Stem Cell Clinic

Moffitt researchers identify protein pathway involved in brain tumor stem cell growth

H. Lee Moffitt Cancer Center & Research Institute

TAMPA, Fla. - Glioblastomas are a highly aggressive type of brain tumor, with few effective treatment options. Moffitt Cancer Center researchers are one step closer to understanding glioblastoma development following the identification of a key protein signaling pathway involved in brain tumor stem cell growth and survival. Brain tumor stem cells are believed to play an important role in glioblastoma development and may be possible therapeutic targets.

The neurotrophin protein pathway controls nerve growth, survival and specialization. In an article published in the Feb. 6 issue of The Journal of Biological Chemistry, Moffitt researchers reported that the neurotrophin pathway is also involved in the survival and growth of brain tumor stem cells. The stem cells have high levels of neurotrophin receptors called TrkB and TrkC. Cellular signals from normal brain cells can activate TrkB and TrkC on the stem cells and stimulate cell growth. And when scientists inhibited TrkB and TrkC, they found decreased stem cell survival. This suggests that TrkB and TrkC may be possible drug targets for stem cells in gliomas and glioblastomas.

"This work might be a first step in developing new treatment approaches targeting brain tumor stem cells. It may also partly explain why brain tumors can grow so quickly since proteins from the surrounding normal brain might be used by the tumor to grow even faster," said Peter A. Forsyth, M.D., chair of the Department of Neuro-Oncology at Moffitt.

Researchers also reported a potential reason why several clinical trials targeting a protein called EGFR in glioblastoma patients have failed to live up to expectations. EGFR is frequently activated in glioblastoma, but results from trials using EGFR inhibitors showed little or no patient improvement. Moffitt scientists discovered that TrkB and TrkC maintain brain stem cell survival and growth even when EGFR inhibitors are used. These observations suggest that one reason why EGFR inhibitors may be ineffective in glioblastoma is that TrkB and TrkC are active, thereby bypassing EGFR inhibition and allowing stem cells to continue to grow.

This is the first time that scientists have shown that TrkB and TrkC are involved in brain tumor stem cell growth. Currently, no drugs that target TrkB and TrkC have been used as brain cancer treatments. Researchers hope that these results might encourage the development of drugs that target both the stem cell compartment and the more differentiated parts of the brain tumor and result in more effective therapies.

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The study was supported by funds The V Foundation for Cancer Research and the Moffitt Cancer Center Foundation.

About Moffitt Cancer Center:

Located in Tampa, Moffitt is one of only 41 National Cancer Institute-designated Comprehensive Cancer Centers, a distinction that recognizes Moffitt's excellence in research, its contributions to clinical trials, prevention and cancer control. Moffitt is the top-ranked cancer hospital in the Southeast and has been listed in U.S. News & World Report's "Best Hospitals" for cancer care since 1999. With more than 4,500 employees, Moffitt has an economic impact in Florida of nearly $1.6 billion. For more information, visit MOFFITT.org, and follow the Moffitt momentum on Facebook, Twitter and YouTube.

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Rowan Researcher Targets Stem Cell-Based Therapy for Rare Childhood Disease

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Newswise STRATFORD Paola Leone, PhD, the director of the Cell and Gene Therapy Center and a professor of Cell Biology at the Rowan University School of Osteopathic Medicine (RowanSOM), has been awarded a three-year, $477,000 grant from the National Institute of Neurological Disorders and Stroke (NINDS) to develop a stem cell-based therapy for Canavan disease, a rare but devastating neurological disorder in children that typically takes a childs life by age 10.

Canavan disease is a fatal, inherited disease caused by a mutation in the aspartaocylase gene, Dr. Leone explained. The disease is characterized by progressive and severe brain atrophy that manifests in delayed development, developmental regression, microcephaly, spasticity, seizures, visual impairment and short life expectancy. There, currently, is no treatment or cure for Canavan disease.

Under Dr. Leones direction, a team of RowanSOM researchers and students will examine the potential of stem cells for the treatment of Canavan disease in an animal model. This new study will build on the research teams preliminary data that demonstrated the successful engraftment of stem cells in animal models.

Our project will generate pre-clinical data to support the development of a stem-cell based therapy for Canavan disease, Dr. Leone said. It will also provide an important opportunity for a new generation of clinical researchers. Both undergraduate and graduate students will participate in this project, providing them with valuable experience to work with an extremely promising therapeutic intervention.

The symptoms of Canavan disease usually appear within the first six months of a childs life. The disease is caused by a genetic mutation that stops cells, called oligodendrocytes, from developing myelin, the fatty substance that coats the nerves in the brain. Without the protective myelin covering, the nerves do not form properly, causing the brain to atrophy. The preliminary research that Dr. Leone conducted showed that the engraftment of stem cells promoted significant recovery of the myelin sheath surrounding the nerves.

Our research represents a significant departure from other studies that have focused solely on strategies to augment the loss of the aspartaocylase function that is highly reduced in the brains of these patients, Dr. Leone said. We believe that any strategy seeking to treat Canavan must include a way to restore the myelin development that is disrupted in children with this disease.

This research is supported by the NINDS of the National Institutes of Health, under grant number 1R15NS088763-01A1.

Journalists wishing to speak with Dr. Leone, should contact Jerry Carey, Rowan University Media and Public Relations at 856-566-6171 or at careyge@rowan.edu.

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New study shows safer methods for stem cell culturing

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A new study led by researchers at The Scripps Research Institute (TSRI) and the University of California (UC), San Diego School of Medicine shows that certain stem cell culture methods are associated with increased DNA mutations. The study points researchers toward safer and more robust methods of growing stem cells to treat disease and injury.

"This is about quality control; we're making sure these cells are safe and effective," said Jeanne Loring, a professor of developmental neurobiology at TSRI and senior author of the study with Louise Laurent, assistant professor at UC San Diego.

Laurent added, "The processes used to maintain and expand stem cell cultures for cell replacement therapies needs to be improved, and the resulting cells carefully tested before use."

The findings were published February 25 in the open-access journal PLOS ONE.

Growing Stem Cells

Because these human stem cells, called "pluripotent stem cells," can differentiate into many types of cells, they could be key to reversing degenerative diseases, such as Parkinson's disease, or repairing injured tissue, such as cardiac muscle after a heart attack. Stem cells are relatively rare in the body, however, so researchers must culture them in dishes.

While all cells run the risk of mutating when they divide, previous research from Loring and her colleagues suggested that stem cell culturing may select for mutations that favor faster cell growth and are sometimes associated with tumors.

"Most changes will not compromise the safety of the cells for therapy, but we need to monitor the cultures so that we know what sorts of changes take place," said the paper's first author Ibon Garitaonandia, a postdoctoral researcher working in Loring's lab at the time of the study.

How to Reduce Mutations

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New study shows safer methods for stem cell culturing

Woman swears by Multiple Sclerosis remedy

IT IS expensive and controversial and the medical community is still divided about its success, but Jenni Saunders is living proof Russia's controversial stem cell treatment program can work.

The Kawana Island resident spent 30 days in Moscow in December receiving stem cell treatment she hoped would help provide some relief from the multiple sclerosis that has been slowly crippling her body for 30 years.

It has been 10 weeks since Ms Saunders' return and she is ecstatic with the results.

The 60-year-old can literally jump for joy.

It's been "years" since Ms Saunders was able to lift both feet off the ground, so the small leap in the air is a giant leap for her.

"I have seen several improvements in the last nine to 10 weeks," she said.

"The pins and needles in my hands and feet are virtually gone and I can stand up with my eyes closed.

"This might not sound like a lot to many people, but to me it is significant."

She says she is the oldest Australian to have attempted the $60,000 treatment, excluding the cost of flights.

The stem cell treatment is not approved for MS sufferers in Australia and people like Ms Saunders have to raise money to pay for the trip, even though it is available in other parts of the world.

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Woman swears by Multiple Sclerosis remedy

Stem cellrecruiting hydrogels based on self-assembling peptides for tissue regeneration

Figure 1. Stem CellRecruiting Hydrogels Based on Self-Assembling Peptides

The Materials for Biomaterials session Best Contribution Award presented by Steve Zinkle goes to Yongmee Jung, Korea Institute of Science and Technology, for the oral presentation Self-assembling peptide nanofiber coupled with neuropeptide substance P for stem cell recruitment.

As a winner of the above Materials Today Asia Contribution Award, Yongmee Jung and Soo Hyun Kim discuss their work with us.

Stem cellbased therapy in regenerative medicine may be one of the best approaches for wound healing and tissue regeneration. Many studies have shown that the trophic effects of transplanted stem cells enhance the treatment of lung, liver, and skin injuries, as well as myocardial infarction [1]. However, although stem cell transplantationincluding cell isolation and cell culture in vitroresults in a good prognosis, there are some limitations, such as high cost, invasiveness, the shortage of cell sources, and the risk of tumorigenesis [2]. To overcome these limitations, technologies for recruiting endogenous stem cells to the site of injury may provide another promising approach, mimicking in situ tissue regeneration by the bodys own wound healing process. Unlike cell-based therapies, this strategy does not need outside cell sources or in vitro cell manipulation. Host stem cells can be mobilized using granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), or stromal cellderived factor-1 alpha (SDF-1), each of which upregulates adhesion molecules and activates chemokine signaling [3]. It has been reported that substance P (SP), another candidate for recruitment of host stem cells, is an injury-inducible factor that acts early in the wound healing process to mobilize CD29+ stromal-like cells, and thus could be used for tissue regeneration [1].

To achieve effective delivery of SP for an extended period and improve the engraftment of recruited cells at the injured site, scaffolds can be constructed from hydrogels with microenvironments similar to the native tissue. Of particular interest are self-assembling peptide (SAP)based hydrogels, which are typically composed of alternating hydrophilic and hydrophobic amino acids organized into 510 nm fibers and assembled into three-dimensional nanofibrous structures under in vivo conditions [4]. The resulting structure resembles nanostructured environments such as collagen hierarchical structures that promote adhesion, proliferation, and differentiation of cells. Furthermore, SAP is versatile enough to incorporate specific motifs based on the desired function with chemical coupling by peptide bond [5].

Recently, we designed bioactive peptide hydrogels that are able to recruit mesenchymal stem cells by coupling SAP to SP. The mixture of SAP and SP-coupled SAP can successfully maintain its nanofibrous structure and be assembled into a 3D scaffold at physiological conditions.

We confirmed the ability of this SP-coupled SAP to attract stem cells both by in vitro cell migration assay and by in vivo real-time cell tracking assay. In vitro, many cells migrated through the 8-m membrane pores and settled onto the lower surfaces of Transwell plates under the influence of SP-coupled SAP. In vivo, we injected the hydrogels into the subcutaneous tissue in nude mice and injected labeled human mesenchymal stem cells (hMSCs) into the tail vein. The migration of the injected cells was tracked in real time using a multispectral imaging system, which demonstrated that the labeled hMSCs supplied via intravenous injection were recruited to the hydrogel-injected site (Figure) [6]. We then applied our bioactive peptide hydrogels, SAP coupled with SP, to several disease models to evaluate their stem cell recruitment abilities and treatment effects on injured tissues. We have studied the effects of these hydrogels on animal models of ischemic hind limb, calvarial defect, myocardial infarction, osteoarthritis, and skin wounds. We observed in each case that in the group treated with SP-coupled peptide hydrogels, many MSCs were recruited to the injured sites, and cell apoptosis and fibrosis of injured tissues were both conspicuously decreased. Moreover, the regeneration of site-specific tissues was enhanced with the injection of stem cellrecruiting peptide hydrogels in various defect models, and tissue functions were accordingly improved without cell transplantation [2, 5, 6]. In conclusion, we have developed injectable bioactive peptides that can recruit MSCs and have evaluated their therapeutic potential on animal defect models. By applying these peptide hydrogels, we were able to deliver SP over an extended period and provide 3D microenvironments to injured regions, allowing bioactive peptides to recruit MSCs successfully, prevent cell apoptosis, and promote tissue regeneration leading to a full recovery of defects. We expect that stem cellrecruiting hydrogels based on SAP could be one of the most powerful tools for tissue regeneration without cell transplantation through the recruitment of endogenous stem cells.

This work was supported by the KIST Institutional Program

1. H. S. Hong, et al., Nat. Med., 15 (2009), pp. 425435 2. J. H. Kim, et al., Biomaterials, 34 (2013), pp. 16571668 3. T. Lapidot, I. Petit, Exp. Hematol., 30 (2002), pp. 973981 4. S. Zhang, et al., Semin. Cancer Biol., 15 (5) (2005), pp. 413420 5. J. E. Kim, et al., Int. J. Nanomedicine, 9 (Suppl 1) (2014), pp. 141157 6. S. H. Kim, et al., Tissue Eng. Part A, E-Pub (2014)

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Stem cellrecruiting hydrogels based on self-assembling peptides for tissue regeneration