Stem Cell Clinic

Stem cell disease model clarifies bone cancer trigger

By Stem Cell Treatment

Using induced pluripotent stem cells (iPSCs), a team led by Mount Sinai researchers has gained new insight into genetic changes that may turn a well known anti-cancer signaling gene into a driver of risk for bone cancers, where the survival rate has not improved in 40 years despite treatment advances.

The study results, published today in the journal Cell, revolve around iPSCs, which since their 2006 discovery have enabled researchers to coax mature (fully differentiated) bodily cells (e.g. skin cells) to become like embryonic stem cells. Such cells are pluripotent, able to become many cell types as they multiply and differentiate to form tissues. The iPSCs can then be converted again as needed into differentiated cells such as heart muscle, nerve cells, bone, etc.

While some seek to use iPSCs as replacements for cells compromised by disease, the new Mount Sinai study sought to determine if they could serve as an accurate model of genetic disease "in a dish." In this context, the dish stands for a self-renewing, unlimited supply of iPSCs or a cell line - which enables in-depth study of disease versions driven by each person's genetic differences. When matched with patient records, iPSCs and iPSC-derived target cells may be able to predict a patient's prognosis and whether or not a given drug will be effective for him or her.

In the current study, skin cells from patient with and without disease were turned into patient-specific iPSC lines, and then differentiated into bone-making cells where both rare and common bone cancers start. This new bone cancer model does a better job than previously used mouse or cellular models of "recapitulating" the features of bone cancer cells driven by key genetic changes.

"Our study is among the first to use induced pluripotent stem cells as the foundation of a model for cancer," said lead author Dung-Fang Lee, PhD, a postdoctoral fellow in the Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai. "This model, when combined with a rare genetic disease, revealed for the first time how a protein known to prevent tumor growth in most cases, p53, may instead drive bone cancer when genetic changes cause too much of it to be made in the wrong place."

Rare Disease Sheds Light on Common Disease

The Mount Sinai disease model research is based on the fact that human genes, the DNA chains that encode instructions for building the body's structures and signals, randomly change all the time. As part of evolution, some code changes, or mutations, make no difference, some confer advantages, and others cause disease. Beyond inherited mutations that contribute to cancer risk, the wrong mix of random, accumulated DNA changes in bodily (somatic) cells as we age also contributes to cancer risk.

The current study focused on the genetic pathways that cause a rare genetic disease called Li-Fraumeni Syndrome or LFS, which comes with high risk for many cancers in affected families. A common LFS cancer type is osteosarcoma (bone cancer), with many diagnosed before the age of 30. Beyond LFS, osteosarcoma is the most common type of bone cancer in all children, and after leukemia, the second leading cause of cancer death for them.

Importantly, about 70 percent of LFS families have a mutation in their version of the gene TP53, which is the blueprint for protein p53, well known by the nickname "the tumor suppressor." Common forms of osteosarcoma, driven by somatic versus inherited mutations, have also been closely linked by past studies to p53 when mutations interfere with its function.

Rare genetic diseases like LFS are good study models because they tend to proceed from a change in a single gene, as opposed to many, overlapping changes seen in more related common diseases, in this case more common, non-inherited bone cancers. The LFS-iPSC based modeling highlights the contribution of p53 alone to osteosarcoma.

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Stem cell disease model clarifies bone cancer trigger

Regeneus hits key stem cell manufacturing milestone

By Stem Cell Treatment

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Regeneus (ASX: RGS) has achieved a key milestone with the manufacture of its off-the-shelf stem cell therapy product Progenza for its First-in-Human trial for the treatment of osteoarthritis.

The company is on track to receive ethics approval and commence recruitment for the trial in the first-half of 2015.

Adding interest the company highlighted the benefit of using adipose or fat tissue over other tissue types by demonstrating the capacity to produce millions of therapeutic doses of Progenza from a single donor.

The production of commercial quantities of stem cells from a single donor is critical to maximise dose-to-dose consistency chief executive officer John Martin said.

This scale of production will minimise clinical trial and regulatory risks while reducing the cost of the final product.

One of the key advantages for manufacturing Progenza at industrial scale is that it uses stem cells sourced from adipose or fat tissue.

Adipose tissue is readily available from donors in large quantities and has significantly higher stem cells per gram of tissue than other tissue sources such as bone marrow or cord tissue.

Also adipose derived stem cells show greater capacity for expansion than stem cells from other tissue types.

Progenza adipose derived stem cells are adult stem cells they are not genetically modified like induced pluripotent stem cells (iPSC).

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Regeneus hits key stem cell manufacturing milestone

Gut instinct: How intestinal stem cells find their niche

By Stem Cell Treatment

22 hours ago by Stephanie Dutchen New research indicates how and when adult intestinal stem cells (dark pink) set up shop at the base of villi, as shown in this image from the intestine of a chick near hatching. Credit: Tabin lab

Mommy, where do intestinal stem cells come from? All right, it's not likely a kindergartner would ask such a question. But evolutionary biologists want to know.

Adult intestinal stem cells live at the bases of our villi, the tiny, fingerlike protuberances that line the intestines and absorb nutrients.

There, the stem cells constantly churn out new intestinal cells to replace those being destroyed by corrosive digestive juices.

The researchers asked: How and when do these stem cells appear in the right place so they can do their job?

Studying mice and chicks, whose intestinal formation is similar to ours, the team found that the entire intestinal lining has stem cell properties at first. As the embryo develops, all but a few cells lose this potential.

"This lends support to the theory that adult stem cells are remnants of a more general pool of cells in the embryo," said Amy Shyer, who conducted the work as a graduate student in the lab of Cliff Tabin at Harvard Medical School and is now a Miller Fellow at the University of California, Berkeley.

As for why these cells are restricted to the villi bases, or crypts, the researchers believe the structure of the developing intestine determines which cells receive signals from neighboring tissues that say, "Stop being stem cells."

About two weeks into development, the intestine, initially a smooth tube, starts to form mountainous zigzags that will ultimately become villi. Cells at the peaks are exposed to signals that suppress stem cell properties, while cells in the valleys don't receive them.

"This opens a new door conceptually," said Shyer. "Tissues that start out uniform but then need to set up regions with regular patternswhich happens in the gut, skin, lungs and other organs during embryonic developmentmight coopt these natural changes in architecture to dictate signals that specify cell fate locally."

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Gut instinct: How intestinal stem cells find their niche

Colorado researchers use horse sense to innovate joint therapies

By Stem Cell Clinic

When Little Brother came up lame six years ago at the age of 8, Brenda Simmons took her horse from one veterinarian specialist to another to find a fix.

Injections of the horse's stem cells into a lower leg joint and tendons relieved his pain and returned full function to a horse that had been unridable.

"He was better than ever, and he's still going strong," the 58-year-old Granby resident said. "I asked the vet, 'Can you do that for me?' "

She couldn't, but a physician in Edwards, Dr. Scott Brandt, did treat her with stem cells.

After crippling pain had sidelined her for years, she said, injection of her own stem cells and other living cell products, taken from her bone marrow and fat tissue, has restored the former runner and skier to a more active life over the past year. She had already had one knee-replacement surgery, but she now believes she can avoid a second one.

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"It's not mainstream. It's still in development," Brandt said of treatment that can cost $8,000 to $12,000 and isn't covered by insurance. "But it will happen in our lifetimes. This will delay or prevent many surgeries."

Many orthopedic specialists remain skeptical of these treatments unsure where proven advancements end and experimentation begins in doctors' offices using people's stem cells along with other biological components.

Yet leading researchers say there is real potential, especially if the Food and Drug Administration eases restrictions on culturing adult stem cells in labs for reinjection.

Even as these alternatives to surgical fixes for knees, backs, hips, shoulders and elbows are being developed, joint surgeries are booming as Americans resist being stiff and sore.

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Colorado researchers use horse sense to innovate joint therapies

Dr. Owen Witte recognized with AACR G.H.A. Clowes Memorial Award

By Uncategorized

PHILADELPHIA -- The American Association for Cancer Research (AACR) is honoring Owen N. Witte, MD, founding director of the Eli & Edythe Broad Center of Regenerative Medicine & Stem Cell Research and distinguished professor of microbiology, immunology, and molecular genetics at the University of California, Los Angeles, with the 55th annual AACR G.H.A. Clowes Memorial Award at the AACR Annual Meeting 2015, to be held in Philadelphia, April 18-22.

Witte, who is also a Howard Hughes Medical Institute investigator and an elected fellow of the AACR Academy, is being recognized for his many contributions to the understanding of human leukemias, immune disorders, and epithelial cancer stem cells. Witte's work, which contributed to the development of several approved targeted therapies, has transformed the lives of patients with Philadelphia chromosome-positive leukemias and B-cell malignancies. He will present his lecture, "Finding Therapeutic Targets for Aggressive Prostate Cancer," Monday, April 20, 5:30 p.m. ET, in the Grand Ballroom of the Pennsylvania Convention Center.

The AACR and Eli Lilly and Company established the G.H.A. Clowes Memorial Award in 1961 to honor Dr. G.H.A. Clowes, a founding member of the AACR and research director at Eli Lilly. This award recognizes an individual with outstanding recent accomplishments in basic cancer research.

Witte's innovative work helped revolutionize modern cancer treatment by defining tyrosine kinases as crucial drug targets in human disease. Most notably, he pinpointed the molecular consequences of the Philadelphia (Ph) chromosome abnormality present in chronic myelogenous leukemia (CML) and related types of leukemia and defined the tyrosine kinase activity of the ABL gene product. These findings played a crucial role in the subsequent development of ABL kinase-targeted therapies, including imatinib (Gleevec), which remains the front-line treatment for Ph-positive CML.

In addition to his research involving ABL, Witte also co-discovered Bruton agammaglobulinemia tyrosine kinase (BTK). This particular kinase is essential for B-cell maturation and when mutated, results in the onset of the immunodeficiency disease, X-linked agammagloblulinemia. Recent studies involving this protein have resulted in the U.S. Food and Drug Administration approval of ibrutinib (Imbruvica), a selective BTK inhibitor, for the treatment of chronic lymphocytic leukemia mantle cell lymphoma, and Waldenstrm macroglobulinemia.

More recently, Witte's work has focused on defining the epithelial stem cell populations that contribute to prostate cancer. He is currently using mass spectrometry approaches to identify kinases that could be potential therapeutic targets for human prostate cancer.

"Much progress has been made in the area of personalized cancer medicine due to the dedication of scientists and physicians around the world, many of whom I've had the pleasure of working with through the AACR's innovative initiatives," said Witte. "But much more work is needed as we seek to understand cancer, which is not a single disease but rather many diseases that develop differently. I thank the AACR for their leadership in this effort and am honored to receive the Clowes Memorial Award."

An active AACR member, Witte has served on the AACR board of directors and several grant review committees. He is a past recipient of the AACR-Richard and Hinda Rosenthal Award and a co-leader of the Stand Up to Cancer Dream Team: Targeting Adaptive Pathways in Metastatic Treatment-Resistant Prostate Cancer. Additionally, he is also serving an appointed term on the President's Cancer Panel.

Witte has been recognized throughout his career with numerous honors. He has received the Nakahara Memorial Lecture Prize, the Cotlove Lectureship from the Academy of Clinical Laboratory Physicians and Scientists, the de Villiers International Achievement Award from the Leukemia and Lymphoma Society, the Warren Alpert Prize, and is elected member of the Institute of Medicine, National Academy of Sciences, and fellow of the American Academy of Arts and Sciences and the American Academy of Microbiology.

Witte received his medical degree from Stanford University School of Medicine in California, and was a postdoctoral fellow at the Center for Cancer Research at the Massachusetts Institute of Technology in Cambridge. He joined the UCLA faculty in 1980.

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Dr. Owen Witte recognized with AACR G.H.A. Clowes Memorial Award

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