Gallicano, Ian , Ph.D.
Differentiation and functional analysis in vitro and in vivo of insulin-secreting beta-islet cells from pluripotent adult stem cells
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Clinical Therapeutics/New Technology\Pharmacologic Treatment of Diabetes or its Complications, Integrated Physiology\Muscle
Type of Grant: Henry Becton Innovation
Project Start Date: July 1, 2010
Project End Date: December 31, 2012
Diabetes is one of the most serious health issues facing America today, affecting 8.0% (23.6 million people) of the American population, and over the last three or four decades, treatment for diabetes has remained essentially the same, involving blood tests and regular insulin supplements. New treatments, such as beta-islet cell transplants, have become available in recent years; however, allograft (same-species) transplants carry a risk of immune rejection and do not always succeed in grafting well into the recipient. Recently, embryonic stem (ES) cells have been used to engineer insulin-producing pancreatic tissue; however, with respect to ES cells, problems such as immune rejection, teratoma risk, and ethical issues still persist preventing their use clinically.
Here, we succeed in generating insulin-secreting pancreatic cells from spermatogonial stem cells (SSCs) directly isolated from human testicular tissue. This method of obtaining beta-islet-like cells solves the ethical, teratoma risk, and immune rejection problems in male diabetes patients. Β-islet-like cells derived from germ-derived pluripotent stem (gPS) cells (produced from human SSCs) secrete insulin and these engineered cells exhibit markers characteristic of normal β-islet cells. Most significantly, grafting the cells into diabetic, athymic mice results in a decrease in blood-glucose levels, demonstrating the ability of these cells to eventually help treat hyperglycemia.
Mentor: Ian Gallicano
Postdoctoral Fellow: Shenglin Chen
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Type 1 diabetes results from the body's failure to produce insulin. It is an autoimmune disease in which the body views the -islet cells (insulin producing cells found in the islets of the pancreas) as a foreign, so the patient's immune system attacks the islets and kills them. It is estimated that ~8% of Americans (~2,000,000 people) who are diagnosed with diabetes have type 1 diabetes. Patients with type 1 diabetes must take insulin delivered by injection or a pump in order to survive. The use of deceased donors for pancreatic transplant has been ongoing for many years, but there is a limited supply of suitable donor material and there is variable success with the procedure. For patients with type 1 diabetes, whole pancreas transplant has been used. An alternative approach has used insulin-producing cells extracted from the donor pancreas. These are implanted most often via the portal vein, so that the islet cells produce insulin as needed by the recipient.
In a paper on pancreatic transplant, the authors noted that 'normal endocrine reserve is rarely achieved, and insulin independence is gradually lost in most cases over time.' The authors concluded that 'the search for alternative sources of regulated insulin-secreting cells must continue, since the current supply of islets from deceased donors cannot meet the demand.' Stem cells, adult or embryonic, represent a novel direction in the search for a biological cure. However, to date, numerous barriers surround and prevent stem cell therapies from treating diabetes. With respect to embryonic stem cells, immune rejection, risk of teratoma formation, and ethical dilemmas remain at the forefront of their delays in clinical application.
Conventional adult stem cells have not lived up to their billing either as they are difficult to generate in the quantities necessary for use in vivo, and they, too, can exhibit immune responses. Even the newly derived induced pluripotent stem (iPS) cells have problems that are showing difficulty in being solved. As a result the search has gone on to find a stem/progenitor cell that is deemed 'suitable' by the FDA for use in the clinic. In light of this, we believe our preliminary data using human germline-derived pluripotent (hgPS) cells show significant promise in addressing these critical barriers.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
The potential impact of stem cell therapy for patients with diabetes is huge. A recent, most exciting discovery in the field of stem cell biology was the observation that spermatogonial stem cells (SSCs) and/or their progenitors in mice and humans could be reprogrammed into pluripotent embryonic stem (ES)-like cells now known as hgPS cells. However, while those observations are considered a major scientific advancement, the ultimate goal is now to translate this work to human patients. With that in mind, we have preliminary data from human testis showing that, in our laboratories, we are able to spontaneously reprogram human germ cells into gPS cells, and then differentiate them into terminally differentiated -ilset-like cells.
Importantly, there is neither addition of genes nor the use of viruses for gene delivery for reprogramming human SSC/progenitor cells, as is the case with the recent work on the reprogramming of somatic cells to pluripotency (iPS cells). Based on the current literature and our preliminary evidence, it is absolutely essential that investigators obtain a thorough understanding of human gPS cells derived from human SSCs and/or progenitors if we are to become serious about translating stem cell therapies from bench-to-bedside. Consequently, we believe that gPS cells derived from human SSC/progenitor cells can differentiate into competent -islet cells for use in the laboratory and eventually in the human body to cure diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Simply put, diabetes has affected more people that I know than any other disease. Many of these people are children, which seems to be an age-group that is becoming more and more affected. Having two little boys of my own, I worry quite a bit that my boys could someday be afflicted with diabetes. I want to do what I can with my PhD to not simply alleviate these worries that I and many other parents harbor, but to bring a normal life back to all of those afflicted.
This award will bring much needed funding to a new stem cell-type that shows great potential for treating, and possibly curing, diabetes. Just as important, working with these cells will open up numerous doors for understanding how cells acquire the ability to produce and secrete insulin in response to sugar. There is much still to learn about diabetes; however, the funds provided by the Henry Becton Innovation Award will allow me to further close this knowledge gap.
In what direction do you see the future of diabetes research going?
This is a difficult question to answer, but for a good reason. There are so many ideas out there right now trying to tackle both types of diabetes that one, or perhaps a few of them, are bound to work. For example, Doug Melton's laboratory working with small molecules to generate islet cells looks promising. Our work with hgPS cells also holds promise as do iPS and hES cells. There are other examples, but the approaches now being taken by many many investigators provides three very important factors for curing disease…imagination, ideas, and innovation. If I had to make an educated guess about diabetes research, I would say that the production of fully functional islet equivalents from stem cells (adult or embryonic) will result in the cure of diabetes. We have most, if not all of the pieces of the puzzle. We now need to figure out where they go to complete the picture.
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