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Jan 28 2014

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Treating the Chicken with the Egg

S3.2The term “stem cell,” stammzellen, was first used in 1868 by the German biologist Ernst Haeckel to describe the original, unicellular progenitor from which Dr. Haekel supposed all multicellular plant and animal life might have descended. The question, Dr. Haeckel asked, was where that progenitor — the original stem cell — came from in the first place. The chicken or the egg?

Since then, just what defines a stem cell has undergone a few changes. The evolutionary sense of Dr. Haeckel’s term has been dropped, but the sense of stem cells being precursor cells, able to become specialized through the process known as differentiation, remains. Because of their ability to become many types of cells and to renew themselves, stem cells hold enormous promise in understanding and treating a variety of diseases.

What’s more, researchers have identified several different types of stem cells. These include what is perhaps the most popularly known type of stem cell, embryonic stem cells (ESCs), which as their name suggests are derived from embryos. Most often, these come from embryos that have been fertilized through in vitro fertilization and then donated for research purposes.

Another type of stem cell, somatic stem cells, are rare, undifferentiated cells found among other differentiated cells. Also called adult stem cells, there are several types of somatic stem cells: hematopoietic stem cells can differentiate into every type of blood cell, while mesenchymal stem cells can become fat, cartilage, and bone cells.

But in the past decade, researchers have detailed another type of stem cell: induced pluripotent stem cells, or iPSCs. Differentiated adult cells that have been “reprogrammed” and forced to express genes, these cells are capable of developing into many or even all cell types. During fiscal 2013, The Children’s Hospital of Philadelphia’s Mitchell J. Weiss, MD, PhD, published two studies of using iPSCs to study the rare congenital blood disorder Diamond Blackfan Anemia and the childhood cancer juvenile myelomonocytic leukemia.

In the anemia study, Dr. Weiss and his colleagues — including investigators Monica Bessler, MD, PhD, and Philip J. Mason, PhD — removed fibroblasts from Diamond Blackfan Anemia patients and reprogrammed the cells into iPSCs. As those iPSCs were stimulated to form blood tissues, like the patient’s original mutated cells they were deficient in producing red blood cells. However, when the researchers corrected the genetic defect that causes the disorder, the iPSCs developed into red blood cells in normal quantities.

“The technology for generating these cells has been moving very quickly,” said Dr. Weiss. “These investigations can allow us to better understand at a molecular level how blood cells go wrong in individual patients — and to test and generate innovative treatments for the patients’ diseases,” he added.

And in April of 2012, Paul J. Gadue, PhD, published a study detailing a brand new type of stem cell, which the investigators call endodermal progenitor (EP) cells. Produced from ESCs and iPSCs, EP cells have two advantages over these other stem cell types: they do not form tumors when transplanted into animals, and they can form functional pancreatic beta cells in the laboratory. Both ESCs and iPSCs in the undifferentiated state will form a type of tumor called a teratoma when transplanted in animal studies, so it has been critical that any cell generated from ESCs or iPSCs and used for transplantation is purified to exclude undifferentiated cells with tumor-forming potential, Dr. Gadue pointed out.

In addition to producing beta cells, the researchers also directed EP cells to develop into liver cells and intestinal cells — both of which normally develop from the endoderm tissue layer early in human development. The challenge, Dr. Gadue said, has been to differentiate stem cells into one particular cell type in culture, as ESCs and iPSCs can form any cell type in the body. EP cells seem to be limited to cells of the endodermal lineage such as liver, pancreas, and intestine, making it easier to generate pure populations of cells from these organs.

“Our cell line offers a powerful new tool for modeling how many human diseases develop,” said Dr. Gadue, who along with Deborah L. French, PhD, is the co-director of CHOP’s human embryonic stem cell/induced pluripotent Stem Cell (hESC/iPSC) core facility. “Additionally, pancreatic beta cells generated from EP cells display better functional ability in the laboratory than beta cells derived from other stem cell populations.”

In a follow-up review published in fiscal 2013 in Current Opinion in Cell Biology, Dr. Gadue and colleagues discussed the generation of endodermal cells from pluripotent stem cells, including EP cells. Stem cells such as EP cells “can be expanded robustly in culture” and “provide a powerful system to study and model human diseases in vitro, as well as generating a source of cells for transplantation.”

Indeed, there is a big push to use stem cells to perform disease modeling with human cells as opposed to mice, as well as to use stem cells to perform drug and toxicity screenings, Dr. Gadue pointed out, noting that while mouse models offer an incredibly valuable resource they are not perfect and using human cells when possible is important. And once they are created, EP cells can be expanded almost without limit — to the point that Dr. Gadue estimates his laboratory has grown “trillions” of cells — which offers researchers a wealth of research resources.

Going forward, Dr. Gadue, has been working with a number of colleagues, including endocrinologist Diva D. De León-Crutchlow, MD, to better understand and hopefully develop treatments for diabetes.

 

Permanent link to this article: http://www.research.chop.edu/blog/treating-chicken-egg/

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