Stem Cell Clinic

Stem Cell Research at Johns Hopkins Medicine: Parkinsons …

Ted Dawson, M.D., Ph.D., professor of neurology and co-director of NeuroICE explains where we are in using stem cells to treat Parkinsons Disease.

Were creating induced pluripotent stem (iPS) cells from patients with Parkinsons disease with the intent of turning them into dopamine neurons that we can study in a dish and also put into animals. We want to see if human iPS derived neurons grown in culture or in a mouse can lead to disease, and if it can, to study the mechanisms of why cells degenerate and test our hypotheses, drugs and targets in human cells.

If you look at the work thats been done in neurodegenerative diseases in animal models, weve been good at slowing progression of disease, but when we go to humans, the trials fail. So why is that? Perhaps because in mice were able to intervene very early in the disease, but in humans were treating late. Maybe the treatment would work if we treated early in humans, but this would require the ability to diagnosis the disease prior to the onset of symptoms. The other possibility is that Parkinsons disease in a mouse is different than a man.

Using iPS cells we can test new therapies in human neurons for the first time. One of the reasons there have been tremendous new therapies with cancers is that scientists can biopsy human tumors and use those cells to design drugs. Now stem cells are putting us in a position to be able to study neurodegenerative diseases in a similar way.

For developmental diseases such as Down syndrome and schizophrenia, theres no question in my mind that iPS will change the ways those diseases are studied and treated. With an adult-onset neurodegenerative disorder that takes 50 years to develop in humans, the big question is whether an iPS cell will have Parkinsons disease after growing in a mouse for a few months. We just dont know. But we need to do the experiment.

Lots of people thought Parkinsons was going to be low hanging fruit for stem cell transplantation. But we still dont fully understand the transplantation process and how to optimize it. There needs to be a lot of work done to get to that point. And medical therapy for Parkinsons is so advanced that transplantation right now probably isnt going to be any better than what we can already do. But that doesnt mean we shouldnt be forging ahead, using stem cells to discover more about the disease in order to find new drugs as well as refine our ideas about transplantation.

--Interviewed by Maryalice Yakutchik

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Stem Cell Research at Johns Hopkins Medicine: Parkinsons ...

Zika virus kills brain cancer stem cells – Washington University School of Medicine in St. Louis

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Virus potentially could be used to treat deadly disease

Brain cancer stem cells (left) are killed by Zika virus infection (image at right shows cells after Zika treatment). A new study shows that the virus, known for killing cells in the brains of developing fetuses, could be redirected to destroy the kind of brain cancer cells that are most likely to be resistant to treatment.

While Zika virus causes devastating damage to the brains of developing fetuses, it one day may be an effective treatment for glioblastoma, a deadly form of brain cancer. New research from Washington University School of Medicine in St. Louis and the University of California San Diego School of Medicine shows that the virus kills brain cancer stem cells, the kind of cells most resistant to standard treatments.

The findings suggest that the lethal power of the virus known for infecting and killing cells in the brains of fetuses, causing babies to be born with tiny, misshapen heads could be directed at malignant cells in the brain. Doing so potentially could improve peoples chances against a brain cancer glioblastoma that is most often fatal within a year of diagnosis.

We showed that Zika virus can kill the kind of glioblastoma cells that tend to be resistant to current treatments and lead to death, said Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine at Washington University School of Medicine and the studys co-senior author.

The findings are published Sept. 5 in The Journal of Experimental Medicine.

Each year in the United States, about 12,000 people are diagnosed with glioblastoma, the most common form of brain cancer. Among them is U.S. Sen. John McCain, who announced his diagnosis in July.

The standard treatment is aggressive surgery, followed by chemotherapy and radiation yet most tumors recur within six months. A small population of cells, known as glioblastoma stem cells, often survives the onslaught and continues to divide, producing new tumor cells to replace the ones killed by the cancer drugs.

In their neurological origins and near-limitless ability to create new cells, glioblastoma stem cells reminded postdoctoral researcher Zhe Zhu, PhD, of neuroprogenitor cells, which generate cells for the growing brain. Zika virus specifically targets and kills neuroprogenitor cells.

In collaboration with co-senior authors Diamond and Milan G. Chheda, MD, of Washington University School of Medicine, and Jeremy N. Rich, MD, of UC San Diego, Zhu tested whether the virus could kill stem cells in glioblastomas removed from patients at diagnosis. They infected tumors with one of two strains of Zika virus. Both strains spread through the tumors, infecting and killing the cancer stem cells while largely avoiding other tumor cells.

The findings suggest that Zika infection and chemotherapy-radiation treatment have complementary effects. The standard treatment kills the bulk of the tumor cells but often leaves the stem cells intact to regenerate the tumor. Zika virus attacks the stem cells but bypasses the greater part of the tumor.

We see Zika one day being used in combination with current therapies to eradicate the whole tumor, said Chheda, an assistant professor of medicine and of neurology.

To find out whether the virus could help treat cancer in a living animal, the researchers injected either Zika virus or saltwater (a placebo) directly into the brain tumors of 18 and 15 mice, respectively. Tumors were significantly smaller in the Zika-treated mice two weeks after injection, and those mice survived significantly longer than the ones given saltwater.

If Zika were used in people, it would have to be injected into the brain, most likely during surgery to remove the primary tumor. If introduced through another part of the body, the persons immune system would sweep it away before it could reach the brain.

The idea of injecting a virus notorious for causing brain damage into peoples brains seems alarming, but Zika may be safer for use in adults because its primary targets neuroprogenitor cells are rare in the adult brain. The fetal brain, on the other hand, is loaded with such cells, which is part of the reason why Zika infection before birth produces widespread and severe brain damage, while natural infection in adulthood causes mild symptoms.

The researchers conducted additional studies of the virus using brain tissue from epilepsy patients and showed that the virus does not infect noncancerous brain cells.

As an additional safety feature, the researchers introduced two mutations that weakened the viruss ability to combat the cells defenses against infection, reasoning that the mutated virus still would be able to grow in tumor cells which have a poor antiviral defense system but would be eliminated quickly in healthy cells with a robust antiviral response.

When they tested the mutant viral strain and the original parental strain in glioblastoma stem cells, they found that the original strain was more potent, but that the mutant strain also succeeded in killing the cancerous cells.

Were going to introduce additional mutations to sensitize the virus even more to the innate immune response and prevent the infection from spreading, said Diamond, who also is a professor of molecular microbiology, and of pathology and immunology. Once we add a few more changes, I think its going to be impossible for the virus to overcome them and cause disease.

Zhu Z, Gorman MJ, McKenzie LD, Chai JN, Hubert CG, Prager BC, Fernandez E, Richner JM, Zhang R, Shan C, Wang X, Shi P-Y, Diamond MS, Rich JN, Chheda MG. Zika Virus Has Oncolytic Activity against Glioblastoma Stem Cells. The Journal of Experimental Medicine. Sept. 5, 2017.

This study was funded by the National Institutes of Health (NIH), grant numbers R01 AI073755, R01 AI104972, CA197718, CA154130, CA169117, CA171652, NS087913 and NS089272; the Pardee Foundation; the Concern Foundation; the Cancer Research Foundation and the McDonnell Center for Cellular and Molecular Neurobiology of Washington University.

Washington University School of Medicines 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked seventh in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Zika virus kills brain cancer stem cells - Washington University School of Medicine in St. Louis

The protein TAZ sends ‘mixed signals’ to stem cells – Phys.Org

September 6, 2017 The protein TAZ (green) in the cytoplasm (the region outside of the nuclei, blue) promotes the self-renewal of human embryonic stem cells. Credit: Xingliang Zhou/Ying Lab, USC Stem Cell

Just as beauty exists in the eye of the beholder, a signal depends upon the interpretation of the receiver. According to new USC research published in Stem Cell Reports, a protein called TAZ can convey very different signalsdepending upon not only which variety of stem cell, but also which part of the stem cell receives it.

When it comes to varieties, some stem cells are "nave" blank slates; others are "primed" to differentiate into certain types of more specialized cells. Among the truly nave are mouse embryonic stem cells (ESCs), while the primed variety includes the slightly more differentiated mouse epiblast stem cells (EpiSCs) as well as so-called human "ESCs"which may not be true ESCs at all.

In the new study, PhD student Xingliang Zhou and colleagues in the laboratory of Qi-Long Ying demonstrated that nave mouse ESCs don't require TAZ in order to self-renew and produce more stem cells. However, they do need TAZ in order to differentiate into mouse EpiSCs.

The scientists observed an even more nuanced situation for the primed varieties of stem cells: mouse EpiSCs and human ESCs. When TAZ is located in the nucleus, this prompts primed stem cells to differentiate into more specialized cell typesa response similar to that of the nave cells. However, if TAZ is in the cytoplasm, or the region between the nucleus and outer membrane, primed stem cells have the opposite reaction: they self-renew.

"TAZ has stirred up a lot of controversy in our field, because it appears to produce diverse and sometimes opposite effects in pluripotent stem cells," said Ying, senior author and associate professor of stem cell biology and regenerative medicine. "It turns out that TAZ can indeed produce opposite effects, depending upon both its subcellular location and the cell type in question."

First author Zhou added: "TAZ provides a new tool to stimulate stem cells to either differentiate or self-renew. This could have important regenerative medicine applications, including the development of a better way to generate the desired cell types for cell replacement therapy."

Explore further: Study reveals how to better master stem cells' fate

More information: Xingliang Zhou et al, Cytoplasmic and Nuclear TAZ Exert Distinct Functions in Regulating PrimedPluripotency, Stem Cell Reports (2017). DOI: 10.1016/j.stemcr.2017.07.019

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The protein TAZ sends 'mixed signals' to stem cells - Phys.Org

Highs and lows in regenerative medicine – pharmaphorum

In Deep Dive: Future Pharma, Shahzad Ali explains how developments in gene editing and screening technology are advancing this rapidly-evolving field, but cautions that the move from gold standard cells to widespread clinical adoption will not be straightforward.

To exploit the capabilities of stem cells for regenerative medicine and drug discovery we must be able to direct the differentiation, and promote the expansion of these cells in vitro efficiently, reproducibly and cost effectively, he explains, going on to describe an innovative cell-based combinatorial screening technology for rapid and efficient identification of optimised protocols for cell expansion, cell differentiation, as well as the provision of human cells for use in drug discovery.

In the article, read more about the capacity of the technology to test thousands of combinations of cell culture variables simultaneously by miniaturising and multiplexing large numbers of stepwise cell culture experiments, increasing throughput by orders of magnitude, and the implications for this evolving field.

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Highs and lows in regenerative medicine - pharmaphorum

Neoepitopes new targets for childhood cancer therapy – BMC Blogs Network (blog)

New research published in Genome Medicine examines neoepitopes, new versions of proteins or peptides that can be produced following cancer-specific mutations. They find that a large fraction of childhood cancers harbor mutations that generate specific neoepitopes making them promising targets for cancer immunotherapy.

Ti-Cheng Chang 6 Sep 2017

T-lymphocytes attacking a cancer cell (pictured). Neoepitopes can be used to prompt T-cells to destroy cancer cells

Neoepitopes derived from tumor-specific mutations are promising targets for cancer immunotherapy. While neoepitopes have been widely explored in adult cancers, the potential for targeted therapies based on neoepitopes in childhood cancers has so far remained uncertain.

Our recent study identifies neoepitopes that could be targets for childhood cancer immunotherapy. Neoepitopes present on tumor cell surface are recognized by T cells, which carry out tumor-specific immune responses. As such, neoepitopes can be used to prompt T-cells to destroy cancer cells, which makes them promising targets for the development of tumor vaccines or other types of T-cell based immunotherapy. Neoepitopes can be synthesized and packed into custom-made vaccines to produce a tumor-destroying immune response in patients. Alternatively, T cells targeting neoepitopes can be transferred into patients for treatment.

Many cancers arise from mutations in genes that regulate cell division or that play a role in important processes like DNA damage repair.

By comparing DNA sequences between normal and cancer cells, we were able to identify cancer-specific mutations that cause genes to produce new versions of proteins or peptides otherwise known as neoepitopes.

Evidence from our study indicates that tumors with defects in DNA damage repair possess an increased number of mutations and neoepitopes

One of the challenges of neoepitope-based immunotherapy is how to efficiently select neoepitopes that prompt an immune response. Recent advances in DNA/RNA sequencing technology and improvement of epitope prediction algorithms allowed us to develop a data analysis method that predicts neoepitopes in 23 subtypes of childhood cancers. The analyses were based on mutated peptides resulting from genetic mutations as well as gene fusion events in cancer cells, by which a part of one gene combines with another.

Our analyses revealed that a large fraction of childhood cancers harbors mutations that generate specific neoepitopes. Several neoepitopes were identified from mutation hotspots genomic positions that are mutated frequently. We also demonstrated that gene fusions can generate neoepitopes in multiple types of childhood cancers, including leukemias.

Mutation rates vary across tumors and recent studies have shown that tumors with a high mutation rate, such as melanoma, have a higher number of neoepitopes than other tumor types. This leads to a hypothesis that tumors bearing more mutations are likely to be more responsive to immunotherapy.

Evidence from our study indicates that tumors with defects in DNA damage repair possess an increased number of mutations and neoepitopes. This subset of cancers, which include childhood high-grade gliomas, may have an enhanced antitumor response to immunotherapy.

The neoepitopes identified in this study, including those from tumor-specific mutations, hotspot mutations (for example, KRAS and histone-3 K27M) and fusion proteins, will serve as a valuable public resource for the development of novel therapeutic strategies against childhood cancers.

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Neoepitopes new targets for childhood cancer therapy - BMC Blogs Network (blog)