Stem Cell for Diabetes – The Children’s Hospital of Philadelphia

Stem cell for diabetes treatment. A new cell line can provide a safe, prolific source of stem cells for researchers to test transplant therapies — as well as study the diseases themselves safely and more accurately than they can in animal models. Beta cells created in the lab can produce some insulin and may potentially be used to replace the beta cells damaged or destroyed in diabetics.

Researchers from The Children’s Hospital of Philadelphia have created a new type of human stem cell that can develop into many kinds of specialized cells — without the danger of turning into cancer.

Calling their creation endodermal progenitor (EP) cells, the new stem cells provides a safe and prolific source for research into potential stem cell transplant therapies, as well as disease modeling. Their findings are published in the April 6 issue of the journal Cell/Stem Cell.

The new EP cells also hold two vital advantages over human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs):
• They don’t form tumors when transplanted into animals.
• They can turn into functional pancreatic beta cells in the laboratory.

The investigators were also able to direct the EP cells to develop into functioning pancreatic beta cells that can actually produce insulin. Since beta cells are damaged in people who have diabetes, the creation of functional beta cells means that they can potentially be used in diabetes and liver treatments in the future.

“Our cell line offers a powerful new tool for modeling how many human diseases develop,” says study leader Dr. Paul J. Gadue, Ph.D., a stem cell biologist in the Center for Cellular and Molecular Therapeutics at The Children’s Hospital of Philadelphia, in a press release. “Additionally, pancreatic beta cells generated from EP cells display better functional ability in the laboratory than beta cells derived from other stem cell populations.”

Aside from producing beta cells, the researchers also turned the EP cells into liver cells and intestinal cells –two kinds of cells that, early in human development, usually develop from the endoderm tissue layer.

Creating ‘steminess’
For the current research, Dr. Gadue’s team manipulated both human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) to become EP cells.

HESCs are derived from human embryos — usually from unused embryos from fertility treatments that are donated for research purposes. But in a bid to skirt the growing controversy over the use of human embryos, scientists in the last few years have been able to reprogram somatic cells — like that of the skin or blood — to become pluripotent. Like hESCs, iPSCs are able to develop into many other types of human cells.

Both types of stem cells can proliferate in great numbers and have the potential to generate all types of tissue. It’s because of these that both stem cells types offer enormous promise for scientists to control cell development precisely — either to study diseases or to develop future stem cell-based treatments.

But when undifferentiated hESCs or iPSCs are transplanted into animals in studies, they form teratomas — or tumors made of many different cell types. To work around this problem, scientists have to purify any cell types generated from hESCs or iPSCs stringently when they are to be used for transplantation. They have to make sure to exclude undifferentiated cells with tumor-forming potential.

“One of the big issues that’s critical when you think about potentially transplanting embryonic stem cells or induced pluripotent stem cells is that you have to make sure there are no undifferentiated cells in that batch, because undifferentiated cells can form tumors called teratomas,” Dr. Gadue told HealthDay News.

The big challenge then was for scientists to develop stem cell lines that don’t potentially grow into cancer.

Preventing cancer-forming
Now, the Children’s Hospital of Philadelphia researchers have created endodermal progenitor (EP) cells that don’t form these tumors — at least for stem cells that may be used in the digestive system or possibly the lungs.

The innermost layer of cells — one of three layers — found in an early embryo is called the endoderm. This eventually develops into the lining of the digestive and respiratory tract. What the researchers did was halt the development of stem cells at what’s called the endodermal stage — and they found that when they did this, the cells also stopped creating teratomas.

Limited pluripotency
But they also discovered that when they delayed cell development at this endodermal stage, the type of cells that could be generated from the stem cells became limited. EP cells can only become cells found in the digestive tract — like intestinal, liver or pancreatic cells, and possibly lung cells, Dr. Gadue reveals.

But the EP stem cells have a nearly unlimited potential to proliferate in the lab — which means they can be a reliable source of millions of stem cells for investigatorswho need intestinal, liver, pancreatic or lung stem cells.

Beta cells to tackle diabetes
Not content with creating a stem cell line that doesn’t produce teratomas, Dr. Gadue’s team went on to create cells in the line that can actually differentiate to become other cells. They created pancreatic beta cells — the type that are damaged or destroyed in people with diabetes.

Diabetics have beta cells in the pancreas that are damaged and can’t create insulin. But the body’s cells use insulin as a chemical “valve” that switches “on” or “off” to allow or stop glucose from entering cells. Without insulin, people with diabetes are forced to ride a dangerous blood sugar rollercoaster — low levels bring blackouts and seizures while high blood sugar levels make them feel fatigued.

To guard against this, people with diabetes depend on a daily insulin injection or an insulin pump. Without either, their blood sugar levels fluctuate uncontrollably and they risk organ failure and death.

The researchers found that, after exposing them to glucose, the newly created beta cells could produced insulin — although not at an optimal level. The cells only produced about 20 percent of the expected insulin.

Thus, while this science is still far away from practical clinical use, the new EP cells have the potential to develop into tissue replacement treatments — such as like supplying beta cells for diabetics or hepatocytes — liver cells — for people with liver disease.

“While more work is needed to characterize EP cells, these may offer a potential source of safe, abundant cells for future diabetes treatments,” Dr. Gadue says.

The 20 percent function, after all, isn’t much different than what’s been seen in other studies, Dr. Juan Dominguez-Bendala, the stem cell development for translation research director at the Diabetes Research Institute in Hollywood, Forida tells HealthDay News. And while maturing beta cells in the lab is often very difficult, these beta cells will often complete maturation once they’ve been transplanted.

Overall, “this (research) presents two major advantages over embryonic stem cells. First, by having this ‘intermediate’ population, we are restricting the differentiation options of the stem cells. For applications such as liver diseases or diabetes, these cells will readily become (liver cells) or beta cells, without unwanted byproducts such as (nerve or heart cells),” Dr. Dominguez-Bendala says. Secondly — and more importantly — he says, they don’t pose the risk of forming tumors.

“If independently confirmed, this approach could certainly be of great potential to design safer and more efficient differentiation protocols for the treatment of diabetes and liver diseases, among other conditions,” he concludes.

And while Dr. Albert Hwa, scientific program manager of cure therapies at the Juvenile Diabetes Research Foundation calls the new research “very interesting and encouraging because they don’t see teratomas,” he also thinks the functionality of the beta cell can be improved. But he seems confident: “This was a first try with this protocol. The function of these cells seems very promising as well,” he says.

Nearly 26 million Americans have diabetes and 90 percent of these cases are of type 2 — linked to poor diet and lack of exercise. The longer a person has diabetes, and the poorer his or her blood sugar control, the more likely he or she will experience serious long-term complications — including heart attack, stroke, blindness, and kidney failure.

Disease modeling
Another significance of the new creation is that the EP cells can be used as a disease-modeling tool for researchers to study how human diseases develop and progress — and ways to treat these diseases, as well.

Dr. Gadue stresses that these promising early results are only the first steps in his team’s EP cells research. The next steps? He says his team will likely focus on taking cells from patients with genetic forms of diabetes or liver disease than work on deriving EP cell lines from these cells to create disease-in-a-dish models. Such models can be used by scientists to study the development and progression of a disease — as well as discover new treatments.

The findings are the culmination of a three-year effort funded by a grant from the National Institutes of Health.

Dr. Gadue’s co-investigators include Dr. Deborah L. French, Dr. Xin Cheng and Dr. Mitchell J. Weiss — all from the The Children’s Hospital of Philadelphia, Dr. Darrell Kotton of the Boston University School of Medicine and Dr. M. Cristina Nostro from the McEwen Centre for Regenerative Medicine in Toronto, Canada.

Founded in 1855 as the nation’s first pediatric hospital, The Children’s Hospital of Philadelphia’s has one of the largest pediatric research programs in the United States and is the no. 3 on the list of grantees receiving funds from the National Institutes of Health.

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