers Turn Back Clock On Old Human Muscle, Restoring Its Ability To Repair And Rebuild Itself

Previous research in animal models has revealed that the ability of adult stem cells to do their job of repairing and replacing damaged tissue is governed by the molecular signals they get from surrounding muscle tissue.  It has also suggested that those signals change with age in ways that preclude productive tissue repair.

Prior studies have also shown that the regenerative function in old stem cells can be revived given the appropriate biochemical signals.  What was not clear until this study was whether similar rules applied for humans.  Unlike humans, laboratory animals are bred to have identical genes and are raised in similar environments. Moreover, the typical human lifespan lasts seven to eight decades, while lab mice are reaching the end of their lives by age 2.

In a new study lead by Professor Irina Conboy, faculty member in the graduate bioengineering program at the University of California, Berkeley, researchers have identified critical biochemical pathways linked to the aging of human muscle. By manipulating these pathways, they were able to turn back the clock on old human muscle, restoring its ability to repair and rebuild itself.

"Our study shows that the ability of old human muscle to be maintained and repaired by muscle stem cells can be restored to youthful vigor given the right mix of biochemical signals," said Conboy.  "This provides promising new targets for forestalling the debilitating muscle atrophy that accompanies aging, and perhaps other tissue degenerative disorders as well."

Stem Cell Treatments To Create Replacement Cartilage Grow Closer To Reality

Following up on previous research at Hopkins described below, Jennifer Elisseeff Phd, speaking this week at the 2009 World Stem Cell Summit in Baltimore, described how she and her colleagues have guided stem cells to patch up patients' damaged and deteriorating knee cartilage.

"And their function is better," she said. "They might not be star athletes, but they can go out and do something like playing doubles tennis," which their injuries had made impossible before treatment.

The hydrogel is placed in the injured cartilage in a honey-like consistency, solidified with ultraviolet light, and attached to the tissue with a "glue" the lab developed. The porous material absorbs the blood and marrow and stem cells released from micro-fractures, guiding it into the shape needed to fill the hole and providing a fertile place to grow.

In a few months, the gel degrades, leaving -- if things work out -- new cartilage formed by the stem cells.

In their first clinical trial, conducted in Europe to take advantage of lower costs and easier regulatory hurdles, Elisseeff's team treated 15 adults who had at least a two-year history of knee cartilage injuries.

One year after treatment, the cartilage defects were still 89 percent filled on average, compared with the 50 percent expected with traditional treatments. And based on ratings of pain reduction and restored function, treatments using the new biogels and stem cells did twice as well as those getting micro-fracture treatments alone.

Embryonic Stem Cell Marker Expression in Human Mesenchymal Stem Cells Differs According to Source

We recently posted about the differences between Induced Pluripotent Stem cells and Embryonic Stem Cells. So a discussion of the differences in Mesenchymal Stem Cells according to source seems timely.  There are company and University research projects, even clinical trials, based on a wide variety of adult stem cells, some of them mesenchymal, some of them not.  It seems odd at times that adult stem cells from different origins are being applied to the same injury or disease problem.

For example, there are clinical studies on various types of heart problem using either adipose or bone marrow derived stem cells as a potential repair or replacement medium.  These are adult stem cells and they're not pluipotent unless they're induced to be.  Adipose (fat) stem cells exist to repair and replace fat or soft tissue and bone marrow stem cells exist to repair and replace the blood and immune system.  To make the point further, you shouldn't get a nerve cell out of either of them.

What they seem, or have seemed, to have in common is that both bone marrow and adipose, among other tissues in the body, generate Mesenchymal stem cells.  The most famous current clinical tests using Mesenchymal cells are those being conducted by Osiris Therapeutics.  At the moment they're having some difficulty  with these studies as is well documented by the company's drop in stock price in the last month.

According to Osiris Therapeutics, mesenchymal cells (MSCs) can selectively differentiate, based on the tissue environment, into various tissue lineages, such as muscle, bone, cartilage, marrow stroma, tendon or fat. In addition, MSCs have anti-inflammatory properties and can prevent fibrosis or scarring. And, as we've just noted, they are common to both adipose and bone marrow. In other words, these are pretty special stem cells, or certainly seem to be.

But are adipose derived MSCs exactly the same as bone marrow derived MSCs? A new study by the University of Latvia attempts to shed light on this question in a finding that says they are not.

Understanding The Differences Between Induced Pluripotent Stem Cells And Embryonic Stem Cells

In July we posted about genetic differences found between Induced Pluripotent Stem (iPS) cells and embryonic stem cells.  Researchers at UCLA and the Broad Stem Cell Institute had performed microarray gene expression profiles on embryonic stem cells and iPS cells to measure the expression of thousands of genes at once, creating a global picture of cellular function.

When the molecular signatures were compared, it was clear that certain genes were expressed differently in embryonic stem cells than they were in iPS cells. The researchers then compared their data to that stored on a National Institutes of Health data base, submitted by laboratories worldwide. They analyzed that data to see if the genetic profiling conducted in other labs validated their findings, and again they found overlapping but distinct differences in gene expression.

UCLA and Broad researchers then analyzed cell lines derived with newer methods that do not require integration of the reprogramming factors. Their analysis again showed different molecular signatures between iPS cells and their embryo-derived counterparts, and these signatures showed a significant degree of overlap with those generated with integrative methods.

"We can’t explain this, but it appears something is different about iPS cells and embryonic stem cells,” said Bill Lowry, a researcher with the Broad Stem Cell Research Center and a study author..“And the differences are there, no matter whose lab the cells come from, whether they’re human or mouse cells or the method used to derive the iPS cells. Perhaps most importantly, many of these differences are shared amongst lines made in various ways.”

In the latest step forward, San Diego School of Medicine and the Salk Institute for Biological Studies in La Jolla have developed a safe strategy for reprogramming cells to a pluripotent state without use of viral vectors or genomic insertions.

Rare Genetic Disease Successfully Reversed Using Bone Marrow Stem Cell Transplantation

Scripps Institute researchers have transplanted bone marrow stem cells in a treatment that successfully addressed the symptoms of cystinosis in a mouse model. The procedure virtually halted the cystine accumulation responsible for the disease and the cascade of cell death that follows.

Cystine is a byproduct of the break down of cellular components the body no longer needs in the cell's "housekeeping" organelles, called lysosomes. Normally, cystine is shunted out of cells, but in cystinosis a gene defect of the lysosomal cystine transporter causes it to build up, forming crystals that are especially damaging to the kidneys and eyes.

In the new study, the researchers found that transplanted bone marrow stem cells carrying the normal lysosomal cystine transporter gene abundantly engrafted into every tissue of the experimental mice. This led to an average drop in cystine levels of about 80 percent in every organ. In addition to preventing kidney dysfunction, there was less deposition of cystine crystals in the cornea, less bone demineralization, and an improvement in motor function.

Liposuction Excess Easily Converted To IPS Cells, Stanford Study Shows

In a finding that independently adds support to the Cellution systems manufactured by Cytori Therapeutics, one of our Sector Companies, and the TGI 1200 System (supplied by privately held Tissue Genesis' to Sector Company BioHeart Inc.), Stanford researchers have found that human fat removed during liposuction conceals versatile cells that are more quickly and easily coaxed to become induced pluripotent stem cells, or iPS cells, than are the skin cells most often used by researchers.

"We've identified a great natural resource," said Stanford surgery professor and co-author of the research, Michael Longaker, MD, who has called the readily available liposuction leftovers "liquid gold." Reprogramming adult cells to function like embryonic stem cells is one way researchers hope to create patient-specific cell lines to regenerate tissue or to study specific diseases in the laboratory.

Korean University To Distribute Puppies Of World's First Cloned Dog

Yes, we know, this is not the type of story we usually follow.  The truth?  It is apparently a first even if, in itself, the event does not advance the cause of stem cell research. Seoul National University (SNU) said the nine dogs were all fathered by Snuppy, an Afghan Hound cloned by disgraced scientist Hwang Woo-suk in 2005, who, as it turns out, may have gotten some important things right without knowing it.  According to a team led by George Daley at Harvard Stem Cell Institute, Hwang may have managed to create stem cells solely from human eggs, without fertilization with sperm. This breakthrough is possibly much more valuable than his original false claims about his work.

"Unfortunately," said Daley, "at the time they published their work they did not know what they had done so they had mistakenly isolated these parthenogenic embryonic stem cells and misrepresented them as true clones." The Daley team concluded that it is possible Hwang and his team managed to pull off the world's first human case of parthenogenesis, or 'virgin birth', a conclusion that would seem to suggest that even with good research it's preferable to know the meaning of what has been accomplished.

But we digress, so back to the puppies.  SNU says researchers used artificial insemination methods to impregnate two other cloned female Afghan Hounds called Bona and Hope to produce the puppies that were born in May 2008. The impregnation was carried out to see if reproductive systems of cloned dogs functioned normally.

Mesenchymal Stem Cells Shown To Aid Acute Lung Injury

Four companies in our Stem Cell Sector work with mesenchymal stem cells.  In the case of all four, the mesenchymal cells are taken from bone marrow. Two of the four are working on stem cell applications involving allogeneic mesenchymal cells. Those two are Athersys, Inc. and Osiris Therapeutics. The stem cell world is currently awaiting results of Osiris's Phase III acute graft versus host disease (GvHD) study. Opexa Therapeutics and Aastrom Biosciences, the other two companies working with mesenchymal cells, use autologous mesenchymal cells in their proposed stem cell treatments. 

This may be significant because UCSF scientists have demonstrated that adult human mesenchymal stem cells reverse the effects of injury in a novel human lung preparation done in the laboratory. The finding, they say, could lead to the development of stem cell therapies for patients with acute lung injury and acute respiratory distress syndrome, conditions that presently have a high rate of mortality and no pharmacological treatments.

The significance of the team’s work includes the discovery of the mechanism responsible for the therapeutic benefit and the development of a human lung-injury model that makes research of potential clinical therapies – like stem cells – possible.  Acute lung injury is a leading cause of acute respiratory failure in critically ill patients.

Induced Pluripotent Stem Cell Research Advances Prompt Unique NIH Autism Research Grant

In a quiet but firm acknowledgement of adult stem cell transplant therapy and treatment potential from Induced Pluripotent Stem Cell research, the National Institute of Health has granted Children's Hospital of Orange County (CHOC) three million dollars over five years to collect skin cells from children with autism.  The skin cells will be induced into becoming neural cells which can then be studied to gain insight into the autism spectrum and hopefully to find corrective measures.

The NIH-funded research at CHOC will apply this new technology to fibroblasts derived from patients whose autism is clinically very well-characterized, as well as those derived from individuals without the disorder.  This efficient, non-invasive method for generating autism neural stem cells from living individuals will allow research that has never been possible before.

It will allow studies of the detailed properties of the induced autism neuron; studies of sufficient statistical power to allow researchers to compare and contrast the effects of autism on the developing human brain; and studies of the influence of environmental factors on these processes. Importantly, all data generated by these investigations will be made widely available to the scientific community. The cells lines themselves will also be made available through the existing CHOC-funded stem cell repository, the NHNSCR, which Dr. Phillip H. Schwartz, Ph.D., created in 2001.

Living Cells React To Guiding Light; Advance Could Enhance Stem Cells' Power

In the world of cord blood stem cells, adult stem cell and embryonic research, or any other evolutionary arena of stem cell research, we have yet to see a contribution from the College of Optics and Photonics or like named department at a major research institution.

Now, researchers have shown for the first time that light energy can gently guide and change the orientation of living cells, demonstrating that optically induced torques can affect components within cells that drive their motility -- their ability to move spontaneously -- and change the orientation of cells within lab cultures.

While earlier studies of cell manipulation have emphasized shielding the cell from the power of  light, University of Central Florida researchers Aristide Dogariu, an optical scientist at the College of Optics and Photonics, and Kiminobu Sugaya, a stem cell researcher at the College of Medicine’s Burnett School of Biomedical Sciences, focused on using that energy to stimulate the cells’ natural tendencies.

Promise of Stem Cells Derived From Fat

Fat stem cells, known as adipose stromal cells, are easily separated from fat tissue after liposuction according to University of Virginia researchers. They add that an advantage of liposuction is that it is less invasive than the process used for harvesting stem cells from bone marrow, the most prized source of adult stem cells. Adipose stromal cells are also more plentiful than bone marrow stem cells, and they are better able to tolerate harsh environments.

This last quality is particularly important. From a medical point of view, it means that adipose stromal cells can be applied under conditions that would destroy other cells. In preclinical studies, Shayn Peirce-Cottler, assistant professor of biomedical engineering, and Dr. Adam Katz,  associate professor of plastic surgery,  have used them successfully to treat chronic diabetic ulcers, open sores characterized by low levels of oxygen and high levels of bacteria.

how blood cells 'talk': Progress Toward Expanding Blood Stem Cells In Vitro

Blood stem cell transplantation is used to treat and cure genetic blood diseases. The more blood stem cells there are to transplant, the better the outcome. But while there is great demand, there is not a large supply, primarily because it is so hard to grow blood stem cells in vitro.

For years, researchers have worked to find a robust and reliable way to expand blood stem cells. So far the answer has evaded everyone. Now, a University of Toronto team, lead by Stem Cell Bioengineering Professor Peter Zandstra, has revealed a mathematical model that links functional cellular assays to specific model outputs, defines cell-level kinetic parameters such as cell cycle rates and self-renewal probabilities as functions of culture variables, and simulates feedback regulation using cell-cell interaction networks.

Our goal "was to understand what regulates human blood stem cell growth outside of the body," said Daniel Kirouac, lead author of the study.

Scripps Institute Stem Cell Research Team Confirms Chinese Mice From Skin Cells iPS Result

And they did it with improved results.  Since Yamanaka and Thompson independently produced embryonic-like stem cells in late 2007, researchers have tried to confirm pluripotency in these cells by producing live mice. For some reason iPS mouse embryos stopped developing about two-thirds of the way through gestation in these past attempts. This led to concerns that iPS cells might be inferior to embryonic stem cells and hinted that reprogramming with four factors ( Both Ymanaka and Thompson used four factors.  However the factors were slightly different, which also raised questions) might not be the best method to produce pluripotent cell lines from patients.

On July 24 we posted about two separate Chinese research teams that had recently accomplished producing mice from induced pluripotent stem cells. Now scientists from the Scripps Research Institute in San Diego, led by Assistant Professor Kristin Baldwin, Ph.D., have confirmed the Chinese accomplishment but with improved results.

Human Induced Pluripotent Stem Cells Produced Without Inserting Genes

Researchers at Worcester Polytechnic Institute's (WPI) Life Sciences and Bioengineering Center (LSBC) and CellThera, a private company also located at the LSBC, have discovered a way to turn on stem cell genes in human fibroblasts from skin cells without the risks associated with inserting extra genes or using viruses.

Dormant stem cell genes OCT4, SOX2 and NANOG, already in the skin cells, were turned on by lowering the amount of atmospheric oxygen the cells were exposed to and by adding a protein called fibroblast growth factor 2 (FGF2) to the culture medium. FGF2 is a naturally occurring protein that is known to be vital for maintaining the pluripotency of embryonic stem cells.

Furthermore, once the stem cell genes were activated and began expressing proteins, the team found those proteins migrated back into the nucleus of the skin cells, precisely as would occur in induced pluripotent stem cells.  "This was an exciting observation," said Raymond Page, PhD, research assistant professor of biology and biotechnology at WPI. "Having these proteins localize to the nucleus is the first step of reprogramming these cells."

Even more surprising, the team found that the stem cell genes OCT4, SOX2 and NANOG were not completely dormant in untreated skins cells, as was presumed. Those genes were, in fact, sending out messages, but those messages were not being translated into the proteins that do the work of making cells pluripotent. "This was quite unexpected," said Tanja Dominko, DVM, PhD, associate professor of biology and biotechnology at WPI and president of CellThera. "Not only does this data force us to rethink what the true markers of pluripotency may be, it suggests there is a natural mechanism at work in these cells regulating the stem cell gene expression. That opens a whole new line of inquiry."

Adapted from the Worcester Polytechnic Institute announcement.

The Eyes Have It: Stem Cell Sector Public Companies vs. Newly Established, Closely-Held, Big Pharma Financed Competitors

Stem cell research is advancing in five arenas:

1. Universities


2. Publicly traded companies


3. Closely held companies with university affiliations


4. Publicly traded companies with University affiliations


5. Closely held or publicly traded stem cell companies with research funding through big pharma partnerships. 

Category five is really small.  So far.  But as research in the stem cell field progresses into scalability and the potential for commercial therapies, researchers will increasingly be in demand by big pharma.  It will be a good fit because researchers will be looking for money.

EyeCyte Inc., founded by Dr. Martin Friedlander of Scrips Research Institute and his former post-doc student Mathew Ritter, now EyeCyte's research and development manager, is our current example of a stem cell start up venture funded by big pharma.

EyeCyte, Inc., is an early stage stem/progenitor cell‐based ophthalmology research and development company based in La Jolla, California. Building on research into the causes of, and potential treatments for, retinal disease by Professor Martin Friedlander, M.D., Ph.D. and his laboratory at Scripps, EyeCyte will use the properties of blood and bone marrow‐derived progenitor cells from patients to pursue the development of treatments for acquired and inherited retinal diseases including diabetic retinopathy, retinopathy of prematurity, retinal vascular occlusive disease, agerelated macular degeneration (AMD) and retinitis pigmentosa.

Questions Raised By Chinese Mice From iPS Cells Experiment; UCLA's Recently Reported iPS vs. Embryonic Cell Differences Is One Of Them

The mainstream press has adopted broad coverage of mice produced from Induced Pluripotent Stem (iPS) cells by two separate Chinese laboratories.  The technique the two teams of Chinese researchers used is called tetraploid complementation. With the tetraploid approach the host cells can form only the placental tissues; all the animal's tissues must come from the iPS cells injected into the blastocyst, or very early embryo.

Until these experiments in China, researchers have never been able to produce living animals via this approach, a result that has created doubts about the true pluripotency of iPS cells. But even with these dramatic results, questions remain, at least one major one suggested by recent research on the differences between iPS and embryonic stem cells conducted at UCLA.

Induced Pluripotent Stem Cells Repair Heart In Mayo Clinic Study

A great deal of work is being done to come up with a method of reverting adult stem cells to an embryonic-like state without making them inherently dangerous in the process. Of course after the adult cells are returned to an embryonic-like state they have to be coaxed into becoming the type of cell that is necessary in the particular regenerative medicine application.

About a month ago a Mayo Clinic study, one that delivered embryonic stem cells to mouse embryos in the earliest stages of development, found that the resulting mice demonstrated a capacity to recover from cardiac injury in adulthood.  According to Mayo this study provides the first evidence that preventive regenerative medicine can successfully be used to treat myocardial infarction through prophylactic intervention.

Mayo researchers injected mouse embryos with embryonic stem cells that had been used to successfully treat ischemic heart disease following heart attack. The resulting animals incorporated between five and 20 percent of labeled stem cell-derived tissue. They were born with no apparent abnormalities, and the tested and control groups had similar overall baseline cardiac disease risk profiles. They also demonstrated similar cardiac performance during the one year follow-up.

Now, In a proof-of-concept study, Mayo researchers have demonstrated that induced pluripotent stem (iPS) cells can be used to treat heart disease. In this study, researchers reprogrammed ordinary fibroblasts, cells that contribute to scars such as those resulting from a heart attack, converting them into stem cells that fix heart damage caused by infarction.

Similarities Between Salamander Limb Regeneration And Stem Cell Repairs Of Damaged Human Muscle?

It turns out that the genes that make muscle stem cells in the embryo are surprisingly not needed in adult muscle stem cells to regenerate muscles after injury, a result that seems to relate to a parallel finding in salamander limb regeneration.

“The paired-box genes, Pax3 and Pax7 are involved in the development of the skeletal muscles," explained lead researcher Christoph Lepper, a predoctoral fellow at Carnegie Institution for Science’s Department of Embryology. "It is well established that both genes are needed to produce muscle stem cells in the embryo. A previous student, Alice Chen, studied how these genes are turned on in embryonic muscle stem cells. I thought that if they are so important in the embryo, they must be important for adult muscle stem cells. Using genetic tricks, I was able to suppress both genes in adult muscle stem cells. I was totally surprised to find that the muscle stem cells are normal without them.”

Perhaps coincidentally, perhaps not, the Carnegie finding brings to mind a recent research result from the Max Planck Institute regarding salamanders.  Salamanders regrow lost limbs and Elly Tanaka at Planck has been studying how they do so. Tanaka and colleagues found that salamander regeneration begins when a clump of cells called a blastema forms at the tip of a lost limb. From the blastema come skin, muscle, bone, blood vessels and neurons, ultimately growing into a limb virtually identical to the old one.

But here's the surprise: Rather than having their cellular clocks fully reset and reverting to an embryonic state, cells in the salamanders’ stumps became slightly less mature versions of the cells they’d been before.  In other words they don't revert to pluripotency.

Company Founded By James Thomson Reprograms Blood Cells into Stem Cells

Cellular Dynamics international (CDI), founded by Jamie Thomson and colleagues from the U. of Wisconsin, recently reported generating pluripotent stem cells from very small volumes of ordinary human blood samples. CDI is privately held.  Its stated mission is to "provide drug screening and toxicity testing products based on breakthrough induced pluripotent stem (iPS) cell technology,"

Once the difficulty of current approaches to inducing pluripotency is overcome (reducing time and cost while producing high quality scalability and safety), this development suggests the possibility of a readily obtainable source of pluripotent stem cells from the millions of blood samples in storage at repositories and healthcare institutions worldwide.

New Cedars-Sinai Regenerative Medicine Institute to Emphasize Induced Pluripotent Research

The Cedars Institute will be housed in new state-of-the-art laboratories being constructed especially for stem cell and regenerative medicine research. At the heart of the Institute will be a specialized core facility for the production of Induced pluripotent stem cells.

Clive N. Svendsen, Jamie Thomson associate and joint leader of the widely-respected Stem Cell and Regenerative Medicine Center at the University of Wisconsin, has been named to lead the new unit.  He has quite a resume; one that includes professor of neurology and anatomy at the University of Wisconsin-Madison, and consulting professor at Stanford University. Svendsen’s research focuses on both modeling and treating neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease) and Parkinson’s disease using a combination of stem cells and growth factors.

NIH Stem Cell Rules Seriously Flawed, Says Stanford Expert

On Monday the National Institutes of Health released their final guidelines detailing what types of human embryonic stem cell research will qualify for federal funding. Although the rules permit federal funding of research on embryonic stem cell lines produced from excess early embryos from in vitro fertilization clinics, they disallow federal support of two key techniques used to derive embryonic stem cells in animals: that of transferring the genetic material from one cell into an egg without a nucleus, and that of stimulating an unfertilized egg to divide.

"In terms of extending the classical embryonic stem cell lines that can be used with federal funding, this is an important step forward," said Stanford University School of Medicine stem cell researcher Irving Weissman, MD. "However, the policy banning funding of other stem cell lines produced by transferring the genetic material from a patient to an egg is a terrible disappointment. It seems inconsistent with the president's promise to allow scientific facts to determine science policy." On March 9, President Barack Obama made a statement about his administration’s approach to science policy, in which he vowed to ensure "that scientific data is never distorted or concealed to serve a political agenda, and that we make scientific decisions based on facts, not ideology."

Blood Stem Cell Growth Factor Found to Reverse Memory Decline in Mice

A human growth factor that stimulates blood stem cells to proliferate in the bone marrow reverses memory impairment in mice genetically altered to develop Alzheimer's disease, researchers at the University of South Florida have found. The granulocyte-colony stimulating factor (GCSF) significantly reduced levels of the brain-clogging protein beta amyloid deposited in excess in the brains of the Alzheimer's mice, increased the production of new neurons and promoted nerve cell connections.

GCSF is a blood stem cell growth factor or hormone routinely administered to cancer patients whose blood stem cells and white blood cells have been depleted following chemotherapy or radiation. GCSF stimulates the bone marrow to produce more white blood cells needed to fight infection. It is also used to boost the numbers of stem cells circulating in the blood of donors before the cells are harvested for bone marrow transplants. Advanced clinical trials are now investigating the effectiveness of GCSF to treat stroke, and the compound was safe and well tolerated in early clinical studies of ischemic stroke patients.

"GCSF has been used and studied clinically for a long time, but we're the first group to apply it to Alzheimer's disease," said USF neuroscientist Juan Sanchez-Ramos, MD, PhD, the study's lead author. "This growth factor could potentially provide a powerful new therapy for Alzheimer's disease – one that may actually reverse disease, not just alleviate symptoms like currently available drugs."

Differences Found Between Induced Pluripotent Stem Cells And Embryonic Stem Cells

One of the arguments for federal funding of embryonic stem cells -- in light of the progress being made in Induced Pluripotent Stem Cell technology -- is pretty straight forward.  Researchers have used 'embryonic-like' to describe the result of induced regression on adult cells, usually skin cells. The reason embryonic-like is used is that we have not been sure whether they were identical to embryonic stem cells.  In fact, we don't know enough about how embryonic stem cells become every cell in the body to know exactly what 'embryonic-like' means.

In another example of the kind of end run occasionally taking place in the rapidly expanding stem cell research arena, UCLA researchers have found that embryonic stem cells and skin cells reprogrammed into embryonic-like cells have inherent molecular differences, demonstrating for the first time that the two cell types are clearly distinguishable from one another.

Athersys To Receive Grant Funds From Ohio's Research Commercialization Program

Following California's lead, and in response to growing acceptance of the benefits of regenerative medicine given sufficient research, more and more states are finding ways to fund research taking place within their borders.

The Center for Stem Cell & Regenerative Medicine (CSCRM), comprised of Case Western Reserve University (CWRU), Cleveland Clinic (CC), University Hospitals (UH), and Athersys, Inc. (ATHX - a Sector Company) has received 5 million dollars from Ohio's Third Frontier Commission under the Research Commercialization Program. The funding will help support new and innovative stem cell technologies including two commercial, four emerging and three pilot projects. This funding will be matched by each of the projects to create a $10 million grant benefiting stem cell and regenerative medicine in Ohio.