Category Archives: Stem Cells

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Main Category: Liver Disease / Hepatitis
Also Included In: Stem Cell Research
Article Date: 03 Feb 2012 - 11:00 PST

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Hepatitis C is a viral disease that leads to inflammation and organ failure. However, researchers are puzzled as to why some individuals are very susceptible to the disease, while others are not.

Researchers believe they could find out how genetic variations produce these different responses by investigating liver cells from different individuals in the lab. However, liver cells are hard to obtain and extremely challenging to grow in a lab dish as they often lose their normal function and structure when removed from the body.

Now, scientists from MIT, Rockefeller University and the Medical College of Wisconsin have found a technique to generate liver-like cells from induced pluripotent stem cells (iPSCs). iPSCs are created from body tissues instead of embryos; the liver-like cells that can be infected with hepatitis C. iPSCs could allow researchers to investigate why individuals respond differently to the disease. The study is published in the Proceedings of the National Academy of Sciences.

Although many research terms have tried to established an infection in cells obtained from iPSCs, this study is the first to have done so. In addition, the new technique could eventually facilitate "personalized medicine." Using tissues obtained from the patient being treated, doctors could test the effectiveness of various medications and customize a treatment for that individual patient.

This study is a joint effort between Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science at MIT; Charles Rice, a professor of virology at Rockefeller; and Stephen Duncan, a professor of human and molecular genetics at the Medical College of Wisconsin.

In 2011, Bhatia and Rice revealed that by growing liver cells on special micropatterned plates that direct their organization, they could influence the cells to grow outside the body. Although, these cells can be infected with hepatitis C, researchers cannot proactively research the role of genetic variation in viral responses, as the cells derive from organs donated for transplantation and represent only a small population.

Bhatia and Rice collaborated with Duncan, who had demonstrated that he could transform iPSCs into liver-like cells, in order to produce cells with more genetic variation.

Often, such iPSCs are taken from skin cells. Researchers can restore these cells to an immature state - the same as embryonic stem cells - which can differentiate into any cell type by switching on specific genes in those cells. The cells can then be directed, once they become pluripotent, to become liver-like cells by switching on genes that regulate liver development.

In this study, MIT postdoc Robert Schwartz and graduate student Kartik Trehan infected those liver-like cells with hepatitis C. They created the viruses to expel a light-producing protein each time they went through their life cycle in order to confirm that infection had taken place.

The primary goal for the team is to obtain cells from individuals who had unusual reactions to hepatitis C infection and transform them into liver cells in order to research their genetics to find out why they responded the way they did.

Bhatia explains:

"Hepatitis C virus causes an unusually robust infection in some people, while others are very good at clearing it. It's not yet known why those differences exist."

One possible reason may be genetic variations in the expression of immune molecules, such as interleukin-28, a protein that has been demonstrated to play a vital role in the response to hepatitis infection. Other potential factors include, cell's susceptibility to having viruses control their replication machinery and other cellular structures, as well as cell's expression of surface proteins that allow the virus to penetrate the cells.

Bhatia explains the liver-like cells generated in this investigation are similar to "late fetal" liver cells. The team is currently working on producing more mature liver cells.

The long-term goal for the team is personalized treatments for individuals with hepatitis. According to Bhatia one could imagine obtaining cells from an individual, making iPSCs, reprogramming them into liver cells and infecting them with the same strain of hepatitis that the individual has. This would allow doctors to test various medications on the cells to find out which ones are better at clearing the infection.

Written by Grace Rattue
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

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Hepatitis Research May Benefit From Stem Cells

Feb. 3, 2012

Using lab-grown human neurons, researchers from the University of Wisconsin-Madison have devised an effective assay for detecting botulinum neurotoxin, the agent widely used to cosmetically smooth the wrinkles of age and, increasingly, for an array of medical disorders ranging from muscle spasticity to loss of bladder control.

The new assay uses neurons, the critical impulse conducting cells of the central nervous system, derived from induced human pluripotent stem cells. It is the first test to employ stem cell derivatives to reliably and quantitatively detect botulinum neurotoxin and the antibodies that can neutralize the toxin's effects.

The assay is likely to draw considerable interest from industry as a potential replacement for the mouse, an animal now used by the thousands to control the potency of pharmaceutical preparations of the powerful neurotoxin.

Using cells provided by Madison-based Cellular Dynamics International, a company that industrially manufactures induced pluripotent stem cells and their derivative tissue cells for use in research and industry, the University of Wisconsin-Madison team devised an assay that is more sensitive than the mouse assay required for quality control of pharmaceutical preparations of botulinum toxin.

"This is an optimal testing platform for botulinum neurotoxin products," explains Sabine Pellett who, with UW-Madison professor of bacteriology Eric A. Johnson, led the new study published this week in the journal Toxicological Sciences. "A cell-based assay that is at least as sensitive and reproducible as the mouse bioassay can serve as a viable alternative and largely eliminate the need to use animals."

The toxin is used most famously for cosmetic purposes to erase the facial wrinkles that come with age. However, it is also used in a growing number of medical applications. Since it was first approved in 1990 for use in human patients with strabismus or cross-eye, the toxin, which works by blocking communication between nerves and muscles, has been used to successfully treat excessive sweating, chronic migraine headaches, painful neck spasms known as dystonia, and muscle conditions associated with cerebral palsy, multiple sclerosis and stroke. In 2010, the Food and Drug Administration (FDA) approved the toxin for use in treating loss of bladder control. Pharmaceutical applications of the toxin underpin a market that easily exceeds $1 billion annually.

Botulinum toxin is a protein produced by the bacterium Clostridium botulinum. It is the most potent toxin known to science and before its first experimental medical application to treat cross-eye was best known as a food poison. The methods to produce the toxin in large quantities and to precise specifications were pioneered at UW-Madison by Johnson and his late mentor, Ed Schantz.

Because of its incredible potency, the quality and dosages of the toxin for medical use must be carefully prepared.

The preparations made by pharmaceutical companies, says Johnson, actually contain very little toxin. To ensure that batches of the agent are of the correct therapeutic dose and of uniform quality, they are tested by injecting mice at a specified dosage that kills half of all mice exposed to the toxin.

"The mouse assay has many drawbacks and hundreds of thousands of mice are used for this every year," Pellett explains. "The most important result of this study is the high sensitivity of the assay, greater than the mouse bioassay, which is required for quality control."

The pharmaceutical industry, Johnson adds, is under pressure from the FDA to develop alternatives to the mouse. One cell-based assay has already been developed by Allergan, the company that makes BOTOX, the most famous trade name for botulinum toxin. However, the details of that assay have not been made available.

"The assay we developed is another cell based assay," notes Pellett, "one that uses normal human neurons derived from induced pluripotent stem cells, and which can be optimized for any pharmaceutical botulinum neurotoxin product."

In addition to Pellett and Johnson, authors of the new study include Regina Whitemarsh and William H. Tepp, of UW-Madison; and Monica. J. Strathman, Lucas G. Chase and Casey Stankewicz of Cellular Dynamics International. The study was funded by the U.S. National Institutes of Health.

See original here:
Neurons from stem cells could replace mice in botulinum test

30-01-2012 09:58 Doctors in Toronto, Canada perform a successful procedure using embryonic stem cells to treat macular degeneration which causes blindness.

See more here:
Stem Cells Offer Hope For The Blind - Video

The Hindu Shinya Yamanaka, Centre for iPS Cell Research and Application, Japan delivering a lecture in Chennai on Thursday. Photo: V. Ganesan

Many more diseases can be targeted, says expert

While applications of induced pluripotent stem cells in stem cell therapy may be limited to a few diseases, its applications in drug discovery are wide-ranging, and many more diseases can be targeted, Shinya Yamanaka, Director, Centre for iPS Cell Research and Application, Japan, has said.

The Japanese scientist, whose breakthrough was the creation of embryonic-like stem cells from adult skin cells, believes that the best chance for stem cell therapy lies in offering hope to those suffering from a few conditions, among them, macular disease, Type 1 Diabetes, and spinal cord injuries.

On the other hand, there were multiple possibilities with drug discovery for a range of diseases, and Prof. Yamanaka was hopeful that more scientists would continue to use iPS for studying this potential.

He currently serves as the Director of the Center for iPS Cell Research and Application and as Professor at the Institute for Frontier Medical Sciences at Kyoto University. He is also a Senior Investigator at the University of California, San Francisco (UCSF) - affiliated J. David Gladstone Institutes.

An invited speaker of the CellPress-TNQ India Distinguished Lectureship Series, co-sponsored by Cell Press and TNQ Books and Journals, Prof. Yamanaka spoke to a Chennai audience on Tuesday evening about those “immortal” cells, that he originally thought would take “forever” to create, but actually took only six years.

“My fixed vision for my research team was to re-programme adult cells to function like embryonic-like stem cells. I knew it could be done, but just didn't know how to do it,” Prof. Yamanaka said.

Embryonic stem cells are important because they are pluripotent, or possess the ability to differentiate into any other type of cell, and are capable of rapid proliferation. However, despite the immense possibilities of that, embryonic cells are a mixed blessing: there are issues with post-transplant rejection (since they cannot be used from a patient's own cells), and many countries of the world do not allow the use of human embryos.

Dr. Yamanaka's solution would scale these challenges if only he and his team could find a way to endow non-embryonic cells with those two key characteristics of embryonic stem cells.

In 2006, he and his team of young researchers — Yoshimi Tokuzawa, Kazutoshi Takahashi and Tomoko Ishisaka — were able to show that by introducing four factors into mouse skin cells, it was possible to generate ES-like mouse cells. The next year, they followed up that achievement, replicating the same strategy and converted human skin cells into iPS cells. “All we need is a small sample of skin (2-3millimetres) from the patient. This will be used to generate skin fibroblasts, and adding the factors, they can be converted to iPS cells. These cells can make any type of cell, including beating cardiac myocytes (heart cells), Prof.Yamanaka explained.

iPS cells hold out for humanity a lot of hope in curing diseases that have a single cell cause. Prominent among them are Lou Gehrig's Disease or Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease. Motor neurons degenerate and die, and no effective treatment exists thus far. One reason is that there have not been good disease models for ALS in humans. It is difficult to get motor neuron from human patients and motor neurons cannot divide.

“Now, iPS cells can proliferate and can be differentiated to make motor neurons in large numbers,” he explained. Already a scientist in Japan has clarified motor neuron cells from iPS. “We are hoping that in the near future we would be able to evolve drug candidates that will be useful for ALS patients.” Treatment of spinal cord injuries using iPS cells has showed good results in mice and monkey specimens, and it is likely that in two or three years, scientists will be ready to start treatment for humans.

Toxicology, or drug side effects, is another area where iPS cells can be of use. Testing drug candidates directly on patients can be extremely dangerous. However, iPS cells can be differentiated into the requisite cell type, and the drugs tested on them for reactions. And yet, as wonderful as they may seem, iPS cells do have drawbacks, and there are multiple challenges to be faced before the technology can be applied to medicine. Are they equivalent and indistinguishable from ES cells? For a technology that has been around for only five years, the questions remain about safety. Also to derive patient-specific iPS cells, the process is time, and money-consuming, Prof. Yamanaka pointed out.

There are however, solutions in the offing, for the man who made the world's jaw drop with his discovery. One would be to create an iPS cell bank, where iPS cells could be created in advance from healthy volunteers donating peripheral blood, and skin fibroblasts, apart from frozen cord blood. The process of setting a rigorous quality control mechanism to select the best and safest iPS clones is on and would be complete within a year or two. “Many scientists are studying iPS cells across the world, and I'm optimistic that because of these efforts, we can overcome the challenges of iPS, and contribute to newer treatments for intractable diseases,” Prof. Yamanaka said.

N. Ram, Director, Kasturi & Sons Limited, introduced the speaker. Mariam Ram, managing director, TNQ India; and Emilie Marcus, executive editor, Cell Press, spoke.

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“Wide-ranging applications for pluripotent stem cells”

In recent court filings, the Food and Drug Administration has asserted that stem cells—you know, the ones our bodies produce naturally—are in fact drugs and subject to its regulatory oversight. So does that make me a controlled substance?

The bizarre controversy revolves around the FDA's attempt to regulate the Centeno-Schultz Clinic in Colorado that performs a nonsurgical stem-cell therapy called Regenexx-SD. It is designed to treat moderate to severe joint, tendon, ligament, and bone pain using only adult stem cells. Doctors draw your blood, spin it through a centrifuge, extract the stem cells and re-inject them into your damaged joints. It uses no other drugs. No drugs means no FDA oversight and that does not sit well with the administration.

The FDA has since argued that a) stem cells are drugs and b) they fall under FDA regulation because the clinic is engaging in interstate commerce. That's right, a process performed at the clinic using the patient's own bodily fluids constitutes interstate commerce because, according to the administration, out-of-state patients using Regenexx-SD would "depress the market for out-of-state drugs that are approved by FDA."

Funny, that sounds less like the FDA protecting the health of the country's citizens and more like the FDA defending its enforcement turf. The two parties have been at odds for over four years now, so we may have a while until we know if every American has in fact become a regulatable good subject to government regulation. [ANH-USA via Slash Gear]

Image via the AP

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According to the FDA, Your Stem Cells Are Now Drugs [Fda]

30-01-2012 06:10 Professor Michael Schneider of Imperial College tells Alan Keys about how stem cell research is leading to treatments for heart disease. Michael describes how the availability of stem cells allows his team to determine the molecules involved in heart cell death and also how to protect those cells from death during a heart attack. Michael foresees a near future where stem cells are combined with other therapies to both repair hearts and enable hearts to self-repair. Alan Keys had his own heart repaired during an operation some years ago and currently chairs a British Heart Foundation patients committee. The British Heart Foundation part-fund the work of Michael's team at Imperial College. This interview was edited down from the original 35 minutes conversation. Read the transcript here: bit.ly Read more about Michael here: bit.ly and here: bit.ly

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Stem cells and heart repair - Video

Scientists believe that if they could study liver cells from different people in the lab, they could determine how genetic differences produce these varying responses. However, liver cells are difficult to obtain and notoriously difficult to grow in a lab dish because they tend to lose their normal structure and function when removed from the body.

Now, researchers from MIT, Rockefeller University and the Medical College of Wisconsin have come up with a way to produce liver-like cells from induced pluripotent stem cells, or iPSCs, which are made from body tissues rather than embryos; the liver-like cells can then be infected with hepatitis C. Such cells could enable scientists to study why people respond differently to the infection.

This is the first time that scientists have been able to establish an infection in cells derived from iPSCs — a feat many research teams have been trying to achieve. The new technique, described this week in the Proceedings of the National Academy of Sciences, could also eventually enable “personalized medicine”: Doctors could test the effectiveness of different drugs on tissues derived from the patient being treated, and thereby customize therapy for that patient.

The new study is a collaboration between Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science at MIT; Charles Rice, a professor of virology at Rockefeller; and Stephen Duncan, a professor of human and molecular genetics at the Medical College of Wisconsin.

Stem cells to liver cells

Last year, Bhatia and Rice reported that they could induce liver cells to grow outside the body by growing them on special micropatterned plates that direct their organization. These liver cells can be infected with hepatitis C, but they cannot be used to proactively study the role of genetic variation in viral responses because they come from organs that have been donated for transplantation and represent only a small population.

To make cells with more genetic variation, Bhatia and Rice decided to team up with Duncan, who had shown that he could transform iPSCs into liver-like cells.

Such iPSCs are derived from normal body cells, often skin cells. By turning on certain genes in those cells, scientists can revert them to an immature state that is identical to embryonic stem cells, which can differentiate into any cell type. Once the cells become pluripotent, they can be directed to become liver-like cells by turning on genes that control liver development.

In the current paper, MIT postdoc Robert Schwartz and graduate student Kartik Trehan took those liver-like cells and infected them with hepatitis C. To confirm that infection had occurred, the researchers engineered the viruses to secrete a light-producing protein every time they went through their life cycle.

“This is a very valuable paper because it has never been shown that viral infection is possible” in cells derived from iPSCs, says Karl-Dimiter Bissig, an assistant professor of molecular and cellular biology at Baylor College of Medicine. Bissig, who was not involved in this study, adds that the next step is to show that the cells can become infected with hepatitis C strains other than the one used in this study, which is a rare strain found in Japan. Bhatia’s team is now working toward that goal.

Genetic differences

The researchers’ ultimate goal is to take cells from patients who had unusual reactions to hepatitis C infection, transform those cells into liver cells and study their genetics to see why they responded the way they did. “Hepatitis C virus causes an unusually robust infection in some people, while others are very good at clearing it. It’s not yet known why those differences exist,” Bhatia says.

One potential explanation is genetic differences in the expression of immune molecules such as interleukin-28, a protein that has been shown to play an important role in the response to hepatitis infection. Other possible factors include cells’ expression of surface proteins that enable the virus to enter the cells, and cells’ susceptibility to having viruses take over their replication machinery and other cellular structures.

The liver-like cells produced in this study are comparable to “late fetal” liver cells, Bhatia says; the researchers are now working on generating more mature liver cells.

As a long-term goal, the researchers are aiming for personalized treatments for hepatitis patients. Bhatia says one could imagine taking cells from a patient, making iPSCs, reprogramming them into liver cells and infecting them with the same strain of hepatitis that the patient has. Doctors could then test different drugs on the cells to see which ones are best able to clear the infection.

Provided by Massachusetts Institute of Technology (news : web)

This story is republished courtesy of MIT News (http://web.mit.edu/newsoffice/), a popular site that covers news about MIT research, innovation and teaching.

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Stem cells could drive hepatitis research forward

Bypassing stem cells, mouse skin cells have been converted directly into cells that become the three main parts of the animal's nervous system, according to new research at the Stanford University School of Medicine.

The startling success of this method seems to refute the idea that "pluripotency" -- the ability of stem cells to become nearly any cell in the body -- is necessary for a cell to transform from one cell type to another.

It raises the possibility that embryonic stem cell research, as well as a related technique called "induced pluripotency," could be supplanted by a more direct way of generating cells for therapy or research.

"Not only do these cells appear functional in the laboratory, they also seem to be able to integrate ... in an animal model," said lead author and graduate student Ernesto Lujan.

The study was published online Jan. 30 in the Proceedings of the National Academy of Sciences.

The finding implies that it may one day be possible to generate a variety of neural-system cells for transplantation that would perfectly match a human patient.

While much research has been devoted to harnessing the potential of embryonic stem cells, taking those cells from an embryo and then implanting them in a patient could prove difficult because they would not match genetically.

The Stanford team is working to replicate the work with skin cells from adult mice and humans.

But Lujan emphasized that

much more research is needed before any human transplantation experiments could be conducted.

In the meantime, however, the ability to quickly and efficiently generate cells -- grown in mass quantities in the laboratory, and maintained over time -- will be valuable in disease and drug-targeting studies.

Contact Lisa M. Krieger at 408-920-5565.

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Stanford scientists bypass stem cells to create nervous system cells