Long-Term Studies Find Enhanced Cord Blood Stem Cell Transplants To Be Safe

Main Category: Stem Cell Research
Also Included In: Transplants / Organ Donations
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An innovative experimental treatment for boosting the effectiveness of stem-cell transplants with umbilical cord blood has a favorable safety profile in long-term animal studies, report scientists from Dana-Farber Cancer Institute, Beth Israel Deaconess Medical Center (BIDMC), and Children's Hospital Boston (CHB).

Analysis of long-term safety testing in nonhuman primates, published online by the journal Cell Stem Cell, revealed that, after one year following transplant, umbilical cord blood units treated with a signaling molecule called 16,16-dimethyl PGE2 reconstituted all the normal types of blood cells, and none of the animals receiving treated cord blood units developed cancer. Wolfram Goessling, MD, PhD, of Dana-Farber and Brigham and Women's Hospital, is the first author of the paper, and Trista North, PhD, of BIDMC is the senior author.

The results of long-term safety studies in mice were previously submitted to the Food and Drug Administration to gain permission for a Phase 1 clinical trial under an Investigational New Drug (IND) application. Principal investigator, Corey Cutler, MD, a Dana-Farber transplant specialist, initiated the trial in 2009 at Dana-Farber and the Massachusetts General Hospital. The IND is sponsored by Fate Therapeutics, Inc. of San Diego.

Goessling and North were post-doctoral fellows in the laboratory of co-author Leonard Zon, MD, a stem cell researcher at CHB and a scientific founder of Fate Therapeutics, when they hit upon 16,16-dimethyl PGE2 while looking for compounds that could regulate the production of hematopoietic stem cells. The initial testing made use of zebra fish models. Goessling commented that "this is the first time a compound discovered in zebra fish has received a nod from the FDA for a clinical trial."

One of the limitations of cord blood as a transplant source is the cells engraft, or "take," in the recipient's bone marrow more slowly than matched donor cells form bone marrow. In addition, there is a higher failure rate for cord blood transplants. Thus there is a need for ways to improve the speed and quality of cord blood transplantation.

Notes:

The research was supported by funding from the Harvard Stem Cell Institute, the National Institutes of Health, and the Howard Hughes Medical Institute.

The other authors are Michael Dovey, PhD, and James M. Harris, BIDMC; Xiao Guan, PhD, and Thorsten Schlaeger, PhD, CHB; Joseph Stegner and Myriam Armant, PhD, Center for Human Cell Therapy, Immune Disease Institute, Boston; Ping Jin, PhD, and David Stroncek, MD, National Institutes of Health, Bethesda, Md.; Naoya Uchida, MD, and John F. Tisdale, MD, National Heart, Lung, and Blood Institute/National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md.; Robyn S. Allen, Robert E. Donahue, VMD, Mark E. Metzger, and Aylin C. Bonifacino, National Heart, Lung, and Blood Institute, Bethesda, Md.

Source:
Bill Schaller
Dana-Farber Cancer Institute

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Fukushima Workers Should Store Own Blood For Future Stem Cell Contingency If Radiation Exposure Was High

In order to prepare for any future stem cell transplants required as a result of accidental exposure to high doses of radiation during clean up, Fukushima workers have been advised to store their own blood now, Japanese experts wrote in the medical journal The Lancet today. Undergoing stem cell transplantation using their own cells - termed autologous transplant - is an option that should be available to them, the authors stress.

The Lancet Correspondence was represented by Dr Tetsuya Tanimoto, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, and Dr Shuichi Taniguchi, Toranomon Hospital, Tokyo.

They wrote:

"The danger of a future accidental radiation exposure is not passed, since there has been a series of serious aftershocks even (during) this April."

Rapidly dividing cells are vulnerable to radiation damage, which can depress bone marrow from a dose of approximately 2 Gy or more. Examples of cells that divide rapidly include reproductive germ cells, hemopoietic cells, and the cells of the intestinal tract. Hemopoietic (hematopoietic) cells are known as precursor cells - they can eventually become any of several types of blood cells.

Using stem cells from a donor for transplantation, known as allogeneic stem-cell transplantation, in previous nuclear accidents has had its problems, such as graft failure, graft-versus-host disease, profound immune suppression after transplantation, and delays in trying to find a donor.

The authors say the workers' own peripheral blood stem cells should be used in case of future transplant needs. Using one's own blood does away with the need for immunosuppressant medications which make the patient very vulnerable to infections, there is no graft-versus-host disease, and no time is wasted hunting around for a donor.

Autologous transplantation can restore normal hemopoietic functionality much more quickly. Collecting the blood has been proven to be safe, and the cells can be frozen and stored.

The stored blood would also be useful for treating future leukemia, a type of cancer linked to radiation exposure. Bone marrow defects could also be treated.

However, the authors add that autologous transplant has its limitations too - it can only address bone injury, and not other tissues, such as skin, lung or GI tract.

The scientists add that there are 107 transplant teams on stand-by in Japan ready to collect and store hemopoietic stem cells from workers who are bravely trying to hold back the radiation. Over 50 European hospitals are also available to help out.

The Nuclear Safety Commission of Japan is concerned about the "physical and psychological burden for nuclear workers". The Commission adds that there is "..no consensus among international authoritative bodies, and no sufficient agreement among the Japanese public."

The authors said:

"The most important mission is to save the nuclear workers' lives and to protect the local communities. Such an approach would be the industry's best defence: if a fatal accident happened to the nuclear workers, the nuclear power industry of Japan would collapse.

(conclusion) The process to completely shut down the reactors in Fukushima is expected to take years. The risk of accidental radiation exposure will thus accumulate for the nuclear workers and banking of their autologous PBSCs will become increasingly important. A judgment of right or wrong on this scheme must be determined from the standpoint of the nuclear workers and their families, not from a point of view of cost-benefit balance in ordinary times. Toranomon Hospital in Tokyo is ready to harvest and bank autologous PBSCs for the nuclear workers upon request. "

"Safety of workers at the Fukushima Daiichi nuclear power plant"
Tetsuya Tanimoto, Naoyuki Uchida, Yuko Kodama, Takanori Teshima, Shuichi Taniguchi
The Lancet DOI:10.1016/S0140-6736(11)60519-9

Written by Christian Nordqvist
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

Key Innovations In Stem-cell Technology: Discoveries Will Advance Medicine And Human Health

A scientist at the Gladstone Institutes has made two significant stem-cell discoveries that advance medicine and human health by creating powerful new approaches for using stem cells and stem-cell-like technology.

In two papers published on April 25 in the Proceedings of the National Academy of Sciences, Sheng Ding, PhD, reveals novel and safer methods not only for transforming embryonic stem cells into large numbers of brain cells with multiple uses, but also for transforming adult skin cells into so-called neural stem cells - cells that are just beginning to become brain cells. Dr. Ding last month joined Gladstone, a leading and independent biomedical-research organization, where he is expected to make a significant contribution to the institute's exemplary stem-cell research.

"This work is an example of what we're expecting from Dr. Ding, one of the world's top chemical biologists in stem-cell science," said Deepak Srivastava, MD, who directs cardiovascular and stem-cell research at Gladstone. "Dr. Ding's perspective as a chemist brings a new approach to our stem-cell work here at Gladstone."

Embryonic stem cells - "pluripotent" cells that can develop into any type of cell in the human body - hold tremendous promise for regenerative medicine, in which damaged organs and tissues can be replaced or repaired. Many in the science community consider the use of stem cells to be key to the future treatment and eradication of a number of diseases, including some on which Gladstone research focuses, such as heart disease, diabetes and Parkinson's disease.

In the first of the two papers, Dr. Ding describes new methods to use embryonic stem cells to develop large numbers of neural stem cells, which are early-stage cells that can later develop into a variety of types of brain cells. With traditional stem-cell development techniques, neural stem cells remain at this early stage for only a short time - and so cannot produce enough new cells to be practical for biomedical use.

But Dr. Ding's new method uses a cocktail of chemicals, first to induce embryonic stem cells to become neural stem cells and then later to arrest the cells from further development. This ability to hold neural stem cells in an intermediate state has enormous implications for cell therapy and for basic biomedical research. Such tissue-specific cells - which have already begun to develop into brain or muscle cells, for example - are limited in number, life span and an ability to develop into any of a variety of cell types that might be required for therapy or research.

In his second paper, Dr. Ding builds on the induced pluripotent stem (iPS) cell technology discovered by Gladstone senior investigator Dr. Shinya Yamanaka, in order to overcome some of the other challenges of working with embryonic stem cells. Because iPS cells are generated from a patient's own skin cells to act like stem cells, they offer a variety of benefits over embryonic stem cells. For example, iPS cells can be ideal for a personalized approach to drug discovery and for rejection-free transplantation, while they wholly avoid the ethical concerns of embryonic stem cells.

In this groundbreaking cellular-reprogramming research, Dr. Ding focuses on reprogramming skin cells into neural stem cells using the existing iPS technology - but with a twist. Dr. Ding never lets the cells enter the pluripotent state of iPS cells, in which they could develop into any type of cell. Instead he uses yet another cocktail of factors to transform the skin cells directly into neural stem cells. Avoiding the pluripotent state is important because it avoids the potential danger that "rogue" iPS cells could develop into a tumor if used to replace or repair damaged organs or tissue. And as with Dr. Ding's embryonic stem-cell research, this cell-reprogramming work also makes it possible to create a far greater number of cells for research or regenerative purposes.

"These cells are not ready yet for transplantation," Dr. Ding said. "But this work removes some of the major technical hurdles to using embryonic stem cells and iPS cells to create transplant-ready cells for a host of diseases."

Notes:

Dr. Ding is a senior investigator at the Gladstone Institute of Cardiovascular Disease and a professor in the department of Pharmaceutical Chemistry at the University of California San Francisco. He has pioneered the development and application of innovative chemical approaches to stem cell biology and regeneration. Dr. Ding earned a bachelor's degree in chemistry with honors from the California Institute of Technology in 1999 and a PhD in chemistry from The Scripps Research Institute four years later. Dr. Ding performed the work described in the two papers at The Scripps Research Institute.

Source:
Mara Brazer
Gladstone Institutes

A. Alfred Taubman Increases His Support For Medical Science Institute At U-M To $100 Million

A. Alfred Taubman has become U-M's largest individual donor, with total giving of more than $142 million. His latest gift of $56 million to the A. Alfred Taubman Medical Research Institute, announced today before the University's Board of Regents, will bring his support of innovative medical science at the University of Michigan to a total of $100 million.

The latest gift of Taubman's $100 million pledge will be added to the endowment that funds the Taubman Institute's efforts to find better treatments and cures for a wide variety of human diseases. In recognition of this tremendous support, the Regents today approved re-naming the Biomedical Science Research Building on the U-M medical campus as the A. Alfred Taubman Biomedical Science Research Building.

"This is one of the most transformative days in the life of the University," says U-M President Mary Sue Coleman. "Alfred Taubman instinctively sees how this level of investment can make huge advances in science and research. As a scientist, I particularly appreciate the freedom his philanthropy will provide researchers as they push the boundaries of medical science because of funding not available from other sources."

"The University of Michigan receives tremendous support from the NIH, National Science Foundation and other agencies. But there is truly no public agency in a position to fund the type of work that Mr. Taubman's gift will now accelerate," Coleman said.

The Board of Regents approved the gift and re-naming of the building at its regular meeting today. Taubman attended the meeting.

"This is a very special day for me. I'm making the largest commitment I've ever made to any institution, but more importantly I've never been as excited about a donation's potential to have an impact on the lives and well-being of people in this nation and around the world," says Taubman.

"It is my family's honor to be a part of the U-M family and to contribute to the work of so many brilliant people. Our goal is to create a legacy of excellence in medical research at the University of Michigan."

Taubman's gift is added to an endowment whose earnings will fund the Taubman Institute and the research of scientists named as Taubman Scholars within the institute for generations to come. These are leading U-M faculty members who are both laboratory scientists and physicians with active clinical practices, which makes the Taubman Institute one of the most unusual medical research organizations in the United States.

Already these gifts have supported the work of numerous U-M scientists, with the goal of turning laboratory research into clinical treatments. Through Taubman Institute support, five human clinical trials have been launched targeting cancer and ALS. The Taubman Institute is also home to the only laboratory producing embryonic stem cell lines in the state. In late March, its scientists announced the creation of its first two embryonic stem cell lines carrying the genes responsible for inherited diseases.

Ora Hirsch Pescovitz, M.D., U-M's executive vice president for medical affairs and chief executive officer of the U-M Health System, praised Taubman for his vision in supporting research that will change the face of biomedical science.

"Around the world, Mr. Taubman is renowned for moving merchandise, moving money and moving markets, but here at U-M he is renowned for moving minds," says Pescovitz. "His extraordinary generosity will make a difference in perpetuity."

The Taubman Institute is part of the U-M Medical School, one of the major components of the U-M Health System.

Fifteen U-M scientists already are being supported through the Taubman Institute in highly promising biomedical research focused on a range of diseases. The research funding they receive as Taubman Scholars allows them the time, freedom and resources they need to explore new frontiers of science and to conduct high-risk, high-reward research that other funding sources often do not support.

One of those scientists is the institute's director, Eva Feldman, M.D., Ph.D., Russell N. DeJong Professor of Neurology, who is leading a human clinical trial of a stem cell therapy for amyotrophic lateral sclerosis (ALS). She also is working to adapt that stem cell therapy to treat Alzheimer's disease.

"Scientists like Eva need to be able to follow their scientific instincts, and I'm glad to be able to provide them with funds that give them that opportunity," says Taubman.

Feldman said the unrestricted funding that Taubman provides scientists is priceless and gives them true freedom to follow innovative approaches to developing treatments for disease.

"What we've been able to achieve because of Mr. Taubman's belief and support is remarkable," Feldman says.

About 20 years ago, Taubman lost a good friend to ALS. And that memory has motivated him to support ALS research at the University of Michigan Medical School. But the research of the Taubman Scholars can be on any disease that affects humankind, from breast cancer and obesity to rare genetic conditions.

James O. Woolliscroft, M.D., Dean of the U-M Medical School and Lyle C. Roll Professor of Medicine, says Taubman's support is critical to identifying fruitful lines of inquiry that can reveal what has not been understood before.

"This additional funding provided to Taubman physician-scientists enables them to pursue creative, high-risk and potentially high return avenues of inquiry that might otherwise go unfunded by traditional government sources," says Woolliscroft. "Mr. Taubman's gift illustrates the power of philanthropy to support research that can address enormous deficits in our understanding of medical science and human health."

Summary: Alfred Taubman's major gifts to the University of Michigan and the U-M Health System With his newest gift to support research at the U-M Medical School, Taubman has become the largest individual donor to the University of Michigan.

His major gifts include:

-- $56 million announced today as the latest portion of a $100 million pledge to the A. Alfred Taubman Medical Research Institute at the Medical School.

-- $22 million given in 2008, also for the Taubman Institute

-- $22 million given in 2007, to initially endow the Taubman Institute and support research including that of Eva Feldman, M.D., Ph.D., who is studying stem cells and other approaches to treat amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease.

-- $30 million for the College of Architecture and Urban Planning, given in 1999, to create an endowment that supports student scholarships and faculty appointments. The College was named in his honor in 1999.

-- $4 million, committed in 2006, to the U-M Museum of Art, toward the museum's $35.4 million facility expansion and restoration project. The museum's striking new space for temporary exhibits is called the Taubman Galleries.

-- $3 million, given in the early 1980s, toward the building of University Hospital and the A. Alfred Taubman Health Care Center, which is a four-story facility for general and specialty outpatient care services.

His other gifts to the University have supported the Taubman Medical Library, the Alfred Taubman Scholarship in the Office of Financial Aid, and the Taubman Program in American Institutions in the College of Literature, Science, and the Arts.

Source: University of Michigan Health System

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Cell Of Origin Found For Squamous Cell Cancer

Squamous cell cancers, which can occur in multiple organs in the body, can originate from hair follicle stem cells, a finding that could result in new strategies to treat and potentially prevent the disease, according to a study by researchers with UCLA's Jonsson Comprehensive Cancer Center and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

Researchers also found that the progeny of those cells, although just a few divisions away from the mother hair follicle stem cells, were not capable of forming squamous cell cancers. Further studying why those progeny, called transit amplifying cells, can't develop cancer could provide vital clues to how squamous cell cancers originate, said William Lowry, an assistant professor of molecular, cell and developmental biology in Life Sciences and senior author of the study.

The study, conducted in mouse models, appears the week of April 18 in the early online edition in the peer-reviewed journal the Proceedings of the National Academy of Sciences (PNAS).

It had been suggested in the literature that squamous cell cancers could arise from the hair follicle, but it was not clear what cell type within the follicle was responsible. This is the first time two distinct cell types in the skin have been compared and contrasted for their ability to develop squamous cell cancers, said Lowry, who is a Jonsson Cancer Center and Broad Stem Cell Research Center scientist.

"It was surprising that the progeny of these stem cells, which are developmentally more restricted, could not develop cancers when the mother stem cells could," said Lowry. "There is something fundamentally different between the two, and it's important that we figure out why one type of cell was able to develop cancer and the other was not. The insights we gain will tell us how these cancers arise in the first place, and could provide us with a wealth of novel targets we could go after to prevent the cancer before it starts."

A type of non-melanoma skin cancer, these cancers form in squamous cells, thin, flat cells found on the surface of the skin, the lining of the hollow organs of the body and the passages of the respiratory and digestive tracts. Squamous cell cancers occur in the skin, lips, mouth, esophagus, bladder, prostate, lungs, vagina, anus and cervix. Despite the common name, these cancers are unique malignancies with significant differences in manifestation and prognosis.

In this study, Lowry and his team sought to determine which cells of the epidermis, or skin, could give rise to squamous cell cancer. They wanted to find out if skin stem cells had properties than made them more prone to develop tumors than non-stem cells, said Andrew White, a post-doctoral fellow in Lowry's lab and first author of the study.

"Adult stem cells are long-lived and can acquire mutations that can cause cancer, but they also have intrinsic properties for self-renewal that are similar to cancer that could make them more tumor prone," White said.

Lowry and his team delivered genetic hits - adding an oncogene that is known to cause cancer and removing a tumor suppressor gene - to the hair follicle stem cells and the transit amplifying cells in two groups of mice and waited to see which developed cancer. Only the mice that received the genetic hits in the hair follicle stem cell population developed squamous cell cancer.

Going forward, White will molecularly profile the hair follicle stem cells and the transit amplifying cells to determine what string of biologic events occur when the cancer-causing genes are delivered. The differences between the two will be illuminating, Lowry said.

"We hope that this will lead to much more specific therapies that target cancer initiation rather than treating the disease once it's established," Lowry said. "If we're lucky, a drug may already exist that will hit a target we identify."

The four-year study was funded by the Jonsson Cancer Center Foundation, a training grant from the California Institute for Regenerative Medicine, the National Institutes of Health, the American Cancer Society, the University of California Cancer Research Coordinating Committee and the Maria Rowena Ross Chair in Cell Biology and Biochemistry.

A Belgium-based team also came to similar conclusions using slightly different methods, confirming the UCLA results. That study is published alongside Lowry's in PNAS.

The stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 200 members, the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research is committed to a multi-disciplinary, integrated collaboration of scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed towards future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine, UCLA's Jonsson Cancer Center, the Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science.

Source:
UCLA's Jonsson Comprehensive Cancer Center

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ACT Files European Clinical Trial Application For Phase 1/2 Study Using Embryonic Stem Cells To Treat Macular Degeneration

Advanced Cell Technology, Inc. ("ACT"; OTCBB: ACTC), a leader in the field of regenerative medicine, announced today that it has filed a clinical trial application (CTA) with the European Medicines and Healthcare products Regulatory Agency (MHRA) seeking clearance to initiate its Phase 1/2 clinical trial using retinal pigment epithelial (RPE) cells derived from human embryonic stem cells (hESCs) to treat patients with Stargardt's Macular Dystrophy (SMD).

"With this filing, our initiatives in Europe are really starting to gain momentum," said Gary Rabin, interim chairman and CEO of ACT. "Through data from this proposed trial, and the two trials we are preparing to commence in the United States, we are eagerly anticipating beginning to assess the capabilities of our RPE cells to repair and regenerate the retina. As in the US, we also intend to file in Europe for clinical trials involving Dry Age-Related Macular Degeneration (Dry AMD) and other degenerative diseases of the retina, concurrently targeting the two largest pharmaceutical markets in the world."

The proposed clinical trial will be a prospective, open-label study that is designed to determine the safety and tolerability of the RPE cells following sub-retinal transplantation to patients with advanced SMD, similar to the FDA-cleared U.S. trial which is set to commence in the first half of this year. During the CTA review process, which requires a minimum of 60 days, the reviewers decide if an applicant is permitted to proceed with its proposed clinical trial. Additional information may be requested from the applicant, which could extend the review period.

"We are very excited about this European filing, because our preclinical data from various animal models with hESC-derived RPE cells have been tremendously encouraging," said Robert Lanza, M.D., chief scientific officer at ACT. "In rats we have seen 100 percent improvement in visual performance over untreated animals without any adverse effects. Near-normal function was also achieved in a mouse model of Stargardt's disease."

In 2010, the US Food and Drug Administration (FDA) granted Orphan Drug designation for ACT's RPE cells for treating SMD, and earlier this year the company received a positive opinion from the Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA) towards designation of this product as an orphan medicinal product for the treatment of Stargardt's disease. ACT anticipates adoption of the EMA's recommendation by the European Commission in coming weeks.

About Stargardt's Macular Dystrophy and Degenerative Diseases of the Retina

Stargardt's Macular Dystrophy (SMD) is one of the most common forms of macular degeneration in the world. SMD causes progressive vision loss, usually starting in children between 10 to 20 years of age. Eventually, blindness results from photoreceptor loss associated with degeneration in the pigmented layer of the retina, called the retinal pigment epithelium or RPE cell layer.

Degenerative diseases of the retina are among the most common causes of untreatable blindness in the world. As many as thirty million people in the United States and Europe suffer from macular degeneration, which represents a $25-30 billion worldwide market that has yet to be effectively addressed. Approximately 10% of people ages 66 to 74 will have symptoms of macular degeneration, the vast majority the "dry" form of AMD which is currently untreatable. The prevalence increases to 30% in patients 75 to 85 years of age.

Source: Advanced Cell Technology, Inc

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'Universal' Virus-Free Method Developed By Scientists To Turn Blood Cells Into 'Beating' Heart Cells

Johns Hopkins scientists have developed a simplified, cheaper, all-purpose method they say can be used by scientists around the globe to more safely turn blood cells into heart cells. The method is virus-free and produces heart cells that beat with nearly 100 percent efficiency, they claim.

"We took the recipe for this process from a complex minestrone to a simple miso soup," says Elias Zambidis, M.D., Ph.D., assistant professor of oncology and pediatrics at the Johns Hopkins Institute for Cell Engineering and the Kimmel Cancer Center.

Zambidis says, "many scientists previously thought that a nonviral method of inducing blood cells to turn into highly functioning cardiac cells was not within reach, but "we've found a way to do it very efficiently and we want other scientists to test the method in their own labs." However, he cautions that the cells are not yet ready for human testing.

To get stem cells taken from one source (such as blood) and develop them into a cell of another type (such as heart), scientists generally use viruses to deliver a package of genes into cells to, first, get them to turn into stem cells. However, viruses can mutate genes and initiate cancers in newly transformed cells. To insert the genes without using a virus, Zambidis' team turned to plasmids, rings of DNA that replicate briefly inside cells and eventually degrade.

Adding to the complexity of coaxing stem cells into other cell types is the expensive and varied recipe of growth factors, nutrients and conditions that bathe stem cells during their transformation. The recipe of this "broth" differs from lab to lab and cell line to cell line.

Reporting in the April 8 issue of Public Library of Science ONE (PLoS ONE), Zambidis' team described what he called a "painstaking, two-year process" to simplify the recipe and environmental conditions that house cells undergoing transformation into heart cells. They found that their recipe worked consistently for at least 11 different stem cell lines tested and worked equally well for the more controversial embryonic stem cells, as well as stem cell lines generated from adult blood stem cells, their main focus.

The process began with Johns Hopkins postdoctoral scientist Paul Burridge, Ph.D., who studied some 30 papers on techniques to create cardiac cells. He drew charts of 48 different variables used to create heart cells, including buffers, enzymes, growth factors, timing, and the size of compartments in cell culture plates. After testing hundreds of combinations of these variables, Burridge narrowed the choices down to between four to nine essential ingredients at each of three stages of cardiac development.

Beyond simplification, an added benefit is reduced cost. Burridge used a cheaper growth media that is one-tenth the price of standard media for these cells at $250 per bottle lasting about one week.

Zambidis says that he wants other scientists to test the method on their stem cell lines, but also notes that the growth "soup" is still a work in progress. "We have recently optimized the conditions for complete removal of the fetal bovine serum from one brief step of the procedure - it's made from an animal product and could introduce unwanted viruses," he says.

In their experiments with the new growth medium, the Hopkins team began with cord blood stem cells and a plasmid to transfer seven genes into the stem cells. They delivered an electric pulse to the cells, making tiny holes in the surface through which plasmids can slip inside. Once inside, the plasmids trigger the cells to revert to a more primitive cell state that can be coaxed into various cell types. At this stage, the cells are called induced pluripotent stem cells (iPSC).

Burridge then bathed the newly formed iPSCs in the now simplified recipe of growth media, which they named "universal cardiac differentiation system." The growth media recipe is specific to creating cardiac cells from any iPSC line.

Finally, they incubated the cells in containers that removed oxygen down to a quarter of ordinary atmospheric levels. "The idea is to recreate conditions experienced by an embryo when these primitive cells are developing into different cell types," says Burridge. They also added a chemical called PVA, which works like glue to make cells stick together.

Nine days later, the nonviral iPSCs turned into functional, beating cardiac cells, each the size of a needlepoint.

Burridge manually counted how often iPSCs formed into cardiac cells in petri dishes by peering into a microscope and identifying each beating cluster of cells. In each of 11 cell lines tested, each plate of cells had an average of 94.5 percent beating heart cells. "Most scientists get 10 percent efficiency for IPSC lines if they're lucky," says Zambidis.

Zambidis and Burridge also worked with Johns Hopkins University bioengineering experts to apply a miniversion of an electrocardiograph to the cells, which tests how cardiac cells use calcium and transmit a voltage. The resulting rhythm showed characteristic pulses seen in a normal human heart.

Virus-free, iPSC-derived cardiac cells could be used in laboratories to test drugs that treat arrhythmia and other conditions. Eventually, bioengineers could develop grafts of the cells that are implanted into patients who suffered heart attacks.

Zambidis' team has recently developed similar techniques for turning these blood-derived iPSC lines into retinal, neural and vascular cells.

Notes:

The research was funded by the Maryland Stem Cell Research Fund and the National Institutes of Health.

Research participants include Susan Thompson, Michal Millrod, Seth Weinberg, Xuan Yuan, Ann Peters, Vasiliki Mahairaki, Vassilis E. Koliatsos, and Leslie Tung at Johns Hopkins.

Source:
Vanessa Wasta
Johns Hopkins Medical Institutions

 

Study Of Umbilical Cord Blood-Derived Stem Cells For Lupus Therapy

Main Category: Lupus
Also Included In: Stem Cell Research
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Human umbilical cord blood-derived mensenchymal stem cells (uMSCs) have been found to offer benefits for treating lupus nephritis (LN) when transplanted into mouse models of systemic lupus erythematosus (SLE). SLE is an autoimmune disease with "myriad immune system aberrations" characterized by diverse clinical conditions, including LN, a leading cause of morbidity and mortality for patients with SLE.

The beneficial results were reported in a study by Taiwanese researchers published in the current issue of Cell Transplantation (20:2), freely available on-line here.

According to corresponding author Dr. Oscar K. Lee of the National Yang-Ming University School of Medicine, MSCs have been shown to possess immune-modulatory capabilities and can alleviate immune responses by inhibiting inflammation as well as the function of mature and immature immune system T cells. Seeking to explore the therapeutic effects of uMSCs in treating LN, their study transplanted umbilical cord blood-derived stem cells into mice modeled with systemic immune diseases closely resembling SLE in humans.

"We found that uMSC transplantation markedly delayed the deterioration of renal function, reduced certain antibody levels, alleviated changes in renal pathology and the development of proteinuria - the presence of excess protein serum in the urine and a sign of renal damage," said Dr. Lee.

The positive difference in survival rate for mice treated at two months of age compared with mice treated at six months of age, led the researchers to conclude that early uMSC transplantation may be most efficacious. The researchers also deduced that their findings favored the use of allogenic (other-donated) rather than autologous (self-donated) MSCs for SLE treatment, which would make sense with an autoimmune disorder.

"The therapeutic effects demonstrated in this pre-clinical study support further exploration of the possibility of using uMSCs from mismatched donors in LN treatment," concluded Dr. Lee.

"The ability of uMSCs to reduce inflammation means that they are likely to be of use in the treatment of autoimmune disorders and this study supports that reasoning and, in this case, also advocates the use of non-self cells," said Dr. David Eve, associate editor of Cell Transplantation and an instructor at the University of South Florida Center of Excellence for Aging and Brain Repair.

Citation:
Chang, J-W.; Hung , S-P.; Wu, H-H.; Wu, W-M.; Yang, A-H.; Tsai, H-L.; Yang, L-Y.; Lee, O. K. Therapeutic Effects of Umbilical Cord Blood-Derived Mesenchymal Stem Cell Transplantation in Experimental Lupus Nephritis. Cell Transplant. 20(2):245-257; 2011.

Source:
David Eve
Cell Transplantation Center of Excellence for Aging and Brain Repair

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To Reprogram Stem Cells Penn Study Eliminates The Use Of Transcription Factors And Increases Efficiency 100-Fold

Researchers at the University of Pennsylvania School of Medicine have devised a totally new and far more efficient way of generating induced pluripotent stem cells (iPSCs), immature cells that are able to develop into several different types of cells or tissues in the body. The researchers used fibroblast cells, which are easily obtained from skin biopsies, and could be used to generate patient-specific iPSCs for drug screening and tissue regeneration.

iPSCs are typically generated from adult non-reproductive cells by expressing four different genes called transcription factors. The generation of iPSCs was first reported in 2006 by Shinya Yamanaka, and multiple groups have since reported the ability to generate these cells using some variations on the same four transcription factors.

The promise of this line of research is to one day efficiently generate patient-specific stem cells in order to study human disease as well as create a cellular "storehouse" to regenerate a person's own cells, for example heart or liver cells. Despite this promise, generation of iPSCs is hampered by low efficiency, especially when using human cells.

"It's a game changer," says Edward Morrisey, PhD, professor in the Departments of Medicine and Cell and Developmental Biology and Scientific Director at the Penn Institute for Regenerative Medicine. "This is the first time we've been able to make induced pluripotent stem cells without the four transcription factors and increase the efficiency by 100-fold." Morrisey led the study published this week in Cell Stem Cell.

"Generating induced pluripotent stem cells efficiently is paramount for their potential therapeutic use," noted James Kiley, PhD, director of the National Heart, Lung, and Blood Institute's Division of Lung Diseases. "This novel study is an important step forward in that direction and it will also advance research on stem cell biology in general."

Before this procedure, which uses microRNAs instead of the four key transcription factor genes, for every 100,000 adult cells re-programmed, researchers were able to get a small handful of iPSCs, usually less than 20. Using the microRNA-mediated method, they have been able to generate approximately 10,000 induced pluripotent stem cells from every 100,000 adult human cells that they start with. MicroRNAs (miRNAs) are short RNA molecules that bind to complementary sequences on messenger RNAs to silence gene expression.

The Morrisey lab discovered this new approach through studies focusing on the role of microRNAs in lung development. This lab was working on a microRNA cluster called miR302/367, which plays an important role in lung endoderm progenitor development. This same microRNA cluster was reported to be expressed at high levels in embryonic stem cells, and iPSCs and microRNAs have been shown to alter cell phenotypes.

The investigators performed a simple experiment and expressed the microRNAs in mouse fibroblasts and were surprised to observe colonies that looked just like iPSCs. "We were very surprised that this worked the very first time we did the experiment," says Morrisey. "We were also surprised that it worked much more efficiently than the transcription factor approach pioneered by Dr. Yamanaka."

Since microRNAs act as repressors of protein expression, it seems likely that they repress the repressors of the four transcription factors and other factors important for maintaining the pluripotent-stem-cell state. However, exactly how the miRNAs work differently compared to the transcription factors in creating iPSCs will require further investigation.

The iPSCs generated by the microRNA method in the Morrisey lab are able to generate most, if not all, tissues in the developing mouse, including germ cells, eggs and sperm. The group is currently working with several collaborators to redifferentiate these iPSCs into cardiomyocytes, hematopoietic cells, and liver hepatocytes.

"We think this method will be very valuable in generating iPSCs from patient samples in a high-throughput manner" says Morrisey. microRNAs can also be introduced into cells using synthetically generated versions of miRNAs called mimics or precursors. These mimics can be easily introduced into cells at high levels, which should allow for a non-genetic method for efficiently generating iPSCs.

"The upshot is that we hope to be able to produce synthetic microRNAs to transform adult cells into induced pluripotent stem cells, which could eventually then be redifferentiated into other cell types, for example, liver, heart muscle or nerve cells" says Morrisey.

Other authors of the study include Frederick Anokye-Danso, Chinmay M. Trivedi, and Jonathan A. Epstein, all from Penn. These studies were funded by the National Heart, Lung and Blood Institute Progenitor Cell Biology Consortium and Division of Lung Disease and the American Heart Association Jon DeHaan Myogenesis Center Award.

Source:
Karen Kreeger
University of Pennsylvania School of Medicine

 

High-Profile Panel To Address Causes, Consequences Of The Politicization Of Science

Science is playing an increasingly prominent role in many controversial political, religious and socio-economic debates, such as those about embryonic stem cells, genetically modified foods, teaching evolution and climate change. As a result, scientists are finding themselves forced into the fray and frustrated when their data and findings are misunderstood by policymakers and the public and even misrepresented for political gains.

At 12:30 p.m. Sunday, April 10, at the Experimental Biology meeting in the Washington, D.C., Convention Center, three high-profile panelists will share their views on how science, the media, politics and society interact and, perhaps more importantly, what scientists themselves can do to communicate more effectively and restore their credibility.

Sponsored by the American Society for Biochemistry and Molecular Biology, the symposium will feature commentary by Nobel Prize winner Elizabeth Blackburn, Dr. James McCarthy, the chairman of the board of directors for the Union of Concerned Scientists, and author Michael Specter, a New Yorker staff writer who wrote the book "Denialism: How Irrational Thinking Hinders Scientific Progress, Harms the Planet and Threatens Our Lives."

The panel will be moderated by NPR science desk correspondent Richard Harris.

"Controversies over the politicization of science in recent history on issues like climate change and embryonic stem-cell research have begun to create an environment in which the public questions the political motivations of even the most unbiased scientist," says Ben Corb, the public affairs director for ASBMB. "This panel really will explore the critical need for scientists to stay above the fray, while also reminding politicians to leave politics out of our nation's laboratories."

The event will be held at 12:30 p.m. Sunday, April 10, in Ballroom C of the convention center.

Source:
Angela Hopp
Federation of American Societies for Experimental Biology

 

Choosing Whether Or Not To Donate IVF Embryos

People who use in vitro fertilization to conceive children often have leftover embryos and must decide whether to store them, dispose of them or possibly donate them for research. A new process developed by researchers at the Stanford University School of Medicine allows these people to make this decision in the privacy of their own homes - without any interaction with clinic personnel or scientists who might benefit from the research.

"There is concern that conflicts of interest and influence by researchers and clinicians may play a role in donor choice," said bioethicist and senior author of the research, Christopher Scott, who directs Stanford's Program on Stem Cells in Society. "The Stanford biobank process allows people time to make the primary decision to donate on their own, when it's right for them. It also allowed us to ask whether donors have preferences as to the type of research they will allow on their embryos."

The study will be published April 8 in Cell Stem Cell. The study includes a description of the process as well as the results of a survey indicating which research options were selected by those who chose to donate their embryos.

People who try in vitro fertilization often find themselves with excess embryos after they either successfully conceive or abandon their attempt to have children. Researchers believe that at least several hundred thousand are stored in clinics around the country. There is routinely a monthly or yearly storage fee to keep the embryos frozen in liquid nitrogen.

Many IVF clinics offer people the option of donating their embryos for research, but the procedures vary and often involve discussions between potential donors and experts as part of the decision-making process. Many also do not specify the types of research for which the embryos could be used.

In the two-part procedure described in the study, which is now used routinely at Stanford, information about potential donation for research is included in the normal embryo-storage bill from the clinic. "At that point," Scott said, "the recipients are free to throw the information away or put it on the coffee table to consider and talk about." Only after the couple has made the initial decision to donate do they interact with Stanford biobank staff members, who use a script to confirm donation choices and answer any questions the potential donors may have.

Specifically, people who indicated that they would like to donate were sent an informed-consent packet outlining the types of research that could be done with the embryos, such as creating embryonic stem cell lines or studying human development. (Research into human development typically occurs during the first 12 days of culture, after which the embryos are no longer grown. Embryonic stem cell research entails creating stem cell lines that can be propagated indefinitely in the laboratory and may be used for both research and therapy.)

Once the potential donors had time to review the material, they then participated in a phone interview with staff members at Stanford's biobank who were unconnected with either the original in vitro fertilization clinic or the researchers who might use the embryos. Staff members followed a script to confirm the donors' preferences and make sure they understood their options - including whether they wanted to be notified if the research unearthed any genetic information that might affect their health or the health of their relatives.

"Many couples were very relieved to have the option to donate their embryos for research and to participate in the field of stem cell research," said Stanford biobank research manager and study first author Tasha Kalista. The researchers found that donors were equally likely to give consent for their use in the creation of embryonic stem cell lines as for the study of human development.

In addition to outlining the new process, the paper also reports on the preferences of the participants. The researchers found that people who choose to donate their embryos for research are primarily concerned that they not be used to make a baby for someone else. Although people have the option to put their embryos up for "adoption," that is an entirely separate process from donating an embryo for research purposes. Nonetheless, many donors asked for reassurance.

The researchers did not have sufficient data to determine what proportion of potential donors chose to either continue storing their embryos or to dispose of them.

The researchers surveyed the preferences of 403 couples who donated 1,356 embryos to Stanford for research. The embryos had been stored at one of 40 in vitro fertilization clinics or three storage facilities in 20 states. About one-fifth of those surveyed had used donated eggs or sperm and were excluded from further analysis because consent for embryonic stem cell research would have also been required from the egg and sperm donors. Of those remaining, 32 percent gave consent for their embryos to be used only for the study of human development and 30 percent only for stem cell research. Thirty-eight percent gave consent for their embryos to be used for either type of research.

In the future, Scott and the other researchers would like to determine what proportion of potential donors choose to give embryos for research. They'd also like to find out if donors' choices are influenced by where they live.

Other Stanford researchers involved in the study include Renee Reijo Pera, PhD, professor of obstetrics and gynecology and director of Stanford's Center for Human Embryonic Stem Cell Research and Education; Barry Behr, PhD, professor of obstetrics and gynecology and director of Stanford's RENEW Biobank; and research associate H. Austinn Freeman. The research was funded by the California Institute for Regenerative Medicine and Stanford University.

Source:
Krista Conger
Stanford University Medical Center

 

Scientists Identify A Surprising New Source Of Cancer Stem Cells

Whitehead Institute researchers have discovered that a differentiated cell type found in breast tissue can spontaneously convert to a stem-cell-like state, the first time such behavior has been observed in mammalian cells. These results refute scientific dogma, which states that differentiation is a one-way path; once cells specialize, they cannot return to the flexible stem-cell state on their own.

This surprising finding, published online this week in the Proceedings of the National Academy of Sciences (PNAS), may have implications for the development of cancer therapeutics, particularly those aimed at eradicating cancer stem cells.

"It may be that if one eliminates the cancer stem cells within a tumor through some targeted agent, some of the surviving non-stem tumor cells will generate new cancer stem cells through spontaneous de-differentiation," says Whitehead Founding Member Robert Weinberg. Cancer stem cells are uniquely capable of reseeding tumors at both primary and distant sites in the body.

During differentiation, less-specialized stem cells mature into many different cell types with defined functions. These differentiated cells work together to form tissues and organs. In breast tissue, for example, differentiated basal cells and luminal cells combine to form milk ducts.

While analyzing cells from human breast tissue, Christine Chaffer, who is a postdoctoral researcher in the Weinberg lab and first author of the PNAS paper, observed a small number of living basal cells floating freely in the tissue culture medium.

Intrigued by the cells' unusual behavior, Chaffer conducted further targeted investigations, including injection of the floating basal cells into mice. After 12 weeks she found that the injected basal cells gave rise to milk duct-like structures containing both basal and luminal cells a clear indication that the floating cells had de-differentiated into stem-like cells.

Until now, no one has shown that differentiated mammalian cells, like these basal cells, have the ability to spontaneously revert to the stem-like state (a behavior described as plasticity).

To see if basal cells could become cancer stem cells, Chaffer inserted cancer-causing genes into the cells. When these transformed cells were injected into mice, the resulting tumors were found to include a cancer stem cell population that descended from the original injected basal (more differentiated) cells. These results indicate that basal cells in breast cancer tumors can serve as a previously unidentified source of cancer stem cells.

As research for new cancer therapies has recently focused on eliminating cancer stem cells, Weinberg cautions that the plasticity seen in these basal cells suggests a more complicated scenario than previously thought.

"Future drug therapies that are targeted against cancer will need to eliminate the cancer stem cells and, in addition, get rid of the non-stem cells in tumors both populations must be removed," says Weinberg, who is also a professor of biology at MIT. "Knocking out one or the other is unlikely to suffice to generate a durable clinical response."

Chaffer is now focusing on what actually prompts these flexible cells to de-differentiate, and in the case of cancer cells, how to stop the cells from converting into cancer stem cells.

"This plasticity can occur naturally, and it seems that the trigger may be a physiological mechanism for restoring a pool of stem cells," says Chaffer. "We believe that certain cells are more susceptible to such a trigger and therefore to conversion from a differentiated to a stem-like state, and that this process occurs more frequently in cancerous cells."

In the case of normal epithelial cells, the observed behavior may also allow patient specific adult stem cells to be derived without genetic manipulation, holding promise for degenerative disease therapy.

This research was supported by the National Health and Medical Research Council of Australia, National Institutes of Health, MIT's Ludwig Center for Molecular Oncology, the Breast Cancer Research Foundation, and a Department of Defense Breast Cancer Research Program Idea Award.

Source: Whitehead Institute for Biomedical Research

 

Pig Stem Cell Transplants: The Key To Future Research Into Retina Treatment

A team of American and Chinese scientists studying the role of stem cells in repairing damaged retina tissue have found that pigs represent an effective proxy species to research treatments for humans. The study, published in Stem Cells, demonstrates how cells can be isolated and transplanted between pigs, overcoming a key barrier to the research.

Treatments to repair the human retina following degenerative diseases remain a challenge for medical science. Unlike species of lower vertebrates the human retina lacks a regenerative pathway meaning that research has focused on cell transplantation.

"The retina is the light sensitive tissue surrounding the inner surface of the eye. Its outer layer is made up of rods and cone photoreceptor cells which convert light signals," said lead author Douglas Dean from the University of Louisville. "Traditionally transplant studies have focused on mice and other rodents because of the variety of genetic material they represent, however mouse retina tissue is rod dominant, which is significantly different to the human eye."

Dr Dean's team turned their attention to pigs because, as with humans, the swine eye contains a cone dominant central visual streak, making it a closer anatomical and physiological match.

"Studies into swine models have been hampered in the past," said Dean, "because the induced pluripotent stem cells (iPSCs) needed for such transplants have not been isolated from pigs, while their compatibility with a host's photoreceptor cells had not been demonstrated."

Dr Dean's team gathered iPSCs from swine skin fibroblasts and demonstrated that these cells differentiated in culture and could be integrated with the cells of a second pig's retina.

While only a small section of the retina was transplanted for this study the results could open a new avenue of research into degenerative conditions as researchers have a more effective human proxy species to work with.

"Our results demonstrate that swine stem cells can be integrated into a damaged swine neural retina," concluded Dean. "This research now lays a foundation for future studies of retinal stem cell transplantation in a swine model."

Full citation: Zhou. L, Wang. W, Liu. Y, Fernandez de Castro. J, Ezashi. T, Telugu. B, Roberts. M, Kaplan. H, Dean. D, "Differentiation of Swine iPSC into Rod Photoreceptors and Their Integration into the Retina", Stem Cells, Wiley-Blackwell, DOI: 10.1002/stem.637

Source:
Alpha Med Press
Wiley-Blackwell

 

Periodontal Stem Cell Transplantation Shows Promise

Periodontal ligament stem cells (PDLSCs) have been found to be the most efficacious of three kinds of clinically tested dental tissue-derived stem cells, reports a study published in the current issue of Cell Transplantation (20:2), freely available on-line here.

According to researchers in Seoul, South Korea, transplantation of PDLSCs into beagle dogs modeled with advanced periodontal (gum) disease that affected their premolars and molars, which are morphologically similar to the corresponding areas in human dentition, was most effective. PDLSCs showed the best regenerating capacity of the periodontal ligament (which attaches the tooth to the alveolar bone in which the teeth sit), alveolar bone, cementum (material that comprises the surface of a tooth's root), peripheral nerve and blood vessels when compared to similar transplants using dental pulp stem cells (taken from the center of teeth) or periapical follicular stem cells (taken from the developing root).

"Periodontitis, characterized by bone resorption, periodontal pocketing and gingival inflammation, is the most common cause of tooth loss in adults and affects 10 to 15 percent of adults worldwide," said corresponding author Dr. Pill-Hoon Choung of the Seoul National University School of Dentistry. "Our study sought to evaluate the effectiveness of autologous stem cell transplantation (i.e. transplant of a patient's own cells) using three kinds of autologous dental stem cells similar to mensenchymal stem cells."

Past efforts at improving periodontal regeneration included xenogenic (from a different species) bone particle graft using growth factors, but the clinical results were generally unsatisfactory, said the researchers.

In their stem cell transplant study, Dr. Choung's group found PDLSCs to be most efficacious of the three cell types since they offered the best results with respect to the quality and quantity of regenerated tissues.

"PDLSCs made more calcium nodules and showed higher alkaline phosphatase (ALP) activity than did the other two stem cell varieties," added Dr. Choung.

The researchers concluded that further studies should investigate which factors influence the stabilization and differentiation in the diseased periodontal microenvironment and which factors make the three kinds of dental stem cells react differently in vivo.

"This study highlights the diverse sources of stem cells available in the tissues of the body for repair and how the optimal cell type for possible treatments needs to be determined - in this case for the treatment of dental-related disorders such as gum disease" said Dr. Paul Sanberg, coeditor-in-chief of Cell Transplantation and executive director of the University of South Florida Center of Excellence for Aging and Brain Repair.

Citation:
Park, J-Y.; Jeon, S. H.; Choung, P-H. Efficacy of periodontal stem cell transplantation in the treatment of advanced periodontitis. Cell Transplantation. 20(2):271-285; 2011.

Source:
David Eve
Cell Transplantation Center of Excellence for Aging and Brain Repair

 

Cardiac Stem Cell Treatment For Heart Failure Discussed By Roberto Bolli At Cannon Lecture

Heart failure affects roughly six million Americans, yet treatment consists of either a heart transplant or the insertion of mechanical devices that assist the heart. This is unacceptable to Roberto Bolli, MD, Chief of the Division of Cardiovascular Medicine at the University of Louisville in Louisville, Ky., which is why he is on a mission to make cardiac stem cell treatment an option for all who must cope with the limitations of a failing heart.

Dr. Bolli is conducting the groundbreaking study, "Cardiac Stem Cell Infusion in Patients with Ischemic cardiOmyopathy (SCIPIO)," in which researchers at the University of Louisville's Jewish Hospital are collaborating with a team led by Piero Anversa, MD, at the Brigham and Women's Hospital in Boston to perfect a technique for using a patient's own cardiac stem cells to regenerate dead heart muscle after a heart attack.

In honor of his illuminating work, the American Physiological Society (APS) selected Dr. Bolli to present the Walter B. Cannon Memorial Lecture at the Experimental Biology 2011 meeting (EB 2011). This lecture is the Society's pre-eminent award lecture and is designed to recognize an outstanding scientist for his or her contributions to the field.

A Tale of Two Proteins

The cardiac stem cell treatment investigated in the SCIPIO trial consists of isolating the patient's cardiac stem cells from part of the upper chamber of the heart (harvested during coronary bypass surgery) and expanding these cells in the lab. Four months after surgery, the cells are infused into scarred cardiac tissue by catheterizing a large artery in the patient's leg. Using the patient's own cardiac stem cells eliminates the possibility of rejection.

Besides SCIPIO, Dr. Bolli is also performing basic research aimed at on enhancing the cardiac stem cells while they are cultured in the lab for expansion. He is working with two proteins, heme oxygenase 1 (HO-1) and nitric oxide synthase (NOS). HO-1 is a protein made in response to cellular stress, such as oxidative stress or oxygen deficiency. It catalyzes the breakdown of heme, which is a molecular component of hemoglobin, the part of the red blood cell that transports oxygen around the body. When HO-1 breaks down heme, one of the by-products is carbon monoxide (CO). NOS, the other protein Dr. Bolli is investigating, is an enzyme that catalyzes the production of nitric oxide (NO). Dr. Bolli is focusing on these two proteins because their catalytic by-products, CO and NO, exert remarkable beneficial effects.

"When the heart muscle is dying because of a heart attack, these gases (CO and NO) are extremely cardioprotective and help the tissue survive," he says. "We are now applying these same proteins to stem cells, using the knowledge that we have gained from 20 years of research in cardioprotection."

A Promising Future

So far, the results are promising. "We have exciting data indicating that if we increase these proteins in stem cells, the stem cells become more resilient and more effective at repairing damage," Dr. Bolli says.

Even with natural cells (in which these proteins are not increased), such as those used in SCIPIO, the results are very encouraging. Improvements seen in patients who have received cardiac stem cell infusion include increased ejection fraction, the fraction of blood pumped through the two lower chambers of the heart. Patients also experience dramatic improvements in what they are able do physically, Dr. Bolli says. "There are people who are almost completely incapacitated, and after they get stem cells, they can do so much more. I have a patient who couldn't walk to the bathroom, and now he can walk two miles."

Dr. Bolli cautions that SCIPIO is a Phase 1 trial, meaning that it is the first round of testing in humans. Its primary purpose is to assess safety and feasibility, rather than efficacy. Yet, he remains optimistic and notes that cardiac stem cells offer the hope of healing the heart. "All of the other treatments currently available - transplants, assist devices, drugs - may prolong life but do not solve the problem. By regenerating new heart muscle, cardiac stem cells could actually solve the problem."

To date, 17 patients have received cardiac stem cells in the SCIPIO trial. Dr. Bolli discussed his research and provided the latest details of how the patients are faring when he presented this year's Cannon Lecture, "The nitric oxide-carbon monoxide module: A fundamental mechanism of cellular resistance to stress," on Saturday, April 9 at the Walter E. Washington Convention Center.

Walter B. Cannon Award Lecture

The Cannon Award lectureship, established in 1982, is the APS' highest award. The individual selected is an outstanding physiological scientist chosen by the President-Elect, with the consent of Council, to lecture on "Physiology in Perspective" during the plenary session of the Society's next annual meeting. At the 1984 fall meeting, the title of the presentation was changed to "Physiology in Perspective: The Walter B. Cannon Lecture."

Source:
Donna Krupa
American Physiological Society

 

Dainippon Sumitomo Pharma Co., Ltd. And Boston Biomedical, Inc. Enter Strategic Partnership On Anti-Cancer Drugs Targeting Cancer Stem Cells

Dainippon Sumitomo Pharma Co., Ltd. ("DSP") and Boston Biomedical, Inc. ("BBI"), announced that they have signed a Product Option License Agreement for BBI608 for all oncology indications in Japan and exclusive right of negotiation for BBI608 for the United States and Canada.

BBI608 is an orally administered, first-in-class, small molecule anti-cancer drug that targets highly malignant cancer stem cells as well as other heterogeneous cancer cells. In clinical trials to date, BBI608 has shown excellent safety, favorable pharmacokinetics, and encouraging signs of anticancer activity. BBI608 is under phase I extension clinical studies in colorectal cancer and phase Ib/II trials in multiple solid tumor types.

Under the terms of the agreement, BBI will receive $15million of upfront payment and clinical trial support upon signing. Based on the outcome of the clinical trials, DSP has the option to acquire exclusive rights for the development and commercialization for BBI608 in Japan. In addition, DSP has an exclusive negotiation right for the United States and Canada for a certain time. During this option agreement period, DSP will pay a maximum of $55million for part of the development costs of BBI608 and for continuation of the option. Assuming DSP exercise the option for Japan, upon successful clinical development and commercialization of BBI608 in Japan, BBI could receive a maximum of approximately $100million in aggregate, including milestone payments associated with successful development and commercialization, in addition to running royalties.

Masayo Tada, President and chief executive officer of DSP, said, "DSP recognizes oncology as an area with high unmet medical needs and has already spent substantial effort, defining it as a major specialty area. We are delighted to enter into this strategic partnership with Boston Biomedical in the oncology area to develop BBI608 as a highly differentiated, novel anti-cancer drug. With the addition of BBI608 to our research pipeline, DSP hopes to raise its presence in the therapeutic area of cancer while making a contribution to treatment for cancer patients."

"We are excited to form this strategic oncology partnership with Dainippon Sumitomo Pharma on BBI608," said Chiang J. Li, Chairman and chief executive officer of BBI. "With DSP's outstanding track record in bringing innovative medicine to patients, this partnership marks not only a significant milestone for BBI as we execute our global development strategy for BBI608, but also a significant step towards translating cancer stem cell science to truly innovative therapeutics for cancer patients."

About BBI608 and Cancer Stem Cells

BBI608 is a first-in-class, cancer stem cell inhibitor, currently in clinical development. Cancer stem cells (CSCs), being refractory to current cancer therapies, represent an emerging approach for designing the next generation of oncology therapeutics. CSCs are considered to be fundamentally responsible for malignant growth, metastasis, and recurrence. These cells are a subpopulation of cancer cells that have self-renewal ability and can differentiate into the heterogeneous cancer cells that comprise the bulk of the tumor mass. CSCs have been isolated from almost every major type of cancer, and have been found to be intrinsically resistant to current cancer therapies. Targeting CSCs, therefore, holds great promise for fundamentally advancing cancer treatment.

BBI608, through its undisclosed molecular target, simultaneously inhibits multiple key cancer cell stemness pathways. BBI608 targets highly malignant CSCs as well as heterogeneous cancer cells. In clinical trials to date, BBI608 has shown excellent safety, favorable pharmacokinetics, and encouraging signs of anticancer activity against a broad range of tumor types. BBI608 is currently in phase I extension in colorectal cancer and phase Ib/II trials for combination therapy with paclitaxel for selected solid tumor types.

Source: Boston Biomedical, Inc

 

Brain Cells Recreated From Skin Cells To Study Schizophrenia Safely

Main Category: Schizophrenia
Also Included In: Autism;  Bipolar;  Stem Cell Research
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A team of scientists at Penn State University, the Salk Institute for Biological Studies, and other institutions have developed a method for recreating a schizophrenic patient's own brain cells, which then can be studied safely and effectively in a Petri dish. The method brings researchers a step closer to understanding the biological underpinnings of schizophrenia. The method also is expected to be used to study other mysterious diseases such as autism and bipolar disorder, and the researchers hope that it will open the door to personalized medicine - customized treatments for individual sufferers of a disease based on genetic and cellular information. The study will be published in a future edition of the journal Nature and will be posted on the journal's advance online website on 13 April 2011.

Gong Chen, an associate professor of biology at Penn State and one of the study's authors, explained that the team first took samples of skin cells from schizophrenic patients. Then, using molecular-biology techniques, they reprogrammed these original skin cells to become unspecialized or undifferentiated stem cells called induced pluripotent stem cells (iPSCs). "A pluripotent stem cell is a kind of blank slate," Chen explained. "During development, such stem cells differentiate into many diverse, specialized cell types, such as a muscle cell, a brain cell, or a blood cell."

After generating iPSCs from skin cells, the authors cultured them to become brain cells, or neurons. They then compared the neurons derived from schizophrenic patients to the neurons created from the iPSCs of healthy individuals. They found that the neurons generated from schizophrenic patients were, in fact, distinct: compared with healthy neurons, they made fewer connections with each other. Kristen Brennand, a Salk researcher and one of the study's authors, then administered a number of frequently prescribed antipsychotic medications to test the drugs' ability to improve how neurons communicate with neighboring cells. "Now, for the very first time, we have a model system that allows us to study how antipsychotic drugs work in live, genetically identical neurons from patients with known clinical outcomes, and we can start correlating pharmacological effects with symptoms," Brennand said.

Chen, who contributed to the study by using electrophysiology techniques to test the function of the iPSC-derived neurons, described the new method as "patient specific," offering a step toward personalized medicine for sufferers of schizophrenia and potentially other diseases. "What's so exciting about this approach is that we can examine patient-derived neurons that are perhaps equivalent to a particular patient's own neural cells," Chen said. "Obviously, we don't want to remove someone's brain cells to experiment on, so recreating the patient's brain cells in a Petri dish is the next best thing for research purposes. Using this method, we can figure out how a particular drug will affect that particular patient's brain cells, without needing the patient to try the drug, and potentially, to suffer the side effects. The patient can be his or her own guinea pig for the design of his or her own treatment, without having to be experimented on directly."

Lead author Fred Gage, a professor at Salk's Laboratory of Genetics and holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases, explained that schizophrenia exemplifies many of the research challenges posed by complex psychiatric disorders. "This model not only affords us the opportunity to look at live neurons from schizophrenia patients and healthy individuals to understand more about the disease mechanism, but also it allows us to screen for drugs that may be effective in reversing it," Gage said.

Schizophrenia, which is defined by a combination of paranoid delusions, auditory hallucinations, and diminished cognitive function, afflicts one percent of the population worldwide, corresponding to nearly three million people in the United States alone. Genetic evidence indicates that many different combinations of genetic lesions - some of them affecting the susceptibility to environmental influences - may lead to a variety of signs and symptoms collectively labeled schizophrenia.

"Nobody knows how much the environment contributes to the disease," said Brennand. "By growing neurons in a dish, we can take the environment out of the equation and start focusing on the underlying biological problems." In another part of the study, Brennand used a modified rabies virus, developed by Salk professors Edward Callaway and John Young, to highlight the connections between neurons. The viral tracer made it apparent that the schizophrenic neurons connected less frequently with each other and had fewer projections growing out from their cell bodies. In addition, gene-expression profiles identified almost 600 genes whose activity was misregulated in these neurons; 25 percent of those genes had been implicated in schizophrenia before.

Gage added that, for many years, mental illness has been thought of as a strictly social or environmental disease. "Many people believed that if affected individuals just worked through their problems, they could overcome them," he said. "But we are showing real biological dysfunctions in neurons that are independent of the environment."

Notes:

In addition to Gage, Brennand, and Chen, other researchers who contributed to the study include Anthony Simone, Jessica Jou, Chelsea Gelboin-Burkhart, Ngoc Tran, Sarah Sangar, Yan Li, Yanglin Mu and Diana Yu in the Gage Laboratory; Shane McCarthy at the Cold Spring Harbor Laboratory in New York; and Jonathan Sebat at the University of California at San Diego.

The work was funded, in part, by the California Institute for Regenerative Medicine, the Lookout Foundation, the Mathers Foundation, and the Helmsley Foundation.

Source:
Barbara Kennedy
Penn State

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Dopamine Controls Formation Of New Brain Cells

A study of the salamander brain has led researchers at Karolinska Institutet in Sweden to discover a hitherto unknown function of the neurotransmitter dopamine. In an article published in the prestigious scientific journal Cell Stem Cell they show how in acting as a kind of switch for stem cells, dopamine controls the formation of new neurons in the adult brain. Their findings may one day contribute to new treatments for neurodegenerative diseases, such as Parkinson's.

The study was conducted using salamanders which unlike mammals recover fully from a Parkinson's-like condition within a four week period. Parkinson's disease is a neurodegenerative disease characterised by the death of dopamine-producing cells in the mid-brain. As the salamander re-builds all lost dopamine-producing neurons, the researchers examined how the salamander brain detects the absence of these cells. This question is a fundamental one since it has not been known what causes the new formation of nerve cells and why the process ceases when the correct number have been made.

What they found out was that the salamander's stem cells are automatically activated when the dopamine concentration drops as a result of the death of dopamine-producing neurons, meaning that the neurotransmitter acts as a constant handbrake on stem cell activity.

"The medicine often given to Parkinson's patients is L-dopa, which is converted into dopamine in the brain," says Dr Andras Simon, who led the study at the Department of Cell and Molecular Biology. "When the salamanders were treated with L-dopa, the production of new dopamine-producing neurons was almost completely inhibited and the animals were unable to recover. However, the converse also applies. If dopamine signalling is blocked, new neurons are born unnecessarily."

As in mammals, the formation of neurons in the salamander mid-brain is virtually non-existent under normal circumstances. Therefore by studying the salamander, scientists can understand how the production of new nerve cells can be resumed once it has stopped, and how it can be stopped when no more neurons are needed. It is precisely in this regulation that dopamine seems to play a vital part. Many observations also suggest that similar mechanisms are active in other animal species too. Further comparative studies can shed light on how neurotransmitters control stem cells in the brain, knowledge that is of potential use in the development of therapies for neurodegenerative diseases.

"One way of trying to repair the brain in the future is to stimulate the stem cells that exist there," says Dr Simon. "This is one of the perspectives from which our study is interesting and further work ought to be done on whether L-dopa, which is currently used in the treatment of Parkinson's, could prevent such a process in other species, including humans. Another perspective is how medicines that block dopamine signalling and that are used for other diseases, such as psychoses, affect stem cell dynamics in the brain."

The salamander is a tailed member of the frog family most known for its ability to regenerate lost body parts, such as entire limbs.

Publication: 'Dopamine Controls Neurogenesis in the Adult Salamander Midbrain in Homeostasis and during Regeneration of Dopamine Neurons', Anders A Berg, Matthew Kirkham, Heng Wang, Jonas Frisén & Andras Simon, Cell Stem Cell, online 7 April 2011.

Source:
Karolinska Institutet

 

GIS Scientists Propose A New Paradigm For Embryonic Stem Cells, Potentially Speeding Up Development Of Disease Therapies

Scientists from the Genome Institute of Singapore (GIS) have put forward a novel explanation for the pluripotency[1] of embryonic stem (ES) cells. Their groundbreaking explanation opens new doors for understanding how stem cells create specific cell types, fundamental knowledge that will drive changes and improvements in the therapeutic and translational usage of stem cells. A better understanding of ES cells could help advance the development of treatments for diseases such as diabetes, Parkinson's disease, and Huntington's disease. The work, published in the journal Cell Stem Cell, was led by Dr Bing Lim, Senior Group Leader of the Stem Cell and Developmental Biology department at the GIS, and Kyle Loh, GIS student from Dr Lim's lab.

By re-examining current data with a fresh eye, Lim and Loh were able to suggest a novel paradigm that may resolve the 30-year-old mystery behind pluripotency. The prevailing model of stem cell pluripotency suggests that stem cell genes active in ES cells prevent these stem cells from turning into specific cell types. This model accounts for how ES cells can remain undifferentiated, but is unable to explain convincingly the ability of stem cells to create any bodily cell type. Lim and Loh suggest that, contrary to current thinking, individual stem cell genes do not completely suppress differentiation, but instead actively direct ES cells to produce particular bodily cell types. In their new paradigm, Lim and Loh propose that the activation of a combination of such stem cell genes within ES cells is what enables ES cells to create any bodily cell type.

[1] Pluripotency refers to the ability of ES cells to differentiate into all bodily cell types. ES cells can potentially create, on demand, any cell type that clinicians or scientists need for therapeutic, biotechnological, or research purposes. Hence, the cells are currently used as a source of specialized cell types used in cell replacement therapies. An understanding of how ES cells are able to produce all these cell types is of intense pragmatic and theoretical interest.

Source
Genome Institute of Singapore