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