Stem Cells Probed as Diabetes TreatmentStem Cells Probed as Diabetes Treatment

New York City—While an autoimmune disease of any type is a serious condition that is often difficult to treat, finding a cure for type 1 diabetes is particularly daunting because of the nature of the pancreas and its insulin-producing beta cells.

“The pancreas is pathetic at regeneration,” said Douglas Melton, PhD, of the Harvard Stem Cell Institute at Harvard University, in Cambridge, Mass.

Thus, finding a way to generate beta cells poses a difficult challenge for researchers. The promise and shortcomings of various options were discussed by Melton and others at the New York Stem Cell Foundation's recent Translational Stem Cell Research Conference.

Progress in type 1 diabetes research and care has been impressive over the past several decades. Advances include an increase in life expectancy and quality of life for patients, the development of standardized tests to monitor disease progression and control, and the introduction of new insulin delivery systems, said Domenico Accili, MD, of Columbia University, in New York City. Scientists also have revealed the important role of glucose control in preventing complications and have been able to preserve patients' neurocognitive function despite repeated bouts of hypoglycemia.

“There has been a lot of progress, incremental and unglamorous but solid and steady, in the care of diabetic patients,” said Accili.

But because insulin is not curative, the hope is that cell replacement therapies could provide long-term insulin production and regulation. Scientists have searched for pancreatic stem cells as a potential source to generate beta cells to treat patients with type 1 diabetes, but “one cannot find any evidence for an adult stem cell in the pancreas,” said Melton. Furthermore, by blocking gene expression specific to islet cells, Accili and colleagues found that islet cells wither away and are not replaced, “suggesting that it's at least uncommon and probably impossible to make new islets from nonislet cell types in the adult pancreas,” said Accili.

Other research has shown that adult pancreatic beta cells are formed by self-duplication of preexisting cells rather than adult stem cell differentiation (Dor Y et al. Nature. 2004;429:41-46). Therefore, it is likely that an individual is born with a certain number of beta cells derived from a small number of progenitors, and those beta cells are the only source of new cells throughout the individual's life.

While it may be impossible to coax other cells in the body to become insulin-producing beta cells, scientists have tried doing so in the laboratory. Researchers were able to induce fibroblast-like cells derived from islets donated postmortem to differentiate into insulin-expressing isletlike cells (Gershengorn MC et al. Science. 2004;306:2261-2264). “But how robust this is and how viable and scaleable this will be remains to be seen,” said Allen Spiegel, MD, of the Albert Einstein College of Medicine, Bronx, NY.

Others have manipulated culture conditions to cause differentiation of human fetal liver cells (which come from the same endodermal germ layer) into insulin-secreting cells (Zalzman M et al. Diabetes. 2005;54:2568-2575). Some have shown that bone marrow stem cells are capable of turning into beta cells, but the findings are preliminary (Thatava T et al. Stem Cells. doi:10.1634/stemcells.2006-0109 [published online September 21, 2006]). Finally, many scientists believe the best potential lies in embryonic stem cells.

“So there are a variety of approaches that have been tried,” said Spiegel. “It's fair to say that none yet is ready for prime time,” he added.

To move research in this area forward, the National Institute of Diabetes and Digestive and Kidney Diseases has created the Beta Cell Biology Consortium (http://www.betacell.org), which brings together scientists and interdisciplinary efforts to learn about pancreatic islet development and function and to ultimately develop a cell-based therapy for insulin delivery. Funds from the consortium's Collaborative Bridging Project are supporting efforts to bring new reagents and resources to diabetes research and care. The consortium's goal is to understand the developmental pathways required to produce a fully functioning pancreatic islet, the mechanisms of beta cell regeneration, and the nature of stem and progenitor cells during normal pancreatic development and in adult pancreatic islets.

While a variety of studies focused on generating beta cells are moving forward, those with the most potential deal with preexisting beta cells or with stem cells, according to Melton. “I firmly believe it is possible to make more beta cells by one of these two methods—there's no reason to believe it can't be done,” he said.

Researchers have tried isolating beta cells from human cadavers and cultivating them in the laboratory. “I believe it's highly likely that one will find a way to amplify them, but whether one can ever do that at a sufficient level to be useful remains to be seen,” said Melton.

A recently completed international multicenter trial exploring the feasibility and reproducibility of islet transplantation with a procedure called the Edmonton protocol revealed that while transplanted islets from deceased donors can provide some patients with long-term insulin production and glycemic stability, insulin independence is usually not sustainable (Shapiro AM et al. N Engl J Med. 2006;355:1318-1330). During the first year following transplantation, most patients lose insulin independence.

Research aimed at stimulating beta cell growth and regeneration may help patients with transplanted islets. “There are some early-stage clinical protocols in adults with long-standing diabetes trying to stimulate regeneration with some of the factors that have emerged as beta cell growth promoters,” said Spiegel. “But we have a long way to go.”

While it would be less difficult to generate ample numbers of embryonic stem cells, scientists have not yet learned how to direct such cells to form insulin-secreting beta cells. However, researchers are discovering signals from adjacent tissues that influence pancreatic development, identifying genes that must be expressed for a cell to become a beta cell, and defining other factors that cause these stem cells to commit to specific pancreatic lineages (Xu X et al. Cloning Stem Cells. 2006;8:96-107).

A recent study revealed a way to convert human embryonic stem cells to endocrine cells capable of synthesizing the pancreatic hormones insulin, glucagon, somatostatin, pancreatic polypeptide, and ghrelin (D’Amour K et al. Nat Biotechnol. doi:10.1038/nbt1259 [published online October 19, 2006]). The process mimics in vivo pancreatic organogenesis, directing cells through stages resembling normal endodermal cell development. The investigators report that the insulin-expressing cells derived from human embryonic stem cells have an insulin content approaching that of adult islets and that they respond to pharmacological modulators and metabolic stimulators in a similar fashion to fetal beta cells. “It's very important work because they used a very systematic progression of growth factors to be able to get the cells to that stage,” said Spiegel. While additional work will be needed to determine how to further differentiate the cells into mature pancreatic islet cells, the results suggest that it may be possible for human embryonic stem cells to generate a renewable source of cells for diabetes therapy.

While some argue that studies with embryonic stem cells would not be necessary if scientists could stimulate beta cell regeneration, others say that such efforts are complementary. “In order to really understand the mechanisms of stimulating endogenous regeneration, we really need to work on human embryonic stem cells to better understand the progression [of cells as they become beta cells],” said Spiegel.

Even if optimal beta cell regeneration—by whatever method—is achieved in patients with type 1 diabetes, the autoimmune process that caused the condition in the first place must also be addressed. “Beta cells may be gunned down, as it were, by the immune system as quickly as they arise,” said Spiegel. Therefore, it will be necessary to suppress the autoimmune response in addition to stimulating beta cell growth and regeneration.

Unfortunately, researchers remain puzzled about the role of autoimmunity in type 1 diabetes. “Do you get diabetes because the beta cell makes a mistake or is it purely an immune system problem?” asked Melton. “This is a very basic question to which we don't know the answer.” Melton is collaborating with other scientists to look for clues through somatic cell nuclear transfer (a technique also known as therapeutic cloning), which involves replacing the nucleus of an egg with the nucleus of a cell from a donor, such as a patient with type 1 diabetes. This technique could reveal details of the dysfunction in immune and beta cells in type 1 diabetes, which occurs in about one in every 400 to 600 children and adolescents and accounts for 5% to 10% of all diagnosed cases of diabetes.

It is still unknown whether researchers will be able to suppress autoimmunity of type 1 diabetes or successfully coax embryonic stem cells into becoming beta cells—let alone harness such cells to cure the disease. But as scientists continue in these efforts, they hope for a change in the government policy banning the use of federal funds for research on stems cells beyond cell lines created before 2001.

“It's very hard to find a cure for diabetes if we're also tethered by qualifications on what kind of reagents one can use and hobbled by all kinds of restrictions,” said Accili.