Loss of Insulin-Producing Cells in Diabetics Might Be Reversed With Sperm Precursor Cells

Remarkable research pointing to a potential new treatment for diabetes was announced this week at Georgetown University Medical Center in Washington, D.C. Scientists succeeded in transforming spermatogonal stem cells, early precursors of sperm cells, into insulin-secreting cells. It is likely that the work represents significant progress in accomplishing the Holy Grail of diabetes research, the replacement of insulin-secreting cells lost to the disease.

In type I diabetes, the early onset form of the disease that often occurs in young children, cells of the pancreas called islet cells or beta cells, which normally secrete insulin, are lost due to autoimmunity. The body’s own immune system attacks and destroys these cells, leaving the sufferer insulin-deficient. Since insulin controls and amplifies the pumping process that transports glucose (sugar) from the blood into the body’s cells to supply fuel, high levels of blood glucose result, and cells are starved of energy. The condition is potentially lethal and must be treated with injections of insulin.

In type II diabetes, which has a later onset, the sufferers retain their islet cells, but the cells do not make enough insulin, probably as the result of genetic vulnerabilities to the disease, which may be exacerbated by excess food consumption and lack of exercise. In the most severe forms of this type of diabetes, the patients also need insulin injections.

The Georgetown scientists obtained new insulin secreting cells by removing about a million of these cells (1 gram) from the testes of deceased human organ donors. They then transplanted the human cells to the backs of diabetic mice that were also deficient in immunity, so that the animals did not reject the human cells. The researchers did nothing more with the cells. In a short time, some of the testis-derived stem cells transformed themselves into cells secreting insulin, which then lowered the levels of glucose in the mice’s blood. The human cells remained active in the mice for about a week.

One of the most remarkable aspects of the research is that no additional genes were added to the testis stem cells. As pluripotent stem cells, they already possessed the latent capacity to secrete insulin. The lead investigator and director of the Transgenic Core Facility at GUMC, G. Ian Gallicano, said, “We found that once you take these cells out of the testes niche, they get confused, and will form all three germ layers within several weeks. These are true, pluripotent stem cells.”

In the past to treat diabetes, insulin-secreting islet cells have been transplanted from organ donors into patients. And insulin-secreting cells have been produced from other kinds of adult cells by the addition of genes or transcription factors to reprogram the cells or restore them to the stem-cell state. But both procedures have drawbacks. Islet cell transplantation must be followed by immunosuppression, which can be associated with severe adverse effects, in order to prevent transplant rejection. Adult stem cell reprogramming to treat diabetes, which remains an experimental procedure at present, can give rise to tumors.

In contrast, one can envision the possibility of a better source of new insulin-secreting cells for diabetics, if the Georgetown researchers make progress with their spermatogonal cell technique to the point that it may be used to treat humans. Male sufferers of the disease, at least, might undergo transplantation of stem cells from their own testes to other regions of their own bodies, in order to produce new insulin-secreting cells. Such a treatment would avoid the drawbacks of immunosuppression, since the cells would not trigger rejection. And risks of inducing neoplasms might be avoided.

In recognizing this remarkable work, one might take note of the fact that Georgetown University is a Jesuit institution. Theologically opposed to stem cell research with human embryos, the scientists at the medical center may have concentrated on working with stem cells from the tissues of adults. Thus, it may result that their religious outlook could lead to a wonderful advancement in the treatment of diabetes.

“Grow Your Own Transplant” May be Possible for Men with Type 1 Diabetes

Researchers turn human testes cells into insulin-producing islet cells; diabetic mice were “cured” for a week

Washington, D.C. – Men with type 1 diabetes may be able to grow their own insulin-producing cells from their testicular tissue, say Georgetown University Medical Center (GUMC) researchers who presented their findings today at the American Society of Cell Biology's 50th annual meeting in Philadelphia. Their laboratory and animal study is a proof of principle that human spermatogonial stem cells (SSCs) extracted from testicular tissue can morph into insulin-secreting beta islet cells normally found in the pancreas. And the researchers say they accomplished this feat without use of any of the extra genes now employed in most labs to turn adult stem cells into a tissue of choice.

“No stem cells, adult or embryonic, have been induced to secrete enough insulin yet to cure diabetes in humans, but we know SSCs have the potential to do what we want them to do, and we know how to improve their yield,” says the study’s lead investigator, G. Ian Gallicano, Ph.D., an associate professor in the Department of Cell Biology and director of the Transgenic Core Facility at GUMC.

Given continuing progress, Gallicano says his strategy could provide a unique solution to treatment of individuals with type 1 diabetes (juvenile onset diabetes). Several novel therapies have been tried for these patients, but each has drawbacks. Transplanting islet cells from deceased donors can result in rejection, plus few such donations are available. Researchers have also cured diabetes in mice using induced pluripotent stem (IPS) cells – adult stem cells that have been reprogrammed with other genes to behave like embryonic stem cells – but this technique can produce teratomas, or tumors, in transfected tissue, as well as problems stemming from the external genes used to create IPS cells, Gallicano says.

Instead of using IPS cells, the researchers turned to a readily available source of stem cells, the SSCs that are the early precursors to sperm cells. They retrieved these cells from deceased human organ donors. Because SSCs already have the genes necessary to become embryonic stem cells, it is not necessary to add any new genes to coax them to morph into these progenitor cells, Gallicano says. “These are male germ cells as well as adult stem cells.” “We found that once you take these cells out of the testes niche, they get confused, and will form all three germ layers within several weeks,” he says. “These are true, pluripotent stem cells.”

The research team took 1 gram of tissue from human testes and produced about 1 million stem cells in the laboratory. These cells showed many of the biological markers that characterize normal beta islet cells. They then transplanted those cells into the back of immune deficient diabetic mice, and were able to decrease glucose levels in the mice for about a week – demonstrating the cells were producing enough insulin to reduce hyperglycemia.
While the effect lasted only week, Gallicano says newer research has shown the yield can be substantially increased. The research was funded in part by the American Diabetes Association, patient contributions to the GUMC Office of Advancement, support from GUMC diabetes specialist Stephen Clement, M.D., and a grant from GUMC.

Co-authors include Anirudh Saraswathula, a student at Thomas Jefferson High School for Science and Technology in Alexandria, Va. GUMC researchers Shenglin Chen Ph.D., Stephen Clement, M.D., Martin Dym, Ph.D., and Asif Zakaria, Ph.D., also contributed to the research. The authors report having no personal financial interests related to the study.

About Georgetown University Medical Center
Georgetown University Medical Center is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health). GUMC’s mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis -- or "care of the whole person." The Medical Center includes the School of Medicine and the School of Nursing and Health Studies, both nationally ranked, the world-renowned Georgetown Lombardi Comprehensive Cancer Center and the Biomedical Graduate Research Organization (BGRO). In fiscal year 2009-2010, GUMC accounted for 79 percent of Georgetown University's extramural research funding.

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